Omic science is rapidly growing and one of the most employed techniques to explore differential patterns in omic datasets is principal component analysis (PCA). However, a method to enlighten the network of omic features that mostly contribute to the sample separation obtained by PCA is missing. An alternative is to build correlation networks between univariately-selected significant omic features, but this neglects the multivariate unsupervised feature compression responsible for the PCA sample segregation. Biologists and medical researchers often prefer effective methods that offer an immediate interpretation to complicated algorithms that in principle promise an improvement but in practice are difficult to be applied and interpreted. Here we present PC-corr: a simple algorithm that associates to any PCA segregation a discriminative network of features. Such network can be inspected in search of functional modules useful in the definition of combinatorial and multiscale biomarkers from multifaceted omic data in systems and precision biomedicine. We offer proofs of PC-corr efficacy on lipidomic, metagenomic, developmental genomic, population genetic, cancer promoteromic and cancer stem-cell mechanomic data. Finally, PC-corr is a general functional network inference approach that can be easily adopted for big data exploration in computer science and analysis of complex systems in physics.

Omic science is rapidly growing and one of the most employed techniques to explore differential patterns in omic datasets is principal component analysis (PCA). However, a method to enlighten the network of omic features that mostly contribute to the sample separation obtained by PCA is missing. An alternative is to build correlation networks between univariately-selected significant omic features, but this neglects the multivariate unsupervised feature compression responsible for the PCA sample segregation. Biologists and medical researchers often prefer effective methods that offer an immediate interpretation to complicated algorithms that in principle promise an improvement but in practice are difficult to be applied and interpreted. Here we present PC-corr: a simple algorithm that associates to any PCA segregation a discriminative network of features. Such network can be inspected in search of functional modules useful in the definition of combinatorial and multiscale biomarkers from multifaceted omic data in systems and precision biomedicine. We offer proofs of PC-corr efficacy on lipidomic, metagenomic, developmental genomic, population genetic, cancer promoteromic and cancer stem-cell mechanomic data. Finally, PC-corr is a general functional network inference approach that can be easily adopted for big data exploration in computer science and analysis of complex systems in physics.

Im Rahmen der VDB-Fortbildungsveranstaltung für Fachreferenten der Ingenieurwissenschaften, die am 8. und 9. Dezember 2005 in der SLUB Dresden stattfand, referierte Prof. Dr.-Ing. Hartmut Worch vom Institut für Werkstoffwissenschaften der TU Dresden (siehe auch SLUB-Kurier, 2006, Heft 1).

The field of biomedical sciences has been expanded through the introduction of a novel cohort of soft and intelligent microrobots that can be remotely operated and controlled through the use of external stimuli, such as ultrasound, magnetic fields, or electric fields, or internal stimuli, such as chemotaxis. The distinguishing factor of these microrobots lies in their propulsion system, which may encompass chemical, physical, or biohybrid mechanisms. Particularly, microrobots propelled by motile cells or microorganisms have found extensive usage because they combine the control/steerability and image-enhancement capabilities of the synthetic microstructures with the taxis and cell-interaction capabilities of the biological components. Spermatozoa (sperms), among other types of motile microorganisms and cells, are promising biological materials for building biohybrid microrobots because they are inherently designed to swim through complex fluids and organs, like those in the reproductive system, without triggering negative immune responses. Sperms are suitable for a variety of gynecological healthcare applications due to their drug encapsulating capability and high drug-carrying stability, in addition to their natural role of fertilization. One objective of this project is to help sperms reach the site of fertilization in vivo where the sperm count is low (20 million sperm per mL), a condition known as oligospermia. In order to reach this goal, we are developing alternative strategies for transporting a significant number of sperms, as well as improving the functionality of sperm-hybrid microcarriers. Here, we use a thermoresponsive hydrogel made of poly(N-isopropylacrylamide) (PNIPAM) and