Duchenne and Becker muscular dystrophy: Cellular mechanisms, image analysis, and computational models: A review.

The muscle is the principal tissue that is capable to transform potential energy into kinetic energy. This process is due to the transformation of chemical energy into mechanical energy to enhance the movements and all the daily activities. However, muscular tissues can be affected by some pathologies associated with genetic alterations that affect the expression of proteins. As the muscle is a highly organized structure in which most of the signaling pathways and proteins are related to one another, pathologies may overlap. Duchenne muscular dystrophy (DMD) is one of the most severe muscle pathologies triggering degeneration and muscle necrosis. Several mathematical models have been developed to predict muscle response to different scenarios and pathologies. The aim of this review is to describe DMD and Becker muscular dystrophy in terms of cellular behavior and molecular disorders and to present an overview of the computational models implemented to understand muscle behavior with the aim of improving regenerative therapy.

Non-destructive Characterization of Skeletal Muscle Extracellular Matrix Morphology by Combining Optical Coherence Tomography (OCT) Imaging with Tissue Clearing.

Histology is an essential step to visualize and analyze the microstructure of any biological tissue; however, histological processing is often irreversible, and histological samples are unable to be imaged or tested further. In this work, a novel non-destructive protocol is proposed for morphological analysis of skeletal muscles, combining Optical Coherence Tomography (OCT) imaging with Tissue Clearing. Imaging combining OCT and Propylene Glycol (PG) as a tissue-clearing agent, was performed on rat tail and extensor digitorum longus (EDL) muscle. The results show that the extracellular matrix morphology of skeletal muscles, including muscular fibers and the whole microstructure architecture were clearly identified. PG improved OCT imaging as measured by image quality metric Contrast Per Pixel CPP (increases by 3.9%), Naturalness Image Quality Evaluator NIQE (decreases by 23%), and Volume of Interest VOI size (higher for CPP and lower for NIQE values). The tendon microstructure was observed with less precision, as collagen fibers could not be clearly detected. The reversibility of the optical effects of the PG on the immersed tissue (in a Phosphate-Buffered Saline solution) was studied comparing native and rehydrated OCT image acquisition from a single EDL sample. Optical properties and microstructure visibility (CPP and NIQE) have been recovered to 99% of the native sample values. Moreover, clearing process caused shrinkage of the tissue recovered to 86% of the original width. Future work will aim to employ the proposed experimental protocol to identify the local mechanical properties of biological tissues.

Influence of growth plate morphology on bone trabecular groups, a framework computational approach.

The morphology of the growth plate undergoes various transformations during each stage of development, affecting its shape, width, density, and other characteristics. This significantly impacts the distribution of stress in the epiphysis of long bones. To the best of our knowledge, this study represents the first attempt to examine the relationship between growth plate morphology and trabecular bone patterns. Our analysis was conducted using a finite element model and we analyzed two medical cases: trabecular patterns in the femoral epiphysis and the calcaneus bone. Our findings revealed a correlation between the formation of main trabecular groups and growth plate morphology. We investigated how an increased density in high-shear stress zones, which are typically located at the periphery of the growth plate, may occur to prevent failure by shear. This is evident in cases such as slipped capital femoral epiphysis or sever's disease, different simulations align with the clinical data available in the literature from a qualitative and quantitative point of view. Our results suggest that further research should focus on understanding the impact of growth plate morphology on bone remodeling and exploring potential preventive measures for different bone disorders.

A unified framework of cell population dynamics and mechanical stimulus using a discrete approach in bone remodelling.

Multiphysics models have become a key tool in understanding the way different phenomenon are related in bone remodeling and various approaches have been proposed, yet, to the best of the author's knowledge there is no model able to link a cell population model with a mechanical stimulus model using a discrete approach, which allows for an easy implementation. This article couples two classical models, the cell population model from Komarova and the Nackenhorst model in a 2D domain, where correlations between the mechanical loading and the cell population dynamics can be established, furthermore the effect of different paracrine and autocrine regulators is seen on the overall density of a portion of trabecular bone. A discretization is performed using frame 1D finite elements, representing the trabecular structure. The Nackenhorst model is implemented by using the finite element method to calculate the strain energy as the main mechanical stimulus that determines the bone mass density evolution in time. This density is normalized to be added to the bone mass percentage proposed by the Komarova model, where coupling terms have been added as well that guarantee a stable response. In the simulations, the equations were solved employing the finite element method with a user subroutine implemented in ABAQUS (2017) and by applying a direct formulation. The methodology presented can model the cell dynamics occurring in bone remodelling in accordance with the asynchronous nature of this process, yet allowing to differentiate zones with higher density, the main trabecular groups are obtained for the proximal femur. Finally, the model is tested in pathological cases, such as osteoporosis and osteopetrosis, yielding results similar to the pathology behavior. Furthermore, the discrete modelling technique is shown to be of use in this particular application.

