Cell behavior under hypoxic conditions. Computational 3D model

During the early stages of bone regeneration, oxygen plays a key role, recruiting mesenchymal stem cells and regulating the processes of differentiation, proliferation, and apoptosis. To study in these effects, a 3D computational model has been developed, where the effects of oxygen in the mentioned processes are considered

Modelado computacional avanzado del comportamiento celular para el estudio y optimización de los procesos de reorganización celular en la regeneración de tejidos y la creación de órganos

Los procesos celulares de diferenciación, migración, proliferación y apoptosis juegan un papel clave en el desarrollo de los tejidos, así como en diferentes enfermedades como el cáncer. Estos procesos dependen de las condiciones mecánicas de la célula y su entorno. A su vez, las células alteran dinámicamente las condiciones de la matriz extracelular, generando y degradando matriz para promover la migración celular o la regeneración de tejidos. Analizar estos procesos en detalle mediante modelos \textit{in-vitro} puede ser complejo y costoso. Abordar estos procesos desde una perspectiva mecánica, mediante el desarrollo de modelos computacionales, puede ser útil para estudiar comportamientos celulares complejos.En esta tesis se han desarrollado dos modelos computacionales diferentes para analizar el comportamiento celular en entornos 3D. El primer modelo, un modelo mecánico que define el equilibrio tensión-deformación de la célula con su entorno, se ha aplicado para estudiar las interacciones entre células. El segundo modelo, un modelo de fluido, basándose en una formulación híbrida (discreta y continua), se ha aplicado para el análisis del crecimiento de tumores no-sólidos en entornos líquidos.Mediante el modelo mecánico, se ha analizado el crecimiento y la diferenciación de células óseas, cardíacas y tumorales, bajo diferentes condiciones mecánicas, eléctricas y químicas. En primer lugar, se ha estudiado el efecto de la concentración de oxígeno en la diferenciación de células madre mesenquimales en osteoblastos, así como en la migración y proliferación de ambos tipos celulares. Posteriormente, se ha estudiado la formación de tejidos cardíacos estructurados mediante la aplicación de estímulos mecánicos y eléctricos direccionados. En este caso, se ha considerado el comportamiento celular colectivo a través de la formación de adhesiones celulares estrechas.En el modelo de fluido, se ha estudiado la formación y el crecimiento de agregados de tumores de mieloma múltiple. En condiciones líquidas, la concentración y distribución de las células juegan un papel clave en el crecimiento de las células tumorales. Además, se ha estudiado la interacción de las células tumorales con las células madre mesenquimales a través de la expresión de diferentes factores que promueven la migración, el crecimiento y la diferenciación de los fibroblastos asociados al cáncer.Los modelos desarrollados han demostrado ser válidos para el estudio del comportamiento celular en una amplia variedad de condiciones. Con estos modelos ha sido posible estudiar los procesos de diferenciación, migración y proliferación bajo los efectos de diferentes estímulos. La aplicación de modelos híbridos para el análisis de entornos líquidos, ha supuesto una enorme reducción del coste computacional, lo que ha permitido aumentar significativamente el número de células consideradas en los cálculos, así como mejorar la definición del entorno celular.<br /

Computational modeling of multiple myeloma interactions with resident bone marrow cells

The interaction of multiple myeloma with bone marrow resident cells plays a key role in tumor progression and the development of drug resistance. The tumor cell response involves contact-mediated and paracrine interactions. The heterogeneity of myeloma cells and bone marrow cells makes it difficult to reproduce this environment in in-vitro experiments. The use of in-silico established tools can help to understand these complex problems. In this article, we present a computational model based on the finite element method to define the interactions of multiple myeloma cells with resident bone marrow cells. This model includes cell migration, which is controlled by stress–strain equilibrium, and cell processes such as proliferation, differentiation, and apoptosis. A series of computational experiments were performed to validate the proposed model. Cell proliferation by the growth factor IGF-1 is studied for different concentrations ranging from 0–10 ng/mL. Cell motility is studied for different concentrations of VEGF and fibronectin in the range of 0–100 ng/mL. Finally, cells were simulated under a combination of IGF-1 and VEGF stimuli whose concentrations are considered to be dependent on the cancer-associated fibroblasts in the extracellular matrix. Results show a good agreement with previous in-vitro results. Multiple myeloma growth and migration are shown to correlate linearly to the IGF-1 stimuli. These stimuli are coupled with the mechanical environment, which also improves cell growth. Moreover, cell migration depends on the fiber and VEGF concentration in the extracellular matrix. Finally, our computational model shows myeloma cells trigger mesenchymal stem cells to differentiate into cancer-associated fibroblasts, in a dose-dependent manner

Role of oxygen concentration in the osteoblasts behavior: A finite element model

Oxygen concentration plays a key role in cell survival and viability. Besides, it has important effects on essential cellular biological processes such as cell migration, differentiation, proliferation and apoptosis. Therefore, the prediction of the cellular response to the alterations of the oxygen concentration can help significantly in the advances of cell culture research. Here, we present a 3D computational mechanotactic model to simulate all the previously mentioned cell processes under different oxygen concentrations. With this model, three cases have been studied. Starting with mesenchymal stem cells within an extracellular matrix with mechanical properties suitable for its differentiation into osteoblasts, and under different oxygen conditions to evaluate their behavior under normoxia, hypoxia and anoxia. The obtained results, which are consistent with the experimental observations, indicate that cells tend to migrate toward zones with higher oxygen concentration where they accelerate their differentiation and proliferation. This technique can be employed to control cell migration toward fracture zones to accelerate the healing process. Besides, as expected, to avoid cell apoptosis under conditions of anoxia and to avoid the inhibition of the differentiation and proliferation processes under conditions of hypoxia, the state of normoxia should be maintained throughout the entire cell-culture process

Finite Element Model for Cardiac Cell mechano-electrical stimulation

Cardiomyocyte behavior is highly dependent on the mechanical and electrical stimuli. We present a computational model, based on the FEM, to evaluate their behavior under electro-mechanical stimulation. Cell migration, adhesion, and collective behavior have been considered. Low stiffness and high alternating electric field have shown to be the best combination

Modelado y propuesta de mejora de un sistema de riego por goteo para el riego de frutales

En el presente proyecto se va a modelar una red de riego por goteo ya instalada. Se busca obtener un modelo que refleje de forma fiel las condiciones de la red real. A partir de este modelo se generará una propuesta de ampliación de dicha red a una serie de parcelas adyacente. Es importante verificar la correspondencia de los datos obtenidos con el modelo y la red real ya que se va a tratar de obtener una ampliación que trabaje de la manera más óptima posible. Las fases del proyecto se definen en 4: a) Recogida de datos para modelar la red. b) Creación de un modelo informático fiel. c) Comprobación de los resultados. d) Propuesta de ampliación de dicha red. Se van a utilizar los conocimientos adquiridos en el grado de ingeniería mecánica de distintas áreas lo cual, sumado a que es un proyecto real, hace el proyecto muy atractivo. Para la caracterización de los elementos se van a aplicar los conocimientos de las asignaturas de la rama de fluidos y con más importancia sobre las demás la asignatura de “Teoría de máquinas e instalaciones de fluidos”. A parte de esto, se aplicarán conocimientos informáticos y de programación por la necesidad de crear un programa de apoyo en la creación de los modelos, así como conocimientos de manipulación y creación de planos técnicos

A comparison of Single- and Double-generator formalisms for Thermodynamics-Informed Neural Networks

The development of inductive biases has been shown to be a very effective way to increase the accuracy and robustness of neural networks, particularly when they are used to predict physical phenomena. These biases significantly increase the certainty of predictions, decrease the error made and allow considerably smaller datasets to be used. There are a multitude of methods in the literature to develop these biases. One of the most effective ways, when dealing with physical phenomena, is to introduce physical principles of recognised validity into the network architecture. The problem becomes more complex without knowledge of the physical principles governing the phenomena under study. A very interesting possibility then is to turn to the principles of thermodynamics, which are universally valid, regardless of the level of abstraction of the description sought for the phenomenon under study. To ensure compliance with the principles of thermodynamics, there are formulations that have a long tradition in many branches of science. In the field of rheology, for example, two main types of formalisms are used to ensure compliance with these principles: one-generator and two-generator formalisms. In this paper we study the advantages and disadvantages of each, using classical problems with known solutions and synthetic data.Comment: 22 pages, 17 figure

Dense discrete phase model for tumor cell growth analysis in fluid environments

Cell-cell and cell-extracellular matrix interactions play a major role in tumor growth, which involves complex molecular intercommunications. We have developed a single-cell computational model in which fluid dynamics and cell-cell interaction are coupled to evaluate the growth of cancer cells in fluidic environments. The results demonstrate that, once the cell concentration increases, the cell-cell interaction increases, decreasing cell maturation time and increasing tumor growth rate

Enhanced Piezoelectric Fibered Extracellular Matrix to Promote Cardiomyocyte Maturation and Tissue Formation: A 3D Computational Model

Mechanical and electrical stimuli play a key role in tissue formation, guiding cell processes such as cell migration, differentiation, maturation, and apoptosis. Monitoring and controlling these stimuli on in vitro experiments is not straightforward due to the coupling of these different stimuli. In addition, active and reciprocal cell–cell and cell–extracellular matrix interactions are essential to be considered during formation of complex tissue such as myocardial tissue. In this sense, computational models can offer new perspectives and key information on the cell microenvironment. Thus, we present a new computational 3D model, based on the Finite Element Method, where a complex extracellular matrix with piezoelectric properties interacts with cardiac muscle cells during the first steps of tissue formation. This model includes collective behavior and cell processes such as cell migration, maturation, differentiation, proliferation, and apoptosis. The model has employed to study the initial stages of in vitro cardiac aggregate formation, considering cell–cell junctions, under different extracellular matrix configurations. Three different cases have been purposed to evaluate cell behavior in fibered, mechanically stimulated fibered, and mechanically stimulated piezoelectric fibered extra-cellular matrix. In this last case, the cells are guided by the coupling of mechanical and electrical stimuli. Accordingly, the obtained results show the formation of more elongated groups and enhancement in cell proliferation

Pau Urdeitx - Finite Element Model for Cardiac Cell mechano-electrical stimulation

Póster presentado en la IX Jornada de Jóvenes Investigadores del I3