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• The effect of Zoledronate on the RANK/RANK-L/OPG pathway in bone remodeling is here investigated with a pharmacokinetic model and a finite element approach. • A chemo-mechano-biological bone remodeling model coupled with a pharmacokinetic one is used to evaluate the effects of systematic and local drug delivery on the bone around the dental implant. For local drug delivery, Fickean diffusion is used to compute the drug concentration distribution in bone around the dental implant. • Systematic drug delivery affects the whole skeleton, while local drug delivery affects only the area around the dental implant. • Local drug delivery reduces the side effects produced by systemic drug administration like increasing bone brittleness and damage far from the implant. The increased life expectancy has boomed the demand of dental implants in the elderly. As a consequence, considering the effect of poorer bone quality, due to aging or associated diseases such as osteoporosis, on the success of dental restoration is becoming increasingly important. Bisphosphonates are one of the most used drugs to overcome the effect of osteoporosis as they increase bone density. Bisphosphonates modify the physiological bone remodeling process by adhering to the bone surface, reducing the activity of osteoclasts. This study aims at comparing the effect on bone remodeling of two drug delivery methods of Bisphosphonates: local delivery by coating the implant surface and systemic delivery. A chemo-mechano-biological bone remodeling model validated in a previous paper was used here. The two drug delivery schemes were modeled by means of a finite element approach. In the systemic drug delivery case, the amount of drug that reaches the bone compartment was calculated using a pharmacokinetic model while in the local drug delivery system, the dose was calculated using Fickean diffusion. In particular, the effect of Zoledronate is studied here. The two drug delivery approaches are compared between them and with a control case with no drug. The results show that the use of Bisphosphonates increases the mechanical strength of bone, thus improving the implant fixation along time. Systemic drug delivery affects the entire skeleton, while local drug delivery only affects the area around the dental implant, which reduces the side effects of Bisphosphonates, such as increasing the mineral content, which may promote bone brittleness and microdamage far from the implant. These results support the conclusion that dental implants coated with Bisphosphonates can be a good solution for osteoporotic or low bone density patients without the long-term side effects of systemic drug delivery. [ABSTRACT FROM AUTHOR]

Microfluidic capacities for both recreating and monitoring cell cultures have opened the door to the use of Data Science and Machine Learning tools for understanding and simulating tumor evolution under controlled conditions. In this work, we show how these techniques could be applied to study Glioblastoma, the deadliest and most frequent primary brain tumor. In particular, we study Glioblastoma invasion using the recent concept of Physically-Guided Neural Networks with Internal Variables (PGNNIV), able to combine data obtained from microfluidic devices and some physical knowledge governing the tumor evolution. The physics is introduced by means of nonlinear advection-diffusion-reaction partial differential equation that models the Glioblastoma evolution for defining the network structure. On the other hand, multilayer perceptrons combined with a nodal deconvolution technique are used for learning the go or grow metabolic behavior which characterises the Glioblastoma invasion. The PGNNIV is here trained using synthetic data obtained from in silico tests created under different oxygenation conditions, using a previously validated model. The unravelling capacity of PGNNIV enables discovering complex metabolic processes in a non-parametric way, thus giving explanatory capacity to the networks, and, as a consequence, surpassing the predictive power of any parametric approach and for any kind of stimulus. Besides, the possibility of working, for a particular tumor, with different boundary and initial conditions, permits the use of PGNNIV for defining virtual therapies and for drug design, thus making the first steps towards in silico personalised medicine. Author summary: In this work, we apply Physically-Guided Neural Networks with Internal Variables (PGNNIV) to the understanding of the Glioblastoma evolution process. We explain the metabolic changes between the proliferative and migrative activity of Glioblastoma cell cultures by using the go or grow activation functions as a pair of internal variables, whose dependence on the oxygen level is unravelled by some building blocks of the whole PGNNIV. Due to its model-free nature, our method is able to identify different classical mechanistic approaches and to outperform cell culture evolution predictions, as we demonstrate in the paper. Unlike Biologically-Informed Neural Networks we can assimilate data obtained from different boundary conditions and under different external stimuli to simulate the tumor progression under arbitrary conditions. We demonstrate this ability by comparing the predictions with different boundary conditions, resulting in different oxygenation conditions. This flexibility enables the use of our proposed method for personalised medical purposes, as the cell culture metabolic information, for a particular tumor, is encapsulated in a sub-network and may be used for arbitrary in silico tests. [ABSTRACT FROM AUTHOR]

