A Fluid-Solid-Growth Solver for Cardiovascular Modeling.

We implement full, three-dimensional constrained mixture theory for vascular growth and remodeling into a finite element fluid-structure interaction (FSI) solver. The resulting "fluid-solid-growth" (FSG) solver allows long term, patient-specific predictions of changing hemodynamics, vessel wall morphology, tissue composition, and material properties. This extension from short term (FSI) to long term (FSG) simulations increases clinical relevance by enabling mechanobioloigcally-dependent studies of disease progression in complex domains.

Fast, Rate-Independent, Finite Element Implementation of a 3D Constrained Mixture Model of Soft Tissue Growth and Remodeling.

Constrained mixture models of soft tissue growth and remodeling can simulate many evolving conditions in health as well as in disease and its treatment, but they can be computationally expensive. In this paper, we derive a new fast, robust finite element implementation based on a concept of mechanobiological equilibrium that yields fully resolved solutions and allows computation of quasi-equilibrated evolutions when imposed perturbations are slow relative to the adaptive process. We demonstrate quadratic convergence and verify the model via comparisons with semi-analytical solutions for arterial mechanics. We further examine the enlargement of aortic aneurysms for which we identify new mechanobiological insights into factors that affect the nearby non-aneurysmal segment as it responds to the changing mechanics within the diseased segment. Because this new 3D approach can be implemented within many existing finite element solvers, constrained mixture models of growth and remodeling can now be used more widely.

Mechanobiological Stability of Biological Soft Tissues.

Like all other materials, biological soft tissues are subject to general laws of physics, including those governing mechanical equilibrium and stability. In addition, however, these tissues are able to respond actively to changes in their mechanical and chemical environment. There is, therefore, a pressing need to understand such processes theoretically. In this paper, we present a new rate-based constrained mixture formulation suitable for studying mechanobiological equilibrium and stability of soft tissues exposed to transient or sustained changes in material composition or applied loading. These concepts are illustrated for canonical problems in arterial mechanics, which distinguish possible stable versus unstable mechanobiological responses. Such analyses promise to yield insight into biological processes that govern both health and disease progression.

Computational Modeling Predicts Immuno-Mechanical Mechanisms of Maladaptive Aortic Remodeling in Hypertension.

Uncontrolled hypertension is a major risk factor for myriad cardiovascular diseases. Among its many effects, hypertension increases central artery stiffness which in turn is both an initiator and indicator of disease. Despite extensive clinical, animal, and basic science studies, the biochemomechanical mechanisms by which hypertension drives aortic stiffening remain unclear. In this paper, we show that a new computational model of aortic growth and remodeling can capture differential effects of induced hypertension on the thoracic and abdominal aorta in a common mouse model of disease. Because the simulations treat the aortic wall as a constrained mixture of different constituents having different material properties and rates of turnover, one can gain increased insight into underlying constituent-level mechanisms of aortic remodeling. Model results suggest that the aorta can mechano-adapt locally to blood pressure elevation in the absence of marked inflammation, but large increases in inflammation drive a persistent maladaptive phenotype characterized primarily by adventitial fibrosis. Moreover, this fibrosis appears to occur via a marked increase in the rate of deposition of collagen having different material properties in the absence of a compensatory increase in the rate of matrix degradation. Controlling inflammation thus appears to be key to reducing fibrosis, but therapeutic strategies should not compromise the proteolytic activity of the wall that is essential to mechanical homeostasis.

Strain-Level Dependent Nonequilibrium Anisotropic Viscoelasticity: Application to the Abdominal Muscle.

Soft connective tissues sustain large strains of viscoelastic nature. The rate-independent component is frequently modeled by means of anisotropic hyperelastic models. The rate-dependent component is usually modeled through linear rheological models or quasi-linear viscoelastic (QLV) models. These viscoelastic models are unable, in general, to capture the strain-level dependency of the viscoelastic properties present in many viscoelastic tissues. In linear viscoelastic models, strain-level dependency is frequently accounted for by including the dependence of multipliers of Prony series on strains through additional evolution laws, but the determination of the material parameters is a difficult task and the obtained accuracy is usually not sufficient. In this work, we introduce a model for fully nonlinear viscoelasticity in which the instantaneous and quasi-static behaviors are exactly captured and the relaxation curves are predicted to a high accuracy. The model is based on a fully nonlinear standard rheological model and does not necessitate optimization algorithms to obtain material parameters. Furthermore, in contrast to most models used in modeling the viscoelastic behavior of soft tissues, it is valid for the large deviations from thermodynamic equilibrium typically observed in soft tissues.

Remodeling of the uterine artery during and early after pregnancy in the mouse.

