Manuel Doblaré - Academia.edu (original) (raw)

Papers by Manuel Doblaré

Biomechanics and Modeling in Mechanobiology, 2007

Bone tissue regeneration using scaffolds is receiving an increasing interest in orthopedic surger... more Bone tissue regeneration using scaffolds is receiving an increasing interest in orthopedic surgery and tissue engineering applications. In this study, we present the geometrical characterization of a specific family of scaffolds based on a face cubic centered (FCC) arrangement of empty pores leading to analytical formulae of porosity and specific surface. The effective behavior of those scaffolds, in terms of mechanical properties and permeability, is evaluated through the asymptotic homogenization theory applied to a representative volume element identified with the unit cell FCC. Bone growth into the scaffold is estimated by means of a phenomenological model that considers a macroscopic effective stress as the mechanical stimulus that regulates bone formation. Cell migration within the scaffold is modeled as a diffusion process based on Fick's law which allows us to estimate the cell invasion into the scaffold microstructure. The proposed model considers that bone growth velocity is proportional to the concentration of cells and regulated by the mechanical stimulus. This model allows us to explore what happens within the scaffold, the surrounding bone and their interaction. The mathematical model has been numerically implemented and qualitatively compared with previous experimental results found in the literature for a scaffold implanted in the femoral condyle of a rabbit. Specifically, the model predicts around 19 and 23% of bone regeneration for non-grafted and grafted scaffolds, respectively, both with an initial porosity of 76%.

Biofabrication

Biofabrication of human tissues has seen a meteoric growth triggered by recent technical advancem... more Biofabrication of human tissues has seen a meteoric growth triggered by recent technical advancements such as human induced pluripotent stem cells (hiPSCs) and additive manufacturing. However, generation of cardiac tissue is still hampered by lack of adequate mechanical properties and crucially by the often unpredictable post-fabrication evolution of biological components. In this study we employ melt electrowriting (MEW) and hiPSC-derived cardiac cells to generate fibre-reinforced human cardiac minitissues. These are thoroughly characterized in order to build computational models and simulations able to predict their post-fabrication evolution. Our results show that MEW-based human minitissues display advanced maturation 28 post-generation, with a significant increase in the expression of cardiac genes such as MYL2, GJA5, SCN5A and the MYH7/MYH6 and MYL2/MYL7 ratios. Human iPSC-cardiomyocytes are significantly more aligned within the MEW-based 3D tissues, as compared to conventiona...

Cell encapsulation in hydrogel-based microspheres has demonstrated successes in regenerative cell... more Cell encapsulation in hydrogel-based microspheres has demonstrated successes in regenerative cell therapy. We developed a workflow based on Atomic Force Microscopy (AFM) and a microfluidic constriction system to characterize stiffness and surface properties of microcapsules.

Jornada de Jóvenes Investigadores del I3A, 2020

La epigenética juega un papel crucial en el desarrollo tumoral, en particular en la adquisición d... more La epigenética juega un papel crucial en el desarrollo tumoral, en particular en la adquisición de resistencia. Se presenta un enfoque novedoso en la comunidad científica, utilizando un modelo matemático con variables internas, inspirado en la teoría de la plasticidad para describir este fenómeno.

Simulations in Biomedicine V, 2003

International Journal of Solids and Structures, 2013

El pandeo lateral es un fenómeno de inestabilidad que adquiere especial importancia en perfiles e... more El pandeo lateral es un fenómeno de inestabilidad que adquiere especial importancia en perfiles esbeltos con pequeña rigidez torsional y pequeña rigidez a flexión en el plano perpendicular al de aplicación de la carga. Este es el caso de la mayoría de los perfiles conformados en frío. Muchas normativas proponen de forma casi exclusiva fórmulas envolventes aproximadas en el caso

eolss.net

Summary In this chapter we review the fundamentals and the formulation of some simple material co... more Summary In this chapter we review the fundamentals and the formulation of some simple material constitutive models both for fluids and solids. First, a short review of the main concepts and definitions of Continuum Mechanics is presented, including kinematics and ...