a non-stimuli-responsive polymer (IPS photoresist) to create four dimensional (4D)-printed sperm-hybrid microcarriers via two-photon polymerization (TPP). We present a multifunctional microcarrier that can: i) transport and deliver multiple motile sperms to increase the likelihood of fertilization, ii) capacitate/hyperactivate the sperms in situ through the local release of heparin, and iii) assist the degradation of the hyaluronic acid (HA), present in extracellular matrix (ECM) of oocyte-cumulus surrounded the Egg. HA degradation occurs through the local action of hyaluronidase-loaded polymersomes (HYAL-Psomes) that have been immobilized on the microcarrier's surface. Dual ultrasonic (US)/photoacoustic (PA) imaging technology can also be used to visualize a swarm of microcarriers, making them ideal candidates for upcoming in vivo applications. In addition, as a second objective, we demonstrate that similar sperm-hybrid microcarriers can be utilized to deliver targeted enzymes and medication for the treatment of gynecological cancer. As proof of concept, we show that combined therapy using enzymes and anti-cancer drugs is an appealing strategy for disrupting the tumor tissue microenvironment and inducing cell apoptosis, thereby offering a more effective cancer therapy. To achieve this, we functionalize the microcarriers with polymersomes loaded with enzymes (such as hyaluronidase and collagenase) and anti-cancer drugs (such as curcumin), respectively, and demonstrate their cargo-release capability, enzyme function, and therapeutic effect for targeting cervical cancer cells in vitro.:Abstract iv 1 Introduction 1 1.1 Motivation 1 1.2 Objectives 3 1.3 Structure of this dissertation 4 2 Background 5 2.1 Introduction on additive manufacturing technology 5 2.2 Direct laser writing (DLW) based on two-photon polymerization 6 2.2.1 Writing principles of two-photon lithography 8 2.2.2 Available materials for two-photon lithography 9 2.2.3 Engineering (Preprogrammed designs) 12 2.3 4D Lithography 13 2.3.1 Biodegradable microrobot 13 2.3.2 Stimuli-responsive micromotors 15 2.3.3 Other 4D-printing approaches 17 2.4 Motion at the microscale (Micromotility) 21 2.4.1 Physical propelled micromotors 23 2.4.2 Chemical propelled micromotors 32 2.4.3 Biohybrid micromotors 34 2.5 Other two-photon polymerized microrobots and their biomedical applications 35 2.5.1 Functionalized carriers 36 2.5.2 Multiple-cell carrying scaffolds 38 2.5.3 Single particle and cell transporters 39 2.6 Comparison of 3D and 4D-lithography with other fabrication methods 42 3 Materials and methods 44 3.1 Synthesis and fabrication 44 3.1.1 Synthesis of PNIPAM 44 3.1.2 Fabrication of microcarrier 44 3.1.3 Preparation of sperm medium and sperm solution 45 3.1.4 Preparation and composition of different body fluids 45 3.1.5 Fluidics channels 46 3.1.6 In situ preparation of microcarriers and sperms 46 3.1.7 Loading of microcarriers with heparin 46 3.1.8 Synthesis of block copolymers (BCPs) 47 3.1.9 Fabrication of Empty-Psomes A and D 48 3.1.10 Preparation of Curcumin complex CU(βCD)2 and calibration curve 49 3.1.11 Fabrication of cargo-loaded Psomes with enzymes and antitumoral drug 50 3.2 Characterization 51 3.2.1 MTS-Assay 51 3.2.2 Toluidine blue assay 52 3.2.3 Characterization of Empty-Psomes A and D: pH cycles and pH titration by dynamic light scattering (DLS) 53 3.2.4 Characterization of cargo-loaded Psomes with enzymes and antitumoral drug 54 3.2.5 Loading efficiency of HYAL-Psomes 55 3.2.6 Loading efficiency of MMPsomes 56 3.2.7 Loading efficiency, stability and release study of CU(βCD)2-Psomes 57 3.2.8 Size and polydispersity analysis of cargo-loaded Psomes in different simulated body fluids by DLS 58 3.2.9 Conformation and stability study of cargo-loaded Psomes in different simulated body fluids by asymmetric flow field flow fractionation (AF4) 59 3.2.10 Immobilization of the cargo-loaded Psomes on the surfaces 61 3.2.11 Enzymatic assay of HYAL for enzyme activity measurement 62 3.2.12 Enzymes assay in different simulated body fluids 64 3.2.13 Stability study of RhB-HYAL-Psomes in different pH 65 3.2.14 Calculation of the magnetic field flux of an external hand-held magnet 66 3.3 Temperature actuation and imaging 67 3.3.1 Temperature actuation test of PNIPAM and video recording 67 3.3.2 Hybrid ultrasound (US) and photoacoustic (PA) Imaging 67 3.4 Other useful information 68 3.4.1 pH and temperature through the female reproductive tract 68 3.4.2 Calculation of the light-to-heat conversion during imaging process 69 4 Multifunctional 4D-printed sperm-hybrid microcarriers for assisted reproduction 72 4.1 Background 72 4.2 Concept and fabrication of the 4D-printed microcarriers 74 4.3 Sperm coupling and geometrical optimization of microcarrier 77 4.4 Characterization