Pregnancy associates with dramatic changes in maternal cardiovascular physiology that ensure that the utero-placental circulation can support the developing fetus. Particularly striking is the marked flow-induced remodeling of uterine arteries during pregnancy and their recovery following birth. Whereas details are available in the literature on alterations in hemodynamics within and changes in the dimensions of uterine arteries during and following pregnancy in mice, we report here the first biaxial biomechanical phenotyping of these arteries during this dynamic period of growth and remodeling (G&R). To gain additional insight into the measured G&R, we also use a computational constrained mixture model to describe and predict findings, including simulations related to complications that may arise during pregnancy. It is found that dramatic pregnancy-induced remodeling of the uterine artery is largely, but not completely, reversed in the postpartum period, which appears to be driven by increases in collagen turnover among other intramural changes. By contrast, data on the remodeling of the ascending aorta, an elastic artery, reveal modest changes that are fully recovered postpartum. There is strong motivation to continue biomechanical studies on this critical aspect of women's health, which has heretofore not received appropriate consideration from the biomechanics community.

Functional outcomes after arthroscopic double button fixation of distal clavicular fractures in athletes.

Distal third clavicle fractures are a frequent pathology in young, active patients, accounting for 30% of all clavicle fractures. There are several treatments available, which range from orthopedic management to surgical treatment with various options including: locking plates, tension bands and button fixation. The aim of this study was to evaluate the clinical and radiologic results of a group of patients treated with the arthroscopic double button fixation technique and, secondly, to analyze the complications and the rate of return to sports. METHODS: Nineteen patients (15 male and 4 Female) with a mean age of 38.2 years (21-64) were included. In all cases, an arthroscopic surgery with double button fixation of the distal third of the clavicle was performed. Functional Outcomes were evaluated with the visual analog scale (VAS) for pain, the American Shoulder and Elbow Surgeons scale (ASES) for functional outcomes. Range of Motion (ROM) was also assessed. RESULTS: The mean follow up was 27.3 months (12 to 54 months). The mean VAS was 0.63 and the mean ASES score was 94.1. The ROM was fully recovered in 17 patients (89,4%). All patients returned to regular sports practice at 3.5 months. Finally, a total of 2 complications were registered (11,6%). CONCLUSION: The arthroscopic double button fixation of distal clavicular fractures is a safety and reliable procedure, and it is associated with favorable functional and radiological outcomes in most patients.

An inverse fitting strategy to determine the constrained mixture model parameters: application in patient-specific aorta.

The Constrained Mixture Model (CMM) is a novel approach to describe arterial wall mechanics, whose formulation is based on a referential physiological state. The CMM considers the arterial wall as a mixture of load-bearing constituents, each of them with characteristic mass fraction, material properties, and deposition stretch levels from its stress-free state to the in-vivo configuration. Although some reports of this model successfully assess its capabilities, they barely explore experimental approaches to model patient-specific scenarios. In this sense, we propose an iterative fitting procedure of numerical-experimental nature to determine material parameters and deposition stretch values. To this end, the model has been implemented in a finite element framework, and it is calibrated using reported experimental data of descending thoracic aorta. The main results obtained from the proposed procedure consist of a set of material parameters for each constituent. Moreover, a relationship between deposition stretches and residual strain measurements (opening angle and axial stretch) has been numerically proved, establishing a strong consistency between the model and experimental data.

A multiscale computational model of arterial growth and remodeling including Notch signaling.

Blood vessels grow and remodel in response to mechanical stimuli. Many computational models capture this process phenomenologically, by assuming stress homeostasis, but this approach cannot unravel the underlying cellular mechanisms. Mechano-sensitive Notch signaling is well-known to be key in vascular development and homeostasis. Here, we present a multiscale framework coupling a constrained mixture model, capturing the mechanics and turnover of arterial constituents, to a cell-cell signaling model, describing Notch signaling dynamics among vascular smooth muscle cells (SMCs) as influenced by mechanical stimuli. Tissue turnover was regulated by both Notch activity, informed by in vitro data, and a phenomenological contribution, accounting for mechanisms other than Notch. This novel framework predicted changes in wall thickness and arterial composition in response to hypertension similar to previous in vivo data. The simulations suggested that Notch contributes to arterial growth in hypertension mainly by promoting SMC proliferation, while other mechanisms are needed to fully capture remodeling. The results also indicated that interventions to Notch, such as external Jagged ligands, can alter both the geometry and composition of hypertensive vessels, especially in the short term. Overall, our model enables a deeper analysis of the role of Notch and Notch interventions in arterial growth and remodeling and could be adopted to investigate therapeutic strategies and optimize vascular regeneration protocols.