Evolutionary processes in biological tissue, such as adaptation or remodeling, represent an enterprising area of research. In this paper, we present a multiscale model for the remodeling of fibered structures, such as bundles of collagen fibrils. With this aim, we introduce a von Mises statistical distribution function to account for the directional dispersion of the fibrils, and we remodel the underlying fibrils by changing their orientation. To numerically compute this process, we make use of the microsphere approach, which provides a useful multiscale tool for homogenizing the microstructure behavior, related to the fibrils of the bundle, in the macroscale of the problem. The results show how the fibrils respond to the stimulus by reorientation of their structure. This process leads to a stiffer material eventually reaching a stationary state. These results are in agreement with those reported in the literature, and they characterize the adaptation of biological tissue to external stimuli. [ABSTRACT FROM AUTHOR]

Tissue engineering is reviving itself, adopting the concept of biomimetics of in vivo tissue development. A basic concept of developmental biology is the modularity of the tissue architecture according to which intermediates in tissue development constitute semiautonomous entities. Both engineering and nature have chosen the modular architecture to optimize the product or organism development and evolution. Bioartificial tissues do not have a modular architecture. On the contrary, artificial organs of modular architecture have been already developed in the field of artificial organs. Therefore the conceptual support of tissue engineering by the field of artificial organs becomes critical in its new endeavor of recapitulating in vitro the in vivo tissue development. [ABSTRACT FROM AUTHOR]

Abstract: A fully three dimensional finite-strain damage model for fibrous soft tissue is here presented. The model assumes uncoupled contributions for the matrix and collagen fibers, and uncoupled bulk and deviatoric response over any range of deformations. A simple isotropic damage mechanism within the framework of continuum damage mechanics has been used to describe the softening behavior under deformation for the matrix. On the other hand, statistical aspects related to the length distribution of the reinforcing fibers lead to a damage model for the reinforcing material. As a result, a general theoretical framework for constitutive modeling of biological soft tissue with continuum damage is obtained. The formulation has been implemented in a finite element framework and the capabilities of the model tested in three computer simulations of inhomogeneous boundary value problems. The results show the quadratic rate of convergence of the implementation and the ability to describe typical stress–strain behavior of fiber reinforced soft tissues. [Copyright &y& Elsevier]

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 osteoporotic patients is still controversial, requiring more experimental and clinical studies. In this work, we investigate the effect of different doses of several drugs, used nowadays in osteoporotic patients, on the evolution of bone density after dental implantation. With this aim, we use a pharmacokinetic–pharmacodynamic (PK/PD) mathematical model that includes the effect of antiresorptive drugs on the RANK/RANK-L/OPG pathway, as well as the mechano-chemical coupling with external mechanical loads. This mechano-PK/PD model is then used to analyze the evolution of bone in normal and osteoporotic mandibles after dental implantation with different drug dosages. We show that using antiresorptive agents such as bisphosphonates or denosumab increases bone density and the associated mechanical properties, but at the same time, it also increases bone brittleness. We conclude that, despite the many limitations of these very complex models, the one presented here is capable of predicting qualitatively the evolution of some of the main biological and chemical variables associated with the process of bone remodeling in patients receiving drugs for osteoporosis, so it could be used to optimize dental implant design and coating for osteoporotic patients, as well as the drug dosage protocol for patient-specific treatments. [ABSTRACT FROM AUTHOR]

