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<p>The work presented in this thesis was focused on design and construction of novel cell-loaded microcapsules by incorporation of bioactive molecules (proteins or peptides) for potential application in hemophilia B treatment. The objective of this study was to improve the viability and functionality of the encapsulated cells by creating biomimetic microenvironments for cells that more closely mimic their physiological extracellular matrix (ECM) environment.</p> <p>Three cell-adhesive molecules were used in this work: fibrinogen and fibronectin, two abundant proteins present in ECM, and arginine-glycine-aspartic acid (RGD) tri-peptide, the minimal essential cell adhesion peptide sequence and the most widely studied peptide for cell adhesion. Alginate, the most commonly used biomaterial used for cell encapsulation, was combined with either of these molecules to create biomimetic microcapsules. Non-modified alginate (control) and modified alginate matrices were used to encapsulate the factor IX (FIX) secreting cells for protein delivery. In this work, FIX-engineered cord blood-derived human mesenchymal stem cells CB MSCs were used as a cell source for FIX delivery.</p> <p>Our data suggested that fibrinogen-alginate, fibronectin-alginate and RGD-alginate microcapsules improved the viability of encapsulated MSC and are applicable in cell therapy technologies. However, fibrinogen-alginate and fibronectin-alginate microcapsules more significantly enhanced the proliferation and protein secretion from the encapsulated cells and may have potential for FIX delivery for hemophilia B and other inherited or acquired protein deficiencies. RGD-alginate microcapsules can v potentially be used for other tissue engineering applications with the aim of enhanced viability and attachment of the enclosed cells. Differentiation studies showed the osteogenic (but not chondrogenic or adipogenic) differentiation capability of FIX-engineered CB MSCs and their efficient FIX secretion while encapsulated in fibrinogen-alginate and fibronectin-alginate microcapsules.</p> / Doctor of Philosophy (PhD)

This thesis presents the design and development of a novel biomimetic jellyfish robot that features ionic polymer metal composite actuators. The shape and swimming style of this underwater vehicle are based on oblate jellyfish species, which are known for their high locomotive efficiency. Ionic polymer metal composites (IPMC) are used as actuators in order to contract the bell and thus propel the jellyfish robot. This research focuses on translating the evolutionary successes of the natural species into a jellyfish robot that mimics the geometry, the swimming style, and the bell deformation cycle of the natural species. Key advantages of using IPMC actuators over other forms of smart material include their ability to exhibit high strain response due to a low voltage input and their ability to act as artificial muscles in water environment. This research specifically seeks to implement IPMC actuators in a biomimetic design and overcome two main limitations of these actuators: slow response rate and the material low blocking force. The approach presented in this document is based on a combination of two main methods, first by optimizing the performance of the IPMC actuators and second by optimizing the design to fit the properties of the actuators by studying various oblate species. Ionic polymer metal composites consist of a semi-permeable membrane bounded by two conductive, high surface area electrode. The IPMCs are manufactured is several variations using the Direct Assembly Process (DAP), where the electrode architecture is controlled to optimize the strain and stiffness of the actuators. The resulting optimized actuators demonstrate peak to peak strains of 0.8 % in air and 0.7 % in water across a frequency range of 0.1-1.0 Hz and voltage amplitude of 2 V. A study of different oblate species is conducted in order to attain a model system that best fits the properties of the IPMC actuators. The Aequorea victoria is chosen based on its bell morphology and kinematic properties that match the mechanical properties of the IPMC actuators. This medusa is characterized by it low swimming frequency, small bell deformation during the contraction phase, and high Froude efficiency. The bell morphology and kinematics of the Aequorea victoria are studied through the computation of the radius of curvature and thus the strain energy stored in the during the contraction phase. The results demonstrate that the Aequorea victoria stores lower strain energy compared to the other candidate species during the contraction phase. Three consecutive jellyfish robots have been built for this research project. The first generation served as a proof of concept and swam vertically at a speed of 2.2 mm/s and consumed 3.2 W of power. The