Anterior Center-Edge Angle Is Less Reliable Than Anterior Wall Index to Predict Anterior Coverage of the Femoral Head.

BACKGROUND: No consensus is available regarding which radiographic measurement most accurately correlates with anterior coverage of the femoral head. PURPOSE: (1) To determine the correlation between 2 measurements of anterior wall coverage: total anterior coverage (TAC) calculated from radiographs and equatorial anterior acetabular sector angle (eAASA) calculated from computed tomography (CT) scans; (2) to define the correlation between anterior center-edge angle (ACEA) and anterior wall index (AWI) with TAC and eAASA; and (3) to investigate what other radiographic metrics may help predict anterior coverage. STUDY DESIGN: Cohort study (Diagnosis); Level of evidence, 3. METHODS: The authors retrospectively reviewed 77 hips (48 patients) for which radiographs and CT scans were obtained for reasons other than hip-related pain. Mean age of the population was 62 ± 22 years; 48 (62%) hips were from female patients. Two observers measured lateral center-edge angle (LCEA), AWI, Tönnis angle, ACEA, CT-based pelvic tilt, and CT-based acetabular version, with all Bland-Altman plots within 95% agreement. Correlation between intermethod measurements was estimated with a Pearson coefficient. Linear regression was used to test the ability of baseline radiographic measurements to predict both TAC and eAASA. RESULTS: Pearson coefficients were r = 0.164 (ACEA vs TAC; P = .155), r = 0.170 (ACEA vs eAASA; P = .140), r = 0.58 (AWI vs TAC; P = .0001), and r = 0.693 (AWI vs eAASA; P < .0001). Multiple linear regression model 1 showed that AWI (ß = 17.8; 95% CI, 5.7 to 29.9; P = .004), CT acetabular version (ß = -0.45; 95% CI, -0.71 to -0.22; P = .001), and LCEA (ß = 0.33; 95% CI, 0.19 to 0.47; P = .001) were useful to predict TAC. Multiple linear regression model 2 revealed that AWI (ß = 25; 95% CI, 15.67 to 34.4; P = .001), CT acetabular version (ß = -0.48; 95% CI, -0.67 to -0.29; P = .001), CT pelvic tilt (ß = 0.26; 95% CI, 0.12 to 0.4; P = .001), and LCEA (ß = 0.21; 95% CI, 0.1 to 0.3; P = .001) accurately predicted eAASA. Model-based estimates and 95% CIs using 2000 bootstrap samples from the original data were 6.16 to 28.6 for AWI in model 1 and 15.1 to 34.26 for AWI in model 2. CONCLUSION: There was a moderate to strong correlation between AWI and both TAC and eAASA, whereas ACEA correlated weakly with the former measurements, thus not being useful to quantify anterior acetabular coverage. Other variables such as LCEA, acetabular version, and pelvic tilt may also help predict anterior coverage in asymptomatic hips.

In vivo development of tissue engineered vascular grafts: a fluid-solid-growth model.

Methods of tissue engineering continue to advance, and multiple clinical trials are underway evaluating tissue engineered vascular grafts (TEVGs). Whereas initial concerns focused on suture retention and burst pressure, there is now a pressing need to design grafts to have optimal performance, including an ability to grow and remodel in response to changing hemodynamic loads. Toward this end, there is similarly a need for computational methods that can describe and predict the evolution of TEVG geometry, composition, and material properties while accounting for changes in hemodynamics. Although the ultimate goal is a fluid-solid-growth (FSG) model incorporating fully 3D growth and remodeling and 3D hemodynamics, lower fidelity models having high computational efficiency promise to play important roles, especially in the design of candidate grafts. We introduce here an efficient FSG model of in vivo development of a TEVG based on two simplifying concepts: mechanobiologically equilibrated growth and remodeling of the graft and an embedded control volume analysis of the hemodynamics. Illustrative simulations for a model Fontan conduit reveal the utility of this approach, which promises to be particularly useful in initial design considerations involving formal methods of optimization which otherwise add considerably to the computational expense.

Neural operator learning of heterogeneous mechanobiological insults contributing to aortic aneurysms.

Thoracic aortic aneurysm (TAA) is a localized dilatation of the aorta that can lead to life-threatening dissection or rupture. In vivo assessments of TAA progression are largely limited to measurements of aneurysm size and growth rate. There is promise, however, that computational modelling of the evolving biomechanics of the aorta could predict future geometry and properties from initiating mechanobiological insults. We present an integrated framework to train a deep operator network (DeepONet)-based surrogate model to identify TAA contributing factors using synthetic finite-element-based datasets. For training, we employ a constrained mixture model of aortic growth and remodelling to generate