I3A - Instituto de Investigación en Ingeniería de Aragón

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M2BEMultiscale in Mechanical and Biological Engineering
http://m2be.unizar.es/

The group M2BE (Multiscale in Mechanical and Biological Engineering) belongs to the Aragón Institute of Engineering Research (I3A) and has been recognised as a Quality Research Group (Grupo Consolidado de Investigación) by the Regional Government of Aragón (Gobierno de Aragón).
 
Currently, the group is composed of 5 PhD faculties (permanent) of the University of Zaragoza: 3 from the Mechanical Engineering Department, 1 from the Hospital Clínico Universitario and 1 from the Applied Mathematics Department of the Centro Universitario de Defensa). There is also a variable number of PostDoc (3) and PhD students (currently 8) involved and supported by the different projects and research contracts.
 
M2BE members have an active participation in two PhD programs, which gives to this group a high qualification:

  • Computational Mechanics Master and Doctorate. It is an interdepartamental program that includes a Mater and a PhD program, with the participation of the Mechanical Engineering and the Applied Mathematics departments (this doctorate has the Excellence certification by the ANECA (National Agency of Evaluation).
  • Biomedical Engineering Postgraduate Program. This program started in the course 07-08, including an interdisciplinary Master in Biomedical Engineering and a PhD program. This master corresponds to a level formation research study, in which are involved the Aragón Institute of Engineering Research (I3A) and the Aragon Nano-science Institute (INA). In the inter-institutional PhD program participates the University of Zaragoza and the Catalonian Polytechnic University, and it has just been evaluated as Excellence certification by the ANECA.

Research Lines

Biomedical Engineering

Mechano-chemo-biology in cell migration: Tissue Engineering and Cancer

Cell migration is a biological process essential for tissue development in different physiological and pathological conditions. Therefore, understanding the mechanisms underlying cell migration is...

Cell migration is a biological process essential for tissue development in different physiological and pathological conditions. Therefore, understanding the mechanisms underlying cell migration is very important to emerging areas of biotechnology which focus on cellular transplantation and the fabrication of artificial tissues (tissue engineering), as well as for the development of new therapeutic strategies for controlling invasive tumor cells. The objective of M2BE is to elucidate the fundamental nature of how cells sense and regulate their migration in response to the mechano-chemical micro-environment.
Both experimental (microfluidics-based) and computational approaches (multiscale analysis) are combined: with in-silico models different theoretical hypotheses can be tested by means of numerical experiments that, when compared with in-vitro experiments, allow validating and helping to reduce the number of experiments, design new experiments and define new hypotheses. These computer models and microfluidic experiments will be complemented with other experiments, such as, Traction Force Microscopy (TFM) and Atomic Force Microscopy (AFM) to characterise cell contraction and scaffold/tissue properties.

Mechanobiology of bone remodelling: Osteoporosis

Osteoporosis weakens bones and increases the probability of mechanical fracture appearance. There are multiple treatments for the osteoporosis that are mainly focused in the prevention of extra...

Osteoporosis weakens bones and increases the probability of mechanical fracture appearance. There are multiple treatments for the osteoporosis that are mainly focused in the prevention of extra loss of bone, and therefore, the incidence of expected fractures decreases. Treatments include a diversity of medicaments (calcium, vitamin D, alendronate, substitutive hormonal therapy, etc.), being none of them completely efficient.
But the osteroporosis is a multifactorial process regulated by multiple factors acting in a coupled way, from hormonal factors, homeostasis of the calcium, haematopoiesis, mechanical conditions, structure and properties of the tissue as material, etc.
The systematic study of the influence of each factor and its interaction with the rest of them is of great complexity and difficulty in order to define clinical testing, screening and animal experimentation. However, the computational modelling, although it does not allow defining specific therapies, it allows exploring and to define guidelines that provide the specific and controlled design of clinical testing or in-vitro experiments. Therefore the main goal of this research line is to assess the potential of the computational models to predict the result of the combination of innovative therapies on factors that affect to the osteoporosis.

Mechanobiology of tissue regeneration

Most tissues cannot regenerate when injured or damaged. M2BE aims to understand which are the mechanisms that regulate regeneration in nature (mainly due to mechanical demands) with applications...