A simple and effective 1D-element discrete-based method for computational bone remodeling.

In-silico models applied to bone remodeling are widely used to investigate bone mechanics, bone diseases, bone-implant interactions, and also the effect of treatments of bone pathologies. This article proposes a new methodology to solve the bone remodeling problem using one-dimensional (1D) elements to discretize trabecular structures more efficiently for 2D and 3D domains. An Euler integration scheme is coupled with the momentum equations to obtain the evolution of material density at each step. For the simulations, the equations were solved by using the finite element method, and two benchmark tests were solved varying mesh parameters. Proximal femur and calcaneus bone were selected as study cases given the vast research available on the topology of these bones, and compared with the anatomical features of trabecular bone reported in the literature. The presented methodology has proven to be efficient in optimizing topologies of lattice structures; It can predict the trend of formation patterns of the main trabecular groups from two different cancellous bones (femur and calcaneus) using domains set up by discrete elements as a starting point. Preliminary results confirm that the proposed approach is suitable and useful in bone remodeling problems leading to a considerable computational cost reduction. Characteristics similar to those encountered in topological optimization algorithms were identified in the benchmark tests as well, showing the viability of the proposed approach in other applications such as bio-inspired design.

In vitro histomechanical effects of enzymatic degradation in carotid arteries during inflation tests with pulsatile loading.

In this paper, the objective is to assess the histomechanical effects of collagen proteolysis in arteries under loading conditions reproducing in vivo environment. Thirteen segments of common porcine carotid arteries (8 proximal and 5 distal) were immersed in a bath of bacterial collagenase and tested with a pulsatile tension/inflation machine. Diameter, pressure and axial load were monitored throughout the tests and used to derive the stress-stretch curves and to determine the secant circumferential stiffness. Results were analysed separately for proximal and distal segments, before and after 1, 2 and 3 h of enzymatic degradation. A histological analysis was performed to relate the arterial microstructure to its mechanical behavior under collagen proteolysis. Control (before enzymatic degradation) and treated populations (after 1, 2 or 3 h of enzymatic degradation) were found statistically incomparable, and histology confirmed the alteration of the fibrous structure of collagen bundles induced by the collagenase treatment. A decrease of the secant circumferential stiffness of the arterial wall was noticed mostly at the beginning of the treatment, and was less pronounced after 1 h. These results constitute an important set of enzymatically damaged arteries that can be used to validate biomechanical computational models correlating structure and properties of blood vessels.

Identifying Local Arterial Stiffness to Assess the Risk of Rupture of Ascending Thoracic Aortic Aneurysms.

It was recently submitted that the rupture risk of an ascending thoracic aortic aneurysm (ATAA) is strongly correlated with the aortic stiffness. To validate this assumption, we propose a non-invasive inverse method to identify the patient-specific local extensional stiffness of aortic walls based on gated CT scans. Using these images, the local strain distribution is reconstructed throughout the cardiac cycle. Subsequently, obtained strains are related to tensions, through local equilibrium equations, to estimate the local extensional stiffness at every position. We apply the approach on 11 patients who underwent a gated CT scan before surgical ATAA repair and whose ATAA tissue was tested after the surgical procedure to estimate the rupture risk criterion. We find a very good correlation between the rupture risk criterion and the local extensional stiffness. Finally it is shown that patients can be separated in two groups: a group of stiff and brittle ATAA with a rupture risk criterion above 0.9, and a group of relatively compliant ATAA with a rupture risk below 0.9. Although these results need to be repeated on larger cohorts to impact the clinical practice, they support the paradigm that local aortic stiffness is an important determinant of ATAA rupture risk.

Inverse identification of local stiffness across ascending thoracic aortic aneurysms.

Aortic dissection is the most common catastrophe of the thoracic aorta, with a very high rate of mortality. Type A dissection is often associated with an ascending thoracic aortic aneurysm (ATAA). However, it is widely acknowledged that the risk of type A dissection cannot be reliably predicted simply by measuring the ATAA diameter and there is a pressing need for more reliable risk predictors. It was previously shown that there is a significant correlation between a rupture criterion based on the ultimate stretch of the ATAA and the local extensional stiffness of the aorta. Therefore, reconstructing regional variations of the extensional stiffness across the aorta appears highly important. In this paper, we present a novel noninvasive inverse method to identify the patient-specific local extensional stiffness of aortic walls based on preoperative gated CT scans. Using these scans, a structural mesh is defined across the aorta with a set of nodes attached to the same material points at different time steps throughout the cardiac cycle. For each node, time variations of the position are analyzed using Fourier series, permitting the reconstruction of the local strain distribution (fundamental term). Relating these strains to tensions with the extensional stiffness, and writing the local equilibrium satisfied by the tensions, the local extensional stiffness is finally derived at every position. The methodology is applied onto the ascending and descending aorta of three patients. Interestingly, the regional distribution of identified stiffness properties appears heterogeneous across the ATAA. Averagely, the identified stiffness is also compared with values obtained using other nonlocal methodologies. The results support the possible noninvasive prediction of stretch-based rupture criteria in clinical practice using local stiffness reconstruction.