of the 4D-printed streamlined microcarriers 78 4.5 Microcarrier loaded with heparin for in situ sperm capacitation 82 4.6 Microcarriers decorated with HYAL-Psomes for in situ degradation of the HA-cumulus complex 86 4.6.1 Immobilization of HYAL-Psomes on the microcarrier’s surface 89 4.6.2 Qualitative study of cumulus cell removal 90 4.7 Sperm-microcarrier motion performance in oviduct-mimicking fluids 91 4.7.1 Capture, transport, and release of sperms 92 4.7.2 Sperm-microcarrier motion performance on ex vivo oviduct tissue 93 4.8 Tracking of a swarm of microcarriers with a dual ultrasound (US) and photoacoustic (PA) imaging system 95 4.9 Summary 96 5 Polymersomes-decorated micromotors with multiple cargos for gynecological cancer therapy 98 5.1 Background 98 5.2 Characterization and size quantification of Psomes before and after loading of cargoes by DLS, and Cryo-TEM 103 5.3 Characterization and size quantification of cargo-loaded Psomes by DLS, and Cryo-TEM in different simulated bodily fluids 104 5.4 Immobilization and characterization of cargo-loaded Psomes on the microcarrier’s surface 106 5.5 Immobilization and characterization of dual cargo-loaded Psomes on the microcarrier’s surface 108 5.6 Investigation of ECM degradation and antitumoral effect of cargo-loaded Psomes 110 5.7 Magnetic and bio-hybrid guidance of microcarriers toward targeted cargo delivery 115 5.8 Summary 117 6 Conclusion and Outlook 119 6.1 Achievements 119 6.2 Outlook 121 Bibliography I List of Figures and Tables XXI Acknowledgements and funding XXIV Scientific publications and contributions XXVI Curriculum Vitae XXVII

In den 1980er Jahren erlangte ein biomedizinisches Modell der Schizophrenie, das von Forschern des Clinical Research Centre im Nordwesten Londons entwickelt wurde, internationale Bedeutung auf dem Gebiet der biologischen Psychiatrie. Es konnte jedoch nicht validiert werden, und die am häufigsten wiederholten Beweise, die zu seiner Stützung herangezogen wurden, erwiesen sich als diagnostisch unbedeutend. Trotz der überwältigenden Popularität pharmazeutischer Behandlungen und biologischer Theorien in der heutigen Psychiatrie ist die Geschichte der biologischen Psychiatrie der Nachkriegszeit voll von Enttäuschungen und unerfüllten Erwartungen. Um die Bedeutung von Fortschritt und Scheitern in der biologischen Psychiatrie der Nachkriegszeit zu beurteilen, bietet das biomedizinische Modell der Schizophrenie des CRC eine nützliche Fallstudie. Indem die Entstehung einer biomedizinischen Tatsache nachgezeichnet und dieses biomedizinische Modell in seinen historisch-epistemologischen Kontext gestellt wird, ergibt sich ein subtileres und komplexeres Bild davon, wie biomedizinisches Wissen produziert wird. Es wird argumentiert, dass die Umwandlung der Schizophrenie von einer funktionellen Psychose zu einer rein biologischen Störung in der Nachkriegszeit sinnbildlich für eine umfassendere Verschiebung der erkenntnistheoretischen Schwelle der Psychiatrie ist. / In the 1980s a biomedical model of schizophrenia developed by researchers at the Clinical Research Centre in north-west London gained international ascendancy in the field of biological psychiatry. It failed, however, to be validated and the most replicated piece of evidence used in its support proved to have no diagnostic significance. Despite the overwhelming popularity of pharmaceutical treatments and biological theories in contemporary psychiatry, the history of postwar biological psychiatry is replete with disappointment and unfulfilled expectations. In order to assess the meaning of progress and failure in postwar biological psychiatry, the CRC biomedical model of schizophrenia offers a useful case study. By tracing the genesis of a biomedical fact and placing this biomedical model in its historical-epistemological context, a more subtle and complex picture of how biomedical knowledge is produced is presented. It is argued that the postwar transformation of schizophrenia from a functional psychosis to a purely biological disorder is emblematic of a wider shift in the epistemological threshold of psychiatry.

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In den gender studies verweist der Begriff Biopolitik zumeist auf die Arbeiten von Michel Foucault, in denen er untersucht, wie in der Moderne die Organisation von und die Sorge um Leben sowie der menschliche Individualkörper ins Zentrum der Politik rücken. Ergänzend bestimmt er Biomacht als im Gegensatz zu früherer, repressiver Macht, produktiv und auf Lebenssteigerung ausgelegt. Entsprechend impliziert Biopolitik eine ambivalente, ebenso fürsorgliche wie kontrollierende Form der Machtausübung.

