Continuum Modeling and Simulation in Bone Tissue Engineering

Bone tissue engineering is currently a mature methodology from a research perspective. Moreover, modeling and simulation of involved processes and phenomena in BTE have been proved in a number of papers to be an excellent assessment tool in the stages of design and proof of concept through in-vivo or in-vitro experimentation. In this paper, a review of the most relevant contributions in modeling and simulation, in silico, in BTE applications is conducted. The most popular in silico simulations in BTE are classified into: (i) Mechanics modeling and sca old design, (ii) transport and flow modeling, and (iii) modeling of physical phenomena. The paper is restricted to the review of the numerical implementation and simulation of continuum theories applied to di erent processes in BTE, such that molecular dynamics or discrete approaches are out of the scope of the paper. Two main conclusions are drawn at the end of the paper: First, the great potential and advantages that in silico simulation o ers in BTE, and second, the need for interdisciplinary collaboration to further validate numerical models developed in BTE.Ministerio de Economía y Competitividad del Gobierno España DPI2017-82501-

Cell-Biomaterial Mechanical Interaction in the Framework of Tissue Engineering: Insights, Computational Modeling and Perspectives

Tissue engineering is an emerging field of research which combines the use of cell-seeded biomaterials both in vitro and/or in vivo with the aim of promoting new tissue formation or regeneration. In this context, how cells colonize and interact with the biomaterial is critical in order to get a functional tissue engineering product. Cell-biomaterial interaction is referred to here as the phenomenon involved in adherent cells attachment to the biomaterial surface, and their related cell functions such as growth, differentiation, migration or apoptosis. This process is inherently complex in nature involving many physico-chemical events which take place at different scales ranging from molecular to cell body (organelle) levels. Moreover, it has been demonstrated that the mechanical environment at the cell-biomaterial location may play an important role in the subsequent cell function, which remains to be elucidated. In this paper, the state-of-the-art research in the physics and mechanics of cell-biomaterial interaction is reviewed with an emphasis on focal adhesions. The paper is focused on the different models developed at different scales available to simulate certain features of cell-biomaterial interaction. A proper understanding of cell-biomaterial interaction, as well as the development of predictive models in this sense, may add some light in tissue engineering and regenerative medicine fields.Ministerio de Ciencia y Tecnología DPI2010-20399-C04-0

Automatic grading of student-specific exercises in large groups of the subject theory of machines and mechanisms

This study establishes an already defined and tested method to grade exercises of kinematics and dynamics within the course entitled “Theory of Machines and Mechanisms” of the Industrial Technologies Engineering Degree at the Seville School of Engineering (Spain). Particular emphasis is made on the automation of grading and personalization of the exercises, due to the large number of students enrolled in this course. The former is made through a teaching platform available at the University of Seville and called Doctus, whilst the latter is achieved by defining the input data of the exercises and the requested results as a function of the digits of the student’s ID. The students must face and solve a personalized problem by their own with the knowledge and competences acquired during the academic course. This paper describes the exercises and the tools used to grade them and shows the satisfactory results obtained with these exercises after three academic courses

Comparison of the volumetric composition of lamellar bone and the woven bone of calluses

Woven tissue is mainly present in the bone callus, formed very rapidly either after a fracture or in distraction processes. This high formation speed is probably responsible for its disorganized microstructure and this, in turn, for its low stiffness. Nonetheless, the singular volumetric composition of this tissue may also play a key role in its mechanical properties. The volumetric composition of woven tissue extracted from the bone transport callus of sheep was investigated and compared with that of the lamellar tissue extracted from the cortical shell of the same bone. Significant differences were found in the mineral and water contents, but they can be due to the different ages of both tissues, which affects the mineral/water ratio. However, the content in organic phase remains more or less constant throughout the mineralization process and has proven to be a good variable to measure the different composition of both tissues, being that content significantly higher in woven tissue. This may be linked to the abnormally high concentration of osteocytes in this tissue, which is likely a consequence of the more abundant presence of osteoblasts secreting osteoid and burying other osteoblasts, which then differentiate into osteocytes. This would explain the high formation rate of woven tissue, useful to recover the short-term stability of the bone. Nonetheless, the more abundant presence of organic phase prevents the woven tissue from reaching a stiffness similar to that of lamellar tissue in the long term, when it is fully mineralized