second generation mimicked the geometry and swimming style of the Aurelia aurita. By tailoring the applied voltage waveform and the flexibility of the bell, the robot swam at an average speed of 1.5 mm/s and consumed 3.5 W of power. The third and final generation mimicked the morphology, swimming behavior, and bell kinematics of the Aequorea victoria. The resulting robot, swam at an average speed of 0.77 mm/s and consumed 0.7 W of power when four actuators are used while it achieved 1.5 mm/s and 1.1 W of power consumption when eight actuators are used. Key parameter including the type of the waveform, the geometry of the bell, and position and size of the IPMC actuators are identified. These parameters can be hit later in order to further optimize the design of an IPMC based jellyfish robot. / Master of Science

<p dir="ltr">Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal pancreatic cancer subtype. The silent tumor progression and aggressive development of chemo-resistance are the primary factors behind the dismal 13% 5-year survival rate. The tumor microenvironment (TME) has been the focus of many pancreatic cancer research since the TME actively interacts with cancer cells to promote tumor growth, drug resistance, and invasion. A thorough comprehension of PDAC cell and TME interaction is crucial to uncover the mechanism and key regulators behind PDAC’s rapid progression, high propensity for metastasis, and exceptional resistance to cancer therapeutics. Hydrogels have emerged as invaluable tools for investigating cell-matrix communication in three-dimensional (3D) environments, as their chemical and mechanical properties can be easily tuned to mimic the dynamic nature of native tissue. However, current biomimetic hydrogels used in PDAC models are elastic and often lack tissue-relevant viscoelastic properties, such as hysteresis and stress-relaxation. Stress-relaxation influences various cellular processes, including differentiation, proliferation, and cancer progression. This dissertation aims to address this gap by introducing viscoelasticity and fast stress relaxation into existing hydrogel platforms to more accurately replicate PDAC tissue mechanics. Specifically, we employ two chemistries: thiol-norbornene photopolymerization and boronic ester dynamic bonding to fabricate gelatin-based hydrogels. Gels formed solely via irreversible thiol-norbornene chemistry exhibit elasticity and slow stress-relaxation, while gels formed with both thiol-norbornene and reversible boronic ester bonds display viscoelastic properties and fast stress-relaxation. Cell-laden hydrogels with varying mechanical properties (low vs high stiffness, slow vs fast relaxation) were used as tools to explore the effects of matrix stiffening and viscoelasticity in promoting cancer aggressiveness. It was revealed that matrix stiffening, coupled with the inclusion of cancer-associated fibroblast induced the epithelial-mesenchymal transition phenotype (EMT) in pancreatic cancer cells. In addition, fast-relaxing hydrogels promoted cancer cell survival, growth, and EMT via engaging integrin β-1 (ITGB1). Blocking of ITGB1 receptors diminished cell growth, however, cells in fast-relaxing gels upregulated SNAIL1, a biomarker of poor cancer prognosis. Collectively, results from these studies describe our recent progress in understanding the mechanism by which stiff and viscoelastic substrates facilitate cancer development and how cellular functions can be controlled via modulating cell receptor-matrix binding.</p>

Esta tesis presenta un conjunto original de procedimientos para la síntesis de nanoestructuras de TiO2 y ZnO por biomimetización de membranas de cáscara de huevo obteniendo materiales valiosos para fotovoltaica como se muestra en su evaluación de rendimiento como ánodo en células solares sensibilizadas por colorante. "El manuscrito está dividido en 7 capítulos. En el primer capítulo, titulado Introducción, se presentan las bases teóricas para la comprensión de los procesos de biomimetización, membranas de cáscara de huevo, síntesis de ZnO y TiO2, y células solares sensibilizadas por colorantes (DSSC). Después del capítulo introductorio, el Capítulo 2 revela los objetivos generales y específicos de esta investigación. Posteriormente, el Capítulo 3 describe el procedimiento experimental utilizado para las síntesis y caracterizaciones de ZnO y TiO2, así como el procedimiento utilizado en el ensamblaje y la caracterización de las células fotovoltaicas. En el capítulo 4 se presentan y discuten los resultados obtenidos con las síntesis y la aplicación de los polvos como fotodoles en DSSC. En este capítulo, hemos decidido subdividirlo en secciones específicas para explicar cuestiones científicas específicas sobre el tema. En el capítulo 5 se presentan las conclusiones del estudio en vista de los diferentes aspectos: obtención de TiO2 biomimético y ZnO, diferencias