Most tissues cannot regenerate when injured or damaged. M2BE aims to understand which are the mechanisms that regulate regeneration in nature (mainly due to mechanical demands) with applications in bone and wound healing in order to improve healing mechanisms: temporal acceleration, regenerate bone large defects, heal chronic wounds, etc. In fact, computational multiscale modelling is used as a tool for the knowledge and test of coupled mutiple mechano-chemical conditions.

Computational evaluation of prostheses and implants

Despite the generally high success rates achieved in recent decades, implant failures related with total hip replacements (THRs) and (TKRs) continues to be an important problema in clinical...

Despite the generally high success rates achieved in recent decades, implant failures related with total hip replacements (THRs) and (TKRs) continues to be an important problema in clinical practice. There are both biological and mechanics causes that contribute to the implants and prostheses failures. M2BE aims to help in the design of prostheses and implants by computational evaluation of its performance. We are mainly focused on hip and knee prostheses. Computational modeling allows us to know the short- and long-term response of the host bone to the incorporation of prosthesis (bone remodeling and resorption), but also we investigate on the implant loosening by incorporation of interface models (osseointegration, debonding of inert interfaces, etc.).

Biomimetics and self-healing materials

Biomimetics studies the structure and function of biological systems as models for the design and engineering of materials and structures. M2BE investigates different biological analogies to...

Biomimetics studies the structure and function of biological systems as models for the design and engineering of materials and structures. M2BE investigates different biological analogies to stimulate researchers in order to engineer materials such as metals, concrete and polymer composites to create new self-healing properties. Again the computational modelling is the tool for the knowledge and test of coupled mutiple self-healing mechanisms.

Key Projects

Biomedical Engineering

DPI2012-32880 - MULTISCALE AND MULTIPHYSIC MODELLING OF SELF HEALING BIOINSPIRED AND BIOMIMETIC MATERIALS: A DESIGN TOOL FOR THE OPTIMIZATION OF THE SELF HEALING RESPONSE IN COATINGS

The mechanical design of new technologic materials requires more efficient mechanisms of damage repair, being most attractive from economical and sustainability viewpoints, that materials can give...

The mechanical design of new technologic materials requires more efficient mechanisms of damage repair, being most attractive from economical and sustainability viewpoints, that materials can give active responses to damage, initiating an autonomous repair whenever and wherever structural or functional damage occur.
The repair mechanisms in these self healing materials depend on their microscopic and macroscopic properties and on the mechanical loading that they are subjected to. Thus, for instance, in polymeric coatings both crack propagation and mobilization of the chemical substances capable of sealing the crack are controlled by internal stresses due to the bounds within the polymer chain, the superficial stresses at the coating-substrate interface and the visco-elastic-plastic material behaviour of the coating.
Given the biomimetic nature of the self healing materials, the biological counterpart of the self healing processes can be identified without loss of generality (for instance, cell migration instead of chemical transport, cellular synthesis instead of precipitation, etc.). Hence, a deep knowledge of the processes behind the healing of biological tissues is regarded necessary to properly understand and contribute to the development of these new materials.
The goal of this project it to propose multiphysics and multiscale models, of biological inspiration, for active (i.e. release of corrosion inhibitors from the coating matrix) and passive (i.e. barrier protection reestablishment) self healing mechanisms in protective coatings to prevent the onset of corrosion at the underlying substrate.
 

DPI2011-22413 - Design and development of a computational tool For the personalised risk fracture prediction in Osteoporotic patients

Osteoporosis is a multifactorial disease which is characterized by low bone mass and weak bone structure, which results in increased fracture risk. In general, bone adapts its mass and...