Evolution of relaxation properties of callus tissue during bone transport

Callus tissue exhibits a viscoelastic behavior that has a strong influence on the distribution of stresses and their evolution with time and, thus, it can affect tissue differentiation during distraction procedures. For this reason, a deep knowledge of that viscoelastic behavior can be very useful to improve current protocols of bone distraction and bone transport. Monitoring stress relaxation of the callus during distraction osteogenesis allows characterizing its viscoelastic behavior. Different procedures have been used in the literature to fit the response of a given viscoelastic model to the force relaxation curve. However, these procedures do not ensure the uniqueness of that fit, which is of the utmost importance for statistical purposes. This work uses a fitting procedure already validated for other tissues that ensures that uniqueness. Very importantly too, the procedure presented here allows obtaining more information from the stress relaxation tests, distinguishing relaxation in different time scales, which provides a deeper insight into the viscoelastic behavior and its evolution over time. As it was observed in the results, relaxation is faster at the first days after osteotomy and becomes slower and more gradual with time. This fact can be directly linked to the temporal evolution of the callus composition (water, organic phase, and mineral content) and also to the progression of tissue differentiation, with a prevalence of hard tissues as time passes

Towards the Experimentally-Informed In Silico Nozzle Design Optimization for Extrusion-Based Bioprinting of Shear-Thinning Hydrogels

Article number 701778Research in bioprinting is booming due to its potential in addressing several manufacturing challenges in regenerative medicine. However, there are still many hurdles to overcome to guarantee cell survival and good printability. For the 3D extrusion-based bioprinting, cell viability is amongst one of the lowest of all the bioprinting techniques and is strongly influenced by various factors including the shear stress in the print nozzle. The goal of this study is to quantify, by means of in silico modeling, the mechanical environment experienced by the bioink during the printing process. Two ubiquitous nozzle shapes, conical and blunted, were considered, as well as three common hydrogels with material properties spanning from almost Newtonian to highly shear-thinning materials following the power-law behavior: Alginate-Gelatin, Alginate and PF127. Comprehensive in silico testing of all combinations of nozzle geometry variations and hydrogels was achieved by combining a design of experiments approach (DoE) with a computational fluid dynamics (CFD) of the printing process, analyzed through a machine learning approach named Gaussian Process. Available experimental results were used to validate the CFD model and justify the use of shear stress as a surrogate for cell survival in this study. The lower and middle nozzle radius, lower nozzle length and the material properties, alone and combined, were identified as the major influencing factors affecting shear stress, and therefore cell viability, during printing. These results were successfully compared with those of reported experiments testing viability for different nozzle geometry parameters under constant flow rate or constant pressure. The in silico 3D bioprinting platform developed in this study offers the potential to assist and accelerate further development of 3D bioprinting.Horizonte 2020 RIA(Unión Europea) 874837Horizonte 2020 (Unión Europea) INSITE 772418Fondo de Investigaciones Científicas (FNRS) T.0256.16Beca José Castillejo CAS17 /0017

Diseño de dispositivos para el análisis experimental del proceso de transporte óseo en ovejas