Biaxial rupture properties of ascending thoracic aortic aneurysms.

UNLABELLED: Although hundreds of samples obtained from ascending thoracic aortic aneurysms (ATAA) of patients undergoing elective surgical repair have already been characterized biomechanically, their rupture properties were always derived from uniaxial tensile tests. Due to their bulge shape, ATAAs are stretched biaxially in vivo. In order to understand the biaxial rupture of ATAAs, our group developed a novel methodology based on bulge inflation and full-field optical measurements. The objective of the current paper is threefold. Firstly, we will review the failure properties (maximum stress, maximum stretch) obtained by bulge inflation testing on a cohort of 31 patients and compare them with failure properties obtained by uniaxial tension in a previously published study. Secondly, we will investigate the relationship between the failure properties and the age of patients, showing that patients below 55years of age display significantly higher strength. Thirdly, we will define a rupture risk based on the extensibility of the tissue and we will show that this rupture risk is strongly correlated with the physiological elastic modulus of the tissue independently of the age, ATAA diameter or the aortic valve phenotype of the patient. STATEMENT OF SIGNIFICANCE: Despite their medical importance, rupture properties of ascending thoracic aortic aneurysms (ATAA) subjected to biaxial tension were inexistent in the literature. In order to address this lack, our group developed a novel methodology based on bulge inflation and full-field optical measurements. Here we report rupture properties obtained with this methodology on 31 patients. It is shown for the first time that rupture occurs when the stretch applied to ATAAs reaches the maximum extensibility of the tissue and that this maximum extensibility correlates strongly with the elastic properties. The outcome is a better detection of at-risk individuals for elective surgical repair.

Predictive Models with Patient Specific Material Properties for the Biomechanical Behavior of Ascending Thoracic Aneurysms.

The aim of this study is to identify the patient-specific material properties of ascending thoracic aortic aneurysms (ATAA) using preoperative dynamic gated computed tomography (CT) scans. The identification is based on the simultaneous minimization of two cost functions, which define the difference between model predictions and gated CT measurements of the aneurysm volume at respectively systole and cardiac mid-cycle. The method is applied on five patients who underwent surgical repair of their ATAA at the University Hospital Center of St. Etienne. For these patients, the aneurysms were collected and tested mechanically using an in vitro bench. For the sake of validation, the mechanical properties found using the in vivo approach and the in vitro bench were compared. We eventually performed finite-element stress analyses based on each set of material properties. Rupture risk indexes were estimated and compared, showing promising results of the patient-specific identification method based on gated CT.

Patient specific stress and rupture analysis of ascending thoracic aneurysms.

An ascending thoracic aortic aneurysm (ATAA) is a serious medical condition which, more often than not, requires surgery. Aneurysm diameter is the primary clinical criterion for determining when surgical intervention is necessary but, biomechanical studies have suggested that the diameter criterion is insufficient. This manuscript presents a method for obtaining the patient specific wall stress distribution of the ATAA and the retrospective rupture risk for each patient. Five human ATAAs and the preoperative dynamic CT scans were obtained during elective surgeries to replace each patient's aneurysm with a synthetic graft. The material properties and rupture stress for each tissue sample were identified using bulge inflation tests. The dynamic CT scans were used to generate patient specific geometries for a finite element (FE) model of each patient's aneurysm. The material properties from the bulge inflation tests were implemented in the FE model and the wall stress distribution at four different pressures was estimated. Three different rupture risk assessments were compared: the maximum diameter, the rupture risk index, and the overpressure index. The peak wall stress values for the patients ranged from 28% to 94% of the ATAA's failure stress. The rupture risk and overpressure indices were both only weakly correlated with diameter (ρ=-0.29, both cases). In the future, we plan to conduct a large experimental and computational study that includes asymptomatic patients under surveillance, patients undergoing elective surgery, and patients who have experienced rupture or dissection to determine if the rupture risk index or maximum diameter can meaningfully differentiate between the groups.

Anisotropic material behaviours of soft tissues in human trachea: an experimental study.

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.

Surgical planning and patient-specific biomechanical simulation for tracheal endoprostheses interventions.

We have developed a system for computer-assisted surgical planning of tracheal surgeries. The system allows to plan the intervention based on CT images of the patient, and includes a virtual database of commercially available prostheses. Automatic segmentation of the trachea and apparent pathological structures is obtained using a modified region growing algorithm. A method for automatic adaptation of a finite element mesh allows to build a patient-specific biomechanical model for simulation of the expected performance of the implant under physiological movement (swallowing, sneezing). Laboratory experiments were performed to characterise the tissues present in the trachea, and movement models were obtained from fluoroscopic images of a patient. Results are reported on the planning and biomechanical simulation of two patients that underwent surgery at our hospital.