Osteoporosis is a multifactorial disease which is characterized by low bone mass and weak bone structure, which results in increased fracture risk. In general, bone adapts its mass and microstructure to mechanical loading. In normal situations, this adaptative process ensures a good balance between bone mass and strength. In the case of osteoporosis, the load adaptative process fails and there is a modification of bone capacity material through its structure and composition. Patients with osteoporosis often experience fractures, indicating that bone strength capacity is affected to a level that the bone cannot withstand normal loading conditions.
The main goal of this project consists on the development of a patient-specific computational tool that estimates the temporal evolution of the risk of fracture in osteoporotic patients and predicts the most adequate therapy to treat and prevent osteoporosis. Therefore, we aim to simulate osteoporosis, different therapies for its prevention and treatment and finally to predict the fracture risk over time in osteoporotic patients. This goal can be achieved by the integration of three complementary engineering methodologies: finite element (FE) modeling, bone remodeling algorithms and medical imaging technology. This combined approach will provide effective means to investigate this important pathological process under tight control of the mechanical and structural factors that affect osteoporosis. Patient-specific models of the radius (wrist) and the femur will be created based on parametrised biomechanical FE models. A bone remodelling algorithm will be proposed to simulate specific osteoporotic tissue. If we want to account also for the evolution of the disease over time, or predict the effects of a pharmacological or mechanical treatment, we have to model the tissue, cell, and constituents scales, because the evolution of the disease comes from the systemic interaction of processes observed at all these different scales. Therefore, this will imply the development of a multiscale approach that will be focused on the cellular interactions based on pure biomechanical factors and biochemical signalling. Currently, computational bone remodeling simulations are very time-consuming, labour-intensive and costly processes. However, there are different numerical strategies based on model reduction that are able to cut down this time of analysis. This will allow near real-time simulations under different bone conditions to predict bone response and its risk of fracture. Finally, all these simulations will be validated with the help of medical imaging technology. The applicability of digital image processing techniques to extract quantitative information from medical images which, a priori cannot be detected or quantified visually by the clinician are changing the current radiological workflow. This methodology will be an important complementary tool able to help in the follow-up of patients improving the prevention and treatment of osteoporosis.
The proposed engineering technology is innovative, integrating different interdisciplinary approaches that at the end look for the development of novel tools for the use of personalised therapies. This predictive computer model will also allow the clinical trial design and improve the interpretation of trial data in context of the individual patient and patient-to-patient variability. As the power of our computers and the sophistication of our models increase, it is reasonable to expect that in a few years personalised computer models will reliably predict a variety of clinical scenarios. The results of this project will provide more personalized, predictive and integrative healthcare.

DPI2012-38090-C03 - MULTISCALE, MICROFLUIDIC & MICROSCOPIC PLATFORM FOR PREDICTIVE SIMULATIONS OF CELL-MATRIX INTERACTIONS: A PRECLINICAL TOOL FOR DRUG TESTING OF ANTI-METASTATIC TREATMENTS (SIM-CELL)

The development of technologies that simulate cell and tissue micro-environments in-vivo is fundamental in many areas of biomedical research such as tissue engineering, regenerative medicine,...

The development of technologies that simulate cell and tissue micro-environments in-vivo is fundamental in many areas of biomedical research such as tissue engineering, regenerative medicine, cancer treatment or drug development. Traditionally, the technologies used in these research areas study important biological problems without considering the critical effect of the micro-environment exert on the behaviour of cells and tissues. Accordingly, microfluidic systems are currently gaining popularity for the in vitro study of cellular processes, because they can be properly designed to simulate realistic micro-environmental conditions. In fact, these in-vitro systems permit the survival of cells within –tissue mimicking- 3D gel scaffolds of precisely defined mechanical and biochemical conditions, where the changes that these factors suffer as consequence of the cell activity can be properly monitored. However, these microdevices still require substantial optimization before they can be applied to the quantitative study of cell-matrix, thus cell-tissue, interactions. To fill this significant gap and complement the microdevice-based experiments with quantitative information, we will develop a virtual multiscale simulation approach (based on new numerical models) and sophisticated quantitative microscopy-based image algorithms. This will allow us to analyse the same phenomena from two complementary methods, thus allowing a quantitative and qualitative validation. Indeed, the combination of methodologies will open new research strategies: using in-silico models, different biological hypotheses can be tested by means of numerical experiments that, when validated using in-vitro experiments, will help designing new experiments and defining new hypotheses.
Therefore, the objective of this project is to create a platform that combines multiscale numerical models, microfluidics and quantification microscopy-based for the sistematic evaluation of cell-matrix interactions under different mechano-chemical conditions. In particular, the aim of the proposed work is to advance in the understanding, assessment and quantification of the effect of these environmental conditions on the metastatic potential of cancerous cells. In fact, we aim not only at understanding how the environmental conditions regulate tumour cell invasion, but also to evaluate how tumour cells are able to modify and alter the environment to facilitate the invasion. This requires the use of sophisticated quantitative microscopy-based image algorithms of the next aspects: cancer cell migration, tissue remodelling and alterations in the endothelial cell (EC) monolayer. To bring the developed technology close to its potential use both in preclinical and clinical settings, we will design high-througput devices that will allow us to test the metastatic potential of cancer cells, in parallel, under several –controlled- experimental conditions, including changes in the biomechanical properties of the environment -simulating different tissue types and conditions- or caused by the use of chemical factors that aim at preventing cell migration.
In conclusion, under SIM-CELL we will develop a miniaturized, high-throughput microdevice, which will be a relevant tool for the pharmacological testing of the anti-metastatic potential of drugs (pre-clinical use) as well as for the design of personalized chemotherapies in the treatment of cancer and the prevention of metastatic spread of tumors to distant organs (clinical use).