In den gender studies verweist der Begriff Biopolitik zumeist auf die Arbeiten von Michel Foucault, in denen er untersucht, wie in der Moderne die Organisation von und die Sorge um Leben sowie der menschliche Individualkörper ins Zentrum der Politik rücken. Ergänzend bestimmt er Biomacht als im Gegensatz zu früherer, repressiver Macht, produktiv und auf Lebenssteigerung ausgelegt. Entsprechend impliziert Biopolitik eine ambivalente, ebenso fürsorgliche wie kontrollierende Form der Machtausübung.

Although liquid ventilation has been researched and studied for the last six decades, it did not achieve its expected optimal performance. Within this work, a deeper understanding of the fluid dynamics during liquid ventilation shall be gathered to extend the already available clinical knowledge about this ventilation strategy. In order to reach this goal, advanced optical flow measurement techniques are applied in different models of the human conductive airways to obtain global velocity fields, identifying prominent flow structures and to determine important dissolved oxygen transport paths. As the velocity measurements revealed, the evolving flow field is strongly dominated by secondary flow effects and is highly dependent on the local airway geometry. During the visualization experiments of the dissolved oxygen concentration fields, different transportation paths occur at inspirational and expirational flow. The initial concentration distribution can be linked to the underlying flow fields but decouples after the peak velocity phases. With higher flow rates/ tidal volumes, a more homogeneously distributed oxygen concentration can be reached.:List of Figures ....................................................................................... VII List of Tables ........................................................................................XIII Nomenclature ........................................................................................ XV 1 Introduction......................................................................................... 1 1.1 Motivation ........................................................................................1 1.2 Research objectives........................................................................... 3 1.3 Outline............................................................................................ 4 2 State of the art .................................................................................... 5 2.1 Liquid Ventilation............................................................................. 5 2.2 In vitro modeling.............................................................................. 8 2.3 Flow measurements ......................................................................... 11 2.4 Gas transport..................................................................................13 3 Flow field measurements ................................................................... 16 3.1 Hydrodynamic Model.......................................................................16 3.1.1 Lung replica ..........................................................................16 3.1.2 Flow parameter .....................................................................18 3.1.3 Limitations ...........................................................................22 3.2 Particle Tracking Velocimetry (PTV) ................................................24 3.2.1 Measurement principle ...........................................................24 3.2.2 Double-frame 2D-PTV ...........................................................25 3.2.3 Time-resolved 3D-PTV ..........................................................28 3.2.4 Phase-locked ensemble PTV ................................................... 31 3.3 Experimental set-up and measurement procedure ...............................33 3.3.1 Lung flow facility...................................................................33 3.3.2 2D-PTV configuration............................................................36 3.3.3 3D-PTV configuration............................................................36 3.4 Results & Discussion........................................................................38 3.4.1 Artificial lung........................................................................38 3.4.2 Realistic lung ........................................................................52 3.5 Conclusion ......................................................................................59 4 Oxygen transport ...............................................................................61 4.1 Hydrodynamic Model....................................................................... 61 4.1.1 Lung replica .......................................................................... 