Scientific Reports, 2021

Bone remodeling identifies the process of permanent bone change with new bone formation and old b... more Bone remodeling identifies the process of permanent bone change with new bone formation and old bone resorption. Understanding this process is essential in many applications, such as optimizing the treatment of diseases like osteoporosis, maintaining bone density in long-term periods of disuse, or assessing the long-term evolution of the bone surrounding prostheses after implantation. A particular case of study is the bone remodeling process after dental implantation. Despite the overall success of this type of implants, the increasing life expectancy in developed countries has boosted the demand for dental implants in patients with osteoporosis. Although several studies demonstrate a high success rate of dental implants in osteoporotic patients, it is also known that the healing time and the failure rate increase, necessitating the adoption of pharmacological measures to improve bone quality in those patients. However, the general efficacy of these antiresorptive drugs for osteopor...

Jornada de Jóvenes Investigadores del I3A, 2018

Los microentornos celulares multi fenotípicos que se reproducen en dispositivos microfluídicos Or... more Los microentornos celulares multi fenotípicos que se reproducen en dispositivos microfluídicos Organ-On-Chip son sistemas biológicos extremadamente complejos de modelar. Para diferentes poblaciones celulares, se deben considerar las interacciones químicas con nutrientes u otras señales, la disposición espacial, la rigidez y características del sustrato, la advección y difusión de fluidos y procesos celulares como la proliferación, la migración, la diferenciación y la muerte. Todos estos fenómenos están altamente acoplados, lo que da lugar en un problema no lineal muy complejo de resolver. En este trabajo se plantea un modelo matemático basado en las ecuaciones del continuo, capaz de reproducir diferentes configuraciones de experimentos llevados a cabo en el laboratorio y que, por lo tanto, serviría para predecir la evolución de poblaciones tumorales, así como la respuesta a terapias diseñadas para combatir el cáncer.

Journal of Applied Polymer Science, 2014

A Poly(L-lactic acid) scaffold prepared by a combination of freeze extraction/porogen leaching me... more A Poly(L-lactic acid) scaffold prepared by a combination of freeze extraction/porogen leaching methods was submitted to static degradation in phosphate buffered saline solution at pH=7.4 and 37 ºC for up to 12 months. After 6 months of degradation the scaffold maintained its integrity, although noticeable changes in permeability and pore size were recorded. After 12 months, SEM pictures showed that most of the trabeculae were broken and the sample disaggregates under minimum loading. Neither weight loss nor crystallinity changes in a first heating calorimetric scan were observed during the degradation experiment. However, after 12 months, a rise in crystallinity, from 13 % to 38 %, and a drop in Tg from 58 ºC to 54 ºC were measured in a second heating scan. The onset of thermal degradation moved from 300 ºC, to 210 ºC after 12 months. Although the elastic modulus suffered only a very slight reduction with degradation time, the aggregate modulus decreased 44 % after 6 months.

Connective Tissue Research, 2013

The influence of culture substrate stiffness (in the kPa range) on chondrocyte behavior has been ... more The influence of culture substrate stiffness (in the kPa range) on chondrocyte behavior has been described. Here we describe the response to variations in substrate stiffness in a soft range (2-20 Pa), as it may play a role in understanding cartilage physiopathology. We developed a system for cell culture in substrates with different elastic moduli using collagen hydrogels and evaluated chondrocytes after 2, 4, and 7 days in monolayer and three-dimensional (3D) cultures. Experiments were performed in normoxia and hypoxia in order to describe the effect of a low oxygen environment on chondrocytes. Finally, we also evaluated if dedifferentiated cells preserve the capacity for mechanosensing. Chondrocytes showed less proliferating activity when cultured in monolayer in the more compliant substrates. Expression of the cartilage markers Aggrecan (Acan), type II collagen (Col2a1), and Sox9 was upregulated in the less stiff gels (both in monolayer and in 3D culture). Stiffer gels induced an organization of the actin cytoskeleton that correlated with the loss of a chondrocyte phenotype. When cells were cultured in hypoxia, we observed changes in the cellular response that were mediated by HIF-1α. Results in 3D hypoxia cultures were opposite to those found in normoxia, but remained unchanged in monolayer hypoxic experiments. Similar results were found for dedifferentiated cells. Chondrocytes respond differently according to the stiffness of the substrate. This response depends greatly on the oxygen environment and on whether the chondrocyte is embedded or grown onto the hydrogel, since mechanosensing capacity was not lost with cell expansion.