La distracción osteogénica, es una técnica que permite generar nuevo tejido óseo a partir de la separación gradual de dos fragmentos óseos. Aunque se han realizado numerosos estudios experimentales sobre el proceso de distracción, no se ha analizado cuantitativamente la evolución de la rigidez del callo durante el proceso de distracción y posteriormente a él. El objetivo de este trabajo es aplicar técnicas experimentales para caracterizar este proceso mecánicamente y validar modelos numéricos del proceso de distracción y consolidación existentes. Para conocer la rigidez del callo en cada momento, se ha diseñado un dispositivo que permite obtener datos experimentales de las fuerzas que pasan por el callo y distractor in vivo, en unos ensayos de transporte óseo en el hueso metatarsiano de ovejas. El diseño de este experimento ha requerido crear una serie de dispositivos. En primer lugar, se optimizó un distractor tipo Ilizarov y se añadieron sistemas de medida de fuerzas. En segundo lugar, fue necesario diseñar un útil para la correcta colocación del distractor durante la intervención quirúrgica. Finalmente, para poder obtener valores de fuerza en el hueso fue necesario el diseño de un sistema de adquisición de datos que permitiera la medida de fuerzas in vivo.Distraction osteogenesis is a technique to generate new bone tissue from the gradual separation of two bone fragments. Although there are many experimental studies about the distraction process, the evolution of the callus stiffness has not been analyzed quantitatively during the distraction and then it. The aim of this work is to apply experimental techniques to characterize this process mechanically and to validate existing numerical models about distraction and consolidation. To know callus stiffness at any time, a device has been design to obtain force in distractor and callus experimental data in vivo, by means of experiments performed in the metatarsus bone of sheep. The design of this experiment requires creating some devices. First, a Ilizarov distractor was optimized and force transducers were added. Secondly, it was necessary to design a tool that allows a correct installation of distractor during surgery. Finally, in order to obtain force values in the bone, it was necessary to design a data acquisition system which allows the measurement of in vivo forces.Junta de Andalucía P09-TEP-519

Multiscale characterisation of cortical bone tissue

Multiscale analysis has become an attractive technique to predict the behaviour of materials whose microstructure strongly changes spatially or among samples, with that microstructure controlling the local constitutive behaviour. This is the case, for example, of most biological tissues-such as bone. Multiscale approaches not only allow, not only to better characterise the local behaviour, but also to predict the field-variable distributions (e.g., strains, stresses) at both scales (macro and micro) simultaneously. However, multiscale analysis usually lacks sufficient experimental feedback to demonstrate its validity. In this paper an experimental and numerical micromechanics analysis is developed with application to cortical bone. Displacement and strain fields are obtained across the microstructure by means of digital image correlation (DIC). The other mechanical variables are computed following the micromechanics theory. Special emphasis is given to the differences found in the different field variables between the micro- and macro-structures, which points out the need for this multiscale approach in cortical bone tissue. The obtained results are used to establish the basis of a multiscale methodology with application to the analysis of bone tissue mechanics at different spatial scales

Model of dissolution in the framework of tissue engineering and drug delivery

Dissolution phenomena are ubiquitously present in biomaterials in many different fields. Despite the advantages of simulation-based design of biomaterials in medical applications, additional efforts are needed to derive reliable models which describe the process of dissolution. A phenomenologically based model, available for simulation of dissolution in biomaterials, is introduced in this paper. The model turns into a set of reaction–diffusion equations implemented in a finite element numerical framework. First, a parametric analysis is conducted in order to explore the role of model parameters on the overall dissolution process. Then, the model is calibrated and validated versus a straightforward but rigorous experimental setup. Results show that the mathematical model macroscopically reproduces the main physicochemical phenomena that take place in the tests, corroborating its usefulness for design of biomaterials in the tissue engineering and drug delivery research areas.Ministerio de Economía y Competitividad MAT2015-71284-

Time-Dependent Collagen Fibered Structure in the Early Distraction Callus: Imaging Characterization and Mathematical Modeling

Collagen is a ubiquitous protein present in regenerating bone tissues that experiences multiple biological phenomena during distraction osteogenesis until the deposition of phosphate crystals. This work combines fluorescence techniques and mathematical modeling to shed light on the mechano-structural processes behind the maturation and accommodation-to-mineralization of the callus tissue. Ovine metatarsal bone calluses were analyzed through confocal images at different stages of the early distraction osteogenesis process, quantifying the fiber orientation distribution and mean intensity as fiber density measure. Likewise, a mathematical model based on the experimental data was defined to micromechanically characterize the apparent stiffening of the tissue within the distracted callus. A reorganization of the fibers around the distraction axis and increased fiber density were found as the bone fragments were gradually separated. Given the degree of significance between the mathematical model and previous in vivo data, reorganization, densification, and bundle maturation phenomena seem to explain the apparent mechanical maturation observed in the tissue theoretically.This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness [Grant No. DPI2017-82501-P]; the Spanish State Research Agency (AEI) [Grant No. PID2020-113790RB-I00/AEI/ 10.13039/501100011033]; and the European Regional Development Fund (FEDER) with the Junta de Andalucı ´a [Grant No. US-1261691]