61 4.1.2 Flow parameter .....................................................................62 4.1.3 Limitations ...........................................................................65 4.2 Oxygen Sensitive Dye ......................................................................66 4.3 Experimental set-up......................................................................... 71 4.4 Results & Discussion........................................................................75 4.4.1 Constant flow rate .................................................................75 4.4.2 Oscillatory flow .....................................................................83 4.5 Conclusion ......................................................................................90 5 Summary............................................................................................ 92 6 Outlook .............................................................................................. 95 Bibliography ............................................................................................ 97 / Trotz intensiver Forschung in den letzten sechs Jahrzehnten, befindet sich die Flüssigkeitsbeatmung immernoch weit entfernt vom klinischen Alltag. Mit dieser Arbeit soll ein Beitrag geleistet werden, um das Wissen um die strömungsmechanischen Effekte während der Flüssigkeitsbeatmung zu vertiefen. Dazu werden verschiedene Modellexperimente durchgeführt, bei welchen moderne laseroptische Strömungsmessmethoden zum Einsatz kommen. Untersucht werden dabei unterschiedlich komplexe Geometrien der leitenden menschlichen Atemwege mit dem Ziel wesentliche Strömungsstrukturen, globale Geschwindigkeitsfelder und wichtige Transportwege des gelösten Sauerstoffs zu identifiziern. Die Geschwindigkeitsmessungen zeigen ein stark durch sekundäre Strömungseffekte dominiertes Geschwindigkeitsfeld, welches wesentlich von der lokalen Geometrie abhängig ist. Durch die qualitative und quantitative Erfassung der gelösten Sauerstoffkonzentrationsfelder können wichtige Transportwege aufgedeckt werden. Diese unterscheiden sich deutlich zwischen inspiratorischer und expiratorischer Strömungsrichtung. Die initialen Konzentrationsfelder stimmen mit den unterliegenden Geschwindigkeitsfeldern überein, unterscheiden sich ab der verzögernden Strömungsphase jedoch. Höhere Volumenströme/Tidalvolumen tragen dabei zu einer gleichmäßigeren Konzentrationsverteilung bei.:List of Figures ....................................................................................... VII List of Tables ........................................................................................XIII Nomenclature ........................................................................................ XV 1 Introduction......................................................................................... 1 1.1 Motivation ........................................................................................1 1.2 Research objectives........................................................................... 3 1.3 Outline............................................................................................ 4 2 State of the art .................................................................................... 5 2.1 Liquid Ventilation............................................................................. 5 2.2 In vitro modeling.............................................................................. 8 2.3 Flow measurements ......................................................................... 11 2.4 Gas transport..................................................................................13 3 Flow field measurements ................................................................... 16 3.1 Hydrodynamic Model.......................................................................16 3.1.1 Lung replica ..........................................................................16 3.1.2 Flow parameter .....................................................................18 3.1.3 Limitations ...........................................................................22 3.2 Particle Tracking Velocimetry (PTV) ................................................24 3.2.1 Measurement principle ...........................................................24 3.2.2 Double-frame 2D-PTV ...........................................................25 3.2.3 Time-resolved 3D-PTV ..........................................................28 3.2.4 Phase-locked ensemble PTV ................................................... 