Computer Methods in Applied Mechanics and Engineering, 2008

In this paper, the application of the natural element method (NEM) to solve inelastic finite defo... more In this paper, the application of the natural element method (NEM) to solve inelastic finite deformation problems in isotropic and fiber-reinforced materials is presented. As most meshless methods, the NEM does not require an explicit connectivity definition. Consequently, it is quite adequate to simulate large strain problems with important mesh distortions, reducing the need for remeshing and projection of results

Computer Methods in Applied Mechanics and Engineering, 2010

The natural element method (NEM) is one of the members of the large family of meshless methods, w... more The natural element method (NEM) is one of the members of the large family of meshless methods, with clear advantages over the finite element method (FEM) in problems involving large mesh distortions or complex geometries where the design of the mesh is costly. These problems are found in many applications like, for instance, simulation of biological structures involving soft tissues, such as, articular joints. One additional advantage of NEM is that it can be easily coupled with finite elements and implemented into any FE framework, including well-known commercial packages. NEM as most other spatial approximation approaches can be applied to evolution problems in two types of time (or pseudo-time) integration schemes, namely implicit and explicit. However, the NEM explicit version has neither been implemented nor sufficiently analyzed, so a comparative study of those two types of NEM time integration schemes is still missing. The main aim of this paper is to discuss issues related to NEM accuracy and stability in its explicit version, and problems related to its implementation into an explicit FE commercial code. Finally, a comparative study addressing the main properties, advantages and disadvantages of both types of NE schemes, implicit and explicit, is presented. Several examples of application are discussed including aspects where NEM is competitive with FEM including modeling of human articular joints like the knee. Explicit NEM allows achieving accurate results for high distortions and complex contact conditions although constraints on time step still are a major drawback and comparable to those known in finite elements to keep stability and accuracy despite the less NEM sensitivity to mesh distortion.

En los ultimos anos, las patologias asociadas a la articulacion temporomandibular (ATM) han cobra... more En los ultimos anos, las patologias asociadas a la articulacion temporomandibular (ATM) han cobrado una gran importancia en odontologia y patologia. Las disfunciones de esta articulacion estan relacionadas con la inestabilidad mecanica y el movimiento irregular de los componentes biomecanicos que la componen. Dentro de los diferentes elementos que forman esta articulacion, es el disco articular la pieza clave dentro de la misma, ya que absorbe las tensiones durante el funcionamiento de la mandibula, proporciona un adecuado contacto entre las superficies oseas y proporciona estabilidad a la articulacion. En este trabajo se desarrollaron dos modelos de elemento finitos bidimensionales de la ATM, uno para una articulacion sana y otro para una patologica afectada de un desplazamiento anterior del disco. En ambos modelos de elementos finitos se introdujeron diferentes modelos de comportamiento para simular de manera real el comportamiento del disco articular. Las simulaciones realizadas ...

Many efforts of research have been made in the Fluid-Structure Interaction (FSI) field in order t... more Many efforts of research have been made in the Fluid-Structure Interaction (FSI) field in order to couple Eulerian (or ALE) formulations in the fluid domain with Lagrangian formulations in the solid domain. See, for instance, [8][16], just to cite a few. In some cases, however, the employ of Lagrangian formulations for both domains seems to be interesting. These cases include—but they are not restricted to—the presence of free surfaces in the fluid, for instance, whose accurate description requires an additional technique (ALE, VoF, level set, among them) in order to capture the position of the free surface. The development of meshless techniques in the nineties opened the possibility of employing Lagrangian formulations for both the solid and fluid domains. This is so since meshless methods are less sensible to “mesh” distortion (i.e., relative nodal displacement) than finite element methods are. Thus, it is possible to employ an updated Lagrangian strategy for the fluid domain, wh...

Revista Facultad De Ingenieria-universidad De Antioquia, 2008

Casi todos los huesos del cuerpo se forman a partir de soportes cartilaginosos en los que se prod... more Casi todos los huesos del cuerpo se forman a partir de soportes cartilaginosos en los que se produce un crecimiento del mismo combinado con un proceso de osificacion que se extiende desde el centro del hueso hasta sus extremos, en un proceso denominado osificacion endocondral. En este periodo de la morfogenesis del tejido oseo los principales factores que controlan el proceso son bioquimicos, siendo la influencia mecanica mucho menor. En este trabajo se presenta un modelo que permite simular este proceso de crecimiento y osificacion del hueso prenatal controlado fundamentalmente por un bucle interactivo inhibidor-activador, en el que se han identificado la hormona paratiroidea (PTHrP) y el Indian Hedgehog (Ihh), mediante la utilizacion de ecuaciones de reaccion-difusion. La utilizacion de estas ecuaciones en combinacion con la simulacion del proceso proliferativo y de crecimiento de las celulas de cartilago (condrocitos) permiten simular con bastante exactitud el proceso de crecimie...

Biomechanics and Modeling in Mechanobiology

Bone remodeling is a fundamental biological process that develops in bone tissue along its whole ... more Bone remodeling is a fundamental biological process that develops in bone tissue along its whole lifetime. It refers to a continuous bone transformation with new bone formation and old bone resorption that changes the internal microstructure and composition of the tissue. The main objectives of bone remodeling are: repair of the internal microcracks; adaptation of the macroscopic stiffness and strength to the actual changing mechanical demands; and control of the calcium homeostasis. Understanding this process and predicting its evolution is critical to reduce the effects of long-term disuse as happens during periods of reduced mobility. It is also important in the design of bone implants to avoid long-term stress shielding. Many mathematical models have been proposed from the earliest purely phenomenological to the latest that include biological knowledge. However, there still exists a lack of connection between the mechanical driving force and the biochemical and cell processes it triggers. Here, and following previous works that model independently the mechanobiological and biochemical processes in bone remodeling, we present a more complete model, useful for both cortical and trabecular bone, that uses a new mechanotransduction approach based on the effect of strains onto the bonding–unbonding rate of RANK / RANKL / OPG receptor–ligand reactions. We compare the results of this model with previous ones, showing a good agreement in similar conditions. We also apply it to realistic situations such as a femoral bone after implantation of a hip prosthesis, getting similar results to the clinical ones in the final bone density distribution. Finally, we extend this approach to the anisotropic case, getting not only the mean density, but also the directional homogenization of the microstructure. This biochemical approach permits, not only to predict the bone evolution under changes in the mechanical loads, but also, to consider anabolic and catabolic drugs to control bone density, such as those used in osteoporosis.

Scientific Reports

Cell-laden hydrogel microspheres have shown encouraging outcomes in the fields of drug delivery, ... more Cell-laden hydrogel microspheres have shown encouraging outcomes in the fields of drug delivery, tissue engineering or regenerative medicine. Beyond the classical single coating with polycations, many other different coating designs have been reported with the aim of improving mechanical properties and in vivo performance of the microspheres. Among the most common strategies are the inclusion of additional polycation coatings and the covalent bonding of the semi-permeable membranes with biocompatible crosslinkers such as genipin. However, it remains challenging to characterize the effects of the interactions between the polycations and the hydrogel microspheres over time in vitro. Here we use a force spectroscopy-based simultaneous topographical and mechanical characterization to study polymer-to-polymer interactions in alginate microspheres with different coating designs, maintaining the hydrogels in liquid. In addition to classical topography parameters, we explored, for the first...