Cód. SSPA: IBiS-DS-22
Lines of Research:
- Computational Biophysics, Quantitative Physiology, Cell Mechanics.
Computational biophysics, and in particular cell mechanics, are relatively new disciplines within the broad field of mechanical engineering. These areas combine the principles of Mechanical Engineering, i.e., the experimentation, modelling and prediction of some biological events and phenomena of interest, in order to shed light on many biological topics that are currently largely unknown from this perspective.
For example, cell movement, migration, growth, formation of populations, capillaries and/or tissues are mechanical processes. The quantification and understanding of the forces and energy that the cell develops in these activities could lead to mechanisms that control them. Likewise, it would be possible to evaluate the mechanical state of cells during these processes under healthy and diseased conditions, such as cancer.
In this context, studies have recently been carried out on the quantification of forces exerted by cells during the angiogenesis process. In this work, developed in collaboration with Prof. Van Oosterwyck (KU Leuven, Belgium), the technique known as TFM (Traction Force Microscopy) has been used, which consists of growing cells on hydrogels containing fluorescent spherical markers.
The development of cellular activity deforms the hydrogel, which is monitored from the markers against an unformed reference state. Prior mechanical calibration of the hydrogel's behavior allows inferring the forces that occur during cell activity (see Figure 1)
In other works, within computational biophysics and cell mechanics, mathematical models of the evolution of tumor populations, mechanical and deformational study of the isolated cell have been carried out. In all these works, the methodology consists of the mathematical development of the phenomenon, numerical implementation and computational simulation.
- Biofabrication and 3D bioprinting – Tissue Engineer
In recent years, the development of patient-personalized implants has increased dramatically due to the potential it represents in many areas of medicine. The group makes use of 3D printing for the repair of large bone defects under load. Currently, the group is analysing the potential of personalised patient tissue engineering by studying the process of immature bone tissue formation in the repair of large bone defects in sheep (project in progress). The scaffolding manufacturing method being used is called robotic molding or robocasting (see figure 2). It is the only AM (Additive Manufacturing) technique that allows ceramic substrates to be constructed using water-based inks with a minimum organic content (< 1% by weight) and minimizing the need for disposable support material. This technique consists of the robotic deposition of highly concentrated colloidal suspensions (inks), capable of supporting their own weight during assembly thanks to a careful control of their composition and rheology. The scaffolding manufactured by robocasting consists of a three-dimensional network of ceramic bars, obtained by extrusion of the ink through an injector tip mounted on a system with 3 motorized axes controlled by computer.
- Biomechanics of bone tissue and regeneration
The work carried out by the group in the field of bone regeneration has been linked to both the computational and experimental study of the process of osteogenic distraction. The results obtained have shown that this technique constitutes an extraordinary test bed for the investigation of the role played by Mechanics in the processes that take place in bone tissue.
From a numerical point of view, a mathematical model of bone distraction has been developed capable of predicting the main characteristics of distraction in different mechanical environments (see Figure 3).
It has been shown that mechanobiological models of bone distraction allow quantitatively and qualitatively to determine the influence of the mechanical environment on tissue differentiation, as well as on their growth, adaptation and structural modification, incorporating the biological and cellular processes involved. Simulating this evolutionary behavior makes it possible to predict processes over time; processes whose experimental evaluation is very costly and sometimes unfeasible.
From the experimental point of view, a multiple study has been carried out that allows the relationship of quantifiable biological parameters (the volume of bone tissue and its distribution in the distraction callus, the proportion of different types of tissues, etc.) with mechanical parameters (the force through the fixative and through the callus, the mechanical properties of the callus tissue, etc.). etc.) during the entire process of osteogenic distraction (see Figure 4). These experimental works have been motivated by the need to provide experimental data on osteogenic distraction in order to improve and validate in silico models.
- Tissue Engineering and Mechanobiology
Tissue Engineering tries to be the meeting point between Biologists, Doctors and Materials Engineers, mainly. Its purpose is to manufacture biomaterials that actively interact with the body, so that it enhances or promotes the functionality of the damaged tissue or organ.
It is therefore a multidisciplinary task that draws on multiple areas of knowledge and actors from different academic backgrounds.
In this field, computational models have been developed for the simulation of bone tissue regeneration in tissue engineering applications. Figure 5 shows the computational results of a bone regeneration model versus actual results taken from CT scans. Figure 6 shows a two-scale (multiscale) simulation for the prediction of bone tissue regeneration in tissue engineering applications. On the one hand, macroscopically, a tissue support made of a porous biomaterial is implanted in the proximal part of a rabbit. From the activity of the animal, the growth of bone tissue in the microstructure of the support is stimulated. Macroscopically, the tissue support disappears (biodegrades) while the defect regenerates. Microscopically, a unit cell is represented, which simulates an elemental representative volume characteristic of the microstructure of the tissue support.
- Bone remodeling models based on cell populations
Computational simulation of the bone remodeling process was the first field of research in Biomechanics to be addressed in the group. It is a classic problem within this science and explains how the mechanical load supported by bone is related to the process of bone renewal and adaptation. But this process is influenced by a multitude of other factors, physiological, genetic, pathological, etc. To include these types of factors, the models developed in the group have evolved from the first, purely phenomenological models that only considered the relationship between mechanical load and bone response, to the more recent, mechanobiological models, which consider a large part of the intercellular signaling processes involved in bone remodeling (see figure 8).
These models account for the concentration of cells involved in bone remodeling, osteoclasts and osteoblasts, as well as their precursors. They also include among their variables the concentration of certain biochemical factors related to the process (PTH, RANK, RANKL, OPG and TGF-β) and certain drugs (denosumab, teriparatide).
This model has recently been applied to predict the loss of bone mass suffered by women with postmenopausal osteoporosis and the subsequent recovery of bone mass when starting treatment with denosumab. The numerical results of this model have been compared with various clinical results, resulting in a very good approximation (see figure 8).
One of the drawbacks of anti-resorptive treatments such as denosumab is the fragility produced in the bone by the excessive mineral content that it reaches when remodeling is inhibited. This fragility sometimes leads to so-called atypical fractures and forces treatment to be stopped for a while or permanently. There is an intermediate alternative, less drastic but little explored, which would consist of adapting the dose of the drug to achieve a compromise between bone mass gain and control of the risk of atypical fracture. Recently, public funding has been requested to develop a research project in which a specific patient model is developed. The aim is to develop a tool that optimises denosumab treatment for each patient. This tool will be developed in collaboration with Professor Peter Pivonka from the Queensland University of Technology, Professor Mª Ángeles Pérez Ansón from the University of Zaragoza and 5 doctors from the Traumatology, Radiology and Rheumatology units of the Virgen del Rocío University Hospital in Seville.