Hallux abducto valgus (HAV), one of the most common forefoot deformities, occurs primarily in elderly women. HAV is a complex disease without a clearly identifiable cause for its higher prevalence in women compared with men. Several studies have reported various skeletal parameters related to HAV. This study examined the geometry of the proximal phalanx of the hallux (PPH) as a potential etiologic factor in this deformity. A total of 43 cadaver feet (22 males and 21 females) were examined by means of cadaveric dissection. From these data, ten representative PPHs for both genders were selected, corresponding to five percentiles for males (0, 25, 50, 75, and 100 %) and five for females. These ten different PPHs were modeled and inserted in ten foot models. Stress distribution patterns within these ten PPH models were qualitatively compared using finite element analysis. In the ten cases analyzed, tensile stresses were larger on the lateral side, whereas compressive stresses were larger on the medial side. The bones of males were larger than female bones for each of the parameters examined; however, the mean difference between lateral and medial sides of the PPH (mean ± SD) was larger in women. Also the shallower the concavity at the base of the PPH, the larger the compressive stresses predicted. Internal forces on the PPH, due to differences in length between its medial and lateral sides, may force the PPH into a less-stressful position. The geometry of the PPH is a significant factor in HAV development influencing the other reported skeletal parameters and, thus, should be considered during preoperative evaluation. Clinical assessment should evaluate the first ray as a whole and not as isolated factors. [ABSTRACT FROM AUTHOR]

Abstract: Background: Human trachea is a multi-component structure composed of cartilage, trachealis muscle, mucosa and submucosa membrane and adventitial membrane. Its mechanical properties are essential for an accurate prediction of tracheal deformation, which has a significant clinic relevance. Efforts have been made in quantifying the material behaviour of tracheal cartilage and trachealis muscle. However, the material behaviours of other components have been least investigated. Methods: Three human cadaveric trachea specimens were used in this study. Trachealis muscle, mucosa and submucosa membrane and adventitia membrane were excised to perform the uniaxial test in axial and circumferential directions. In total, 72 tissue strips were prepared and tested. Tangent modulus was used to quantified the stiffness of each tissue strip at various stretch levels. Results: The obtained results indicated that all types of tracheal soft tissues were highly non-linear and anisotropic. Trachealis muscle in the circumferential direction had the most excellent extensibility; and the adventitial collagen membrane in the circumferential direction was the stiffest. Conclusion: This study is helpful in understanding the material behaviour of trachea. Obtained results can be used for computational and analytic modelling to quantify the tracheal deformation. [Copyright &y& Elsevier]

Coronary bifurcations represent specific regions of the arterial tree that are susceptible to atherosclerotic lesions. While the effects of vessel compliance, curvature, pulsatile blood flow, and cardiac motion on coronary endothelial shear stress have been widely explored, the effects of myocardial contraction on arterial wall stress/strain (WS/S) and vessel stiffness distributions remain unclear. Local increase of vessel stiffness resulting from wall-strain stiffening phenomenon (a local process due to the nonlinear mechanical properties of the arterial wall) may be critical in the development of atherosclerotic lesions. Therefore, the aim of this study was to quantify WS/S and stiffness in coronary bifurcations and to investigate correlations with plaque sites. Anatomic coronary geometry and cardiac motion were generated based on both computed tomography and MRI examinations of eight patients with minimal coronary disease. Computational structural analyses using the finite element method were subsequently performed, and spatial luminal arterial wall stretch (LWStretch) and stiffness (LWStiff) distributions in the left main coronary bifurcations were calculated. Our results show that all plaque sites were concomitantly subject to high LWStretch and high LWStiff, with mean amplitudes of 34.7 ± 1.6% and 442.4 ± 113.0 kPa, respectively. The mean LWStiff amplitude was found slightly greater at the plaque sites on the left main coronary artery (mean value: 482.2 ± 88.1 kPa) compared with those computed on the left anterior descending and left circumflex coronary arteries (416.3 ± 61.5 and 428.7 ± 181.8 kPa, respectively). These findings suggest that local wall stiffness plays a role in the initiation of atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