Patient-specific predictions for bone treatments. CAD-BONE

CAD-BONE addresses a multidisciplinary research that will transform current technology radically improving the development of patient-specific computer models for the modelling of bone remodelling...

CAD-BONE addresses a multidisciplinary research that will transform current technology radically improving the development of patient-specific computer models for the modelling of bone remodelling/healing to predict short and long-term bone response after surgical interventions. In fact, CAD-BONE will combine image processing, musculoskeletal modelling tools, finite element analysis and bone remodeling/healing algorithms to provide an understanding of the individual functional outcome of patient treatments from standard clinical radiographs.
 
All these computer technologies have already been developed, but never have been combined and integrated to create a computer tool with a predictive purpose. To successfully achieve this objective we are facing different scientific and technological challenges. Firstly, patient-specific finite element models of specific bones will be automatically constructed (including geometries, loads and boundary conditions). Secondly, currently, bone remodelling/healing computer models are very slow, labour-intensive and costly processes.
 
CAD-BONE will investigate different numerical strategies based on model reduction to accelerate these simulations with the aim to achieve near real-time results (in minutes of real-time). And, finally, quantitative validation of these patient-specific models will be developed. Such a validation will require a quantitative comparison between real bone density distributions obtained by computer tomography (CT) and those predicted from computer simulations.
 
For more info: http://cadbone.unizar.es

INSILICO-CELL Predictive modelling and simulation in mechano-chemo-biology: a computer multi-approach (European Union Starting Grant / ERC-2012-StG - Proposal No 306571)

Living tissues are regulated by multi-cellular collectives mediated at cellular level through complex interactions between mechanical and biochemical factors. A further understanding of these...

Living tissues are regulated by multi-cellular collectives mediated at cellular level through complex interactions between mechanical and biochemical factors. A further understanding of these mechanisms could provide new insights in the development of therapies and diagnosis techniques, reducing animal experiments.
M2BE proposes a combined and complementary methodology to advance in the knowledge of how cells interact with each other and with the environment to produce the large-scale organization typical of tissues. I will couple in-silico and in-vitro models for investigating the micro-fabrication of tissues in-vitro using a 3D multicellular environment. By computational cell-based modelling of tissue development, M2BE uses a multiscale and multiphysics approach to investigate various key factors: how environmental conditions (mechanical and biochemical) drives cell behaviour, how individual cell behaviour produces multicellular patterns, how cells respond to the multicellular environment, how cells are able to fabricate new tissues and how cell-matrix interactions affect these processes. In-vitro experiments will be developed to validate numerical models, determine their parameters, improve their hypotheses and help designing new experiments. The in-vitro experiments will be performed in a microfluidic platform capable of controlling biochemical and mechanical conditions in a 3D environment. This research is applied in three applications, where the role of environment conditions is important and the main biological events are cell migration, cell-matrix and cell-cell interactions: bone regeneration, wound healing and angiogenesis.

Key Technologies

Biomedical Engineering

Mechanical design by means of Finite Element Simulations (ABAQUS)
Multiphysics analysis (COMSOL)
Multiscale and multiphysics numerical simulations
Microfluidics and Traction Force Microscopy experiments
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