entre los polvos sintetizados por biomimetización de las membranas de cáscara de huevo, y la caracterización de las células construidas con los polvos biomiméticos. / Esta tesi presenta un conjunt original de procediments per a la síntesi de nanoestructuras de TiO2 i ZnO per biomimetización de membranes de corfa d'ou obtenint materials valuosos per a fotovoltaica com es mostra en la seua avaluació de rendiment com a ànode en cèl·lules solars sensibilitzades per colorant. &#34;El manuscrit està dividit en 7 capítols. En el primer capítol, titulat Introducció, es presenten les bases teòriques per a la comprensió dels processos de biomimetización, membranes de corfa d'ou, síntesi de ZnO i TiO2, i cèl·lules solars sensibilitzades per colorants (DSSC) . Després del capítol introductori, el Capítol 2 revela els objectius generals i específics d'esta investigació. Posteriorment, el Capítol 3 descriu el procediment experimental utilitzat per a les síntesis i caracteritzacions de ZnO i TiO2, així com el procediment utilitzat en l'acoblament i la caracterització de les cèl·lules fotovoltaiques. En el capítol 4 es presenten i discutixen els resultats obtinguts amb les síntesis i l'aplicació de les pols com fotodoles en DSSC. En este capítol, hem decidit subdividir-ho en seccions específiques per a explicar qüestions científiques específiques sobre el tema. En el capítol 5 es presenten les conclusions de l'estudi en vista dels diferents aspectes: obtenció de TiO2 biomimético i ZnO, diferències entre les pols sintetitzats per biomimetización de les membranes de corfa d'ou, i la caracterització de les cèl·lules construïdes amb les pols biomiméticos. / This thesis introduces an original set of procedures for the Synthesis of ZnO and TiO2 nanostructures by biomimetization of eggshell membranes obtaining valuable materiales for photovoltaic as shown on their performance evaluation as anode in Dye-Sensitized Solar Cells". The manuscript is divided into 7 chapters. In the first chapter, entitled Introduction, it is presented the theoretical bases for the understanding of the biomimetization processes, eggshell membranes, ZnO and TiO2 syntheses, and dye-sensitized solar cells (DSSC). After the introductory chapter, Chapter 2 reveals the general and specific objectives of this research. Subsequently, Chapter 3 describes the experimental procedure used for the syntheses and characterizations of ZnO and TiO2 as well as the procedure used in the assembly and characterization of the photovoltaic cells. In chapter 4 are presented and discussed the results obtained with the syntheses and application of the powders as photoanodes in DSSC. In this chapter, we have chosen to subdivide it into specific sections to explain specific scientific issues on the subject. In chapter 5 the conclusions of the study are presented in view of the different aspects: obtaining ZnO and biomimetic TiO2, differences between the powders synthesized by biomimetization of eggshell membranes, and the characterization of the cells constructed with the biomimetic powders. / Camaratta, R. (2018). Synthesis Of ZnO and TiO2 By Biomimetization Of Eggshell Membranes And Its Evaluation As Anode In Dye-Sensitized Solar Cells [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/113416

Neurodegenerative disorders are characterised by the activation of brain-resident microglia cells and by the infiltration of peripheral T cells. However, their interplay in disease has not been clarified yet. It is difficult to investigate complex cellular dynamics in living animals, and simple two-dimensional (2D) cell culture models do not resemble the soft 3D structure of brain tissue. Therefore, we developed a biomimetic 3D in vitro culture system for co-cultivation of microglia and T cells. As the activation and/or migration of immune cells in the brain might be affected by components of the extracellular matrix, defined 3D fibrillar collagen I-based matrices were constructed and modified with hyaluronan and/or chondroitin sulphate, resembling aspects of brain extracellular matrix. Murine microglia and spleen-derived T cells were cultured alone or in co-culture on the constructed matrices. Microglia exhibited in vivo-like morphology and T cells showed enhanced survival when co-cultured with microglia or to a minor degree in the presence of glia-conditioned medium. The open and porous fibrillar structure of the matrix allowed for cell invasion and direct cell-cell interaction, with stronger invasion of T cells. Both cell types showed no dependence on the matrix modifications. Microglia could be activated on the matrices by lipopolysaccharide resulting in interleukin-6 and tumour necrosis factor-α secretion. The findings herein indicate that biomimetic 3D matrices allow for cocultivation and activation of primary microglia and T cells and provide useful tools to study their interaction in vitro.