31 3.3 Experimental set-up and measurement procedure ...............................33 3.3.1 Lung flow facility...................................................................33 3.3.2 2D-PTV configuration............................................................36 3.3.3 3D-PTV configuration............................................................36 3.4 Results & Discussion........................................................................38 3.4.1 Artificial lung........................................................................38 3.4.2 Realistic lung ........................................................................52 3.5 Conclusion ......................................................................................59 4 Oxygen transport ...............................................................................61 4.1 Hydrodynamic Model....................................................................... 61 4.1.1 Lung replica .......................................................................... 61 4.1.2 Flow parameter .....................................................................62 4.1.3 Limitations ...........................................................................65 4.2 Oxygen Sensitive Dye ......................................................................66 4.3 Experimental set-up......................................................................... 71 4.4 Results & Discussion........................................................................75 4.4.1 Constant flow rate .................................................................75 4.4.2 Oscillatory flow .....................................................................83 4.5 Conclusion ......................................................................................90 5 Summary............................................................................................ 92 6 Outlook .............................................................................................. 95 Bibliography ............................................................................................ 97

Background: In the life sciences, the amount of literature and experimental data grows at a tremendous rate. In order to effectively access and integrate these data, biomedical ontologies – controlled, hierarchical vocabularies – are being developed. Creating and maintaining such ontologies is a difficult, labour-intensive, manual process. Many computational methods which can support ontology construction have been proposed in the past. However, good, validated systems are largely missing. Motivation: The biocuration community plays a central role in the development of ontologies. Any method that can support their efforts has the potential to have a huge impact in the life sciences. Recently, a number of semantic search engines were created that make use of biomedical ontologies for document retrieval. To transfer the technology to other knowledge domains, suitable ontologies need to be created. One area where ontologies may prove particularly useful is the search for alternative methods to animal testing, an area where comprehensive search is of special interest to determine the availability or unavailability of alternative methods. Results: The Dresden Ontology Generator for Directed Acyclic Graphs (DOG4DAG) developed in this thesis is a system which supports the creation and extension of ontologies by semi-automatically generating terms, definitions, and parent-child relations from text in PubMed, the web, and PDF repositories. The system is seamlessly integrated into OBO-Edit and Protégé, two widely used ontology editors in the life sciences. DOG4DAG generates terms by identifying statistically significant noun-phrases in text. For definitions and parent-child relations it employs pattern-based web searches. Each generation step has been systematically evaluated using manually validated benchmarks. The term generation leads to high quality terms also found in manually created ontologies. Definitions can be retrieved for up to 78% of terms, child ancestor relations for up to 54%. No other validated system exists that achieves comparable results. To improve the search for information on alternative methods to animal testing an ontology has been developed that contains 17,151 terms of which 10% were newly created and 90% were re-used from existing resources. This ontology is the core of Go3R, the first semantic search engine in this field. When a user performs a search query with Go3R, the search engine expands this request using the structure and terminology of the ontology. The machine classification employed in Go3R is capable of distinguishing documents related to alternative methods from those which are not with an F-measure of 90% on a manual benchmark. Approximately 200,000 of the 19 million documents listed in PubMed were identified as relevant, either because a specific term was contained or due to the automatic classification. The Go3R search engine is available on-line under www.Go3R.org.