Abstract: The shape of tracheal cartilage has been widely treated as symmetric in analytical and numerical models. However, according to both histological images and in vivo medical image, tracheal cartilage is of highly asymmetric shape. Taking the cartilage as symmetric structure will induce bias in calculation of the collapse behavior, as well as compliance and muscular stress. However, this has been rarely discussed. In this paper, tracheal collapse is represented by considering its asymmetric shape. For comparison, the symmetric shape, which is reconstructed by half of the cartilage, is also presented. A comparison of cross-sectional area, compliance of airway and stress in the muscular membrane, determined by asymmetric shape and symmetric shape is made. The result indicates that the symmetric assumption brings a small error, around 5% in predicting the cross-sectional area under loading conditions. The relative error of compliance is more than 10%. Particularly when the pressure is close to zero, the error could be more than 50%. The model considering the symmetric shape results in a significant difference in predicting stress in muscular membrane by either under- or over-estimating it. In conclusion, tracheal cartilage should not be treated as a symmetric structure. The results obtained in this study are helpful in evaluating the error induced by the assumption in geometry. [Copyright &y& Elsevier]

Abstract: Background: Despite being the stiffest airway of the bronchial tree, the trachea undergoes significant deformation due to intrathoracic pressure during breathing. The mechanical properties of the trachea affect the flow in the airway and may contribute to the biological function of the lung. Method: A Fung-type strain energy density function was used to investigate the nonlinear mechanical behavior of tracheal cartilage. A bending test on pig tracheal cartilage was performed and a mathematical model for analyzing the deformation of tracheal cartilage was developed. The constants included in the strain energy density function were determined by fitting the experimental data. Result: The experimental data show that tracheal cartilage is a nonlinear material displaying higher strength in compression than in tension. When the compression forces varied from −0.02 to −0.03N and from −0.03 to −0.04N, the deformation ratios were 11.03±2.18% and 7.27±1.59%, respectively. Both were much smaller than the deformation ratios (20.01±4.49%) under tension forces of 0.02 to 0.01N. The Fung-type strain energy density function can capture this nonlinear behavior very well, whilst the linear stress–strain relation cannot. It underestimates the stability of trachea by exaggerating the displacement in compression. This study may improve our understanding of the nonlinear behavior of tracheal cartilage and it may be useful for the future study on tracheal collapse behavior under physiological and pathological conditions. [Copyright &y& Elsevier]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Despite the high success rate achieved in current dental implantation, there are still important problems to solve like incomplete early osteointegration, bone damage, and long‐term implant loosening. Highly compliant stress absorbers are a possible solution to these problems. Although several works examined the stress‐strain distribution in bone without and with absorbers to show their favorable results, none of them analyzed their impact on long‐term remodeling. Here, we analyze this effect by comparing the evolution of stress and bone mass density without and with different designs of absorbers with those of the healthy tooth. Several finite element models with ABAQUS, corresponding to each design considered, were built to obtain the mechanical conditions in bone and implant. Then a mechanobiological bone remodeling model that considers damage accumulation and its repair during the remodeling process was used to compute the bone density redistribution. This approach allows assessing both the short‐term density loss and the relative micromovement between bone and implant. We analyze the stress distributions in both bone and implant as well as the relative micromovement of the implant. We also present the evolution of damage and bone volume fraction. These results show that the addition of absorbers can reduce the stress in the bone around the implant. The obtained results also show that using stress absorbers reduces damage in bone, while increasing the number of absorbers does not necessarily improves damage reduction. We conclude that using implants with a correct design of absorbers prevents damage and stress shielding, reducing implant loosening. [ABSTRACT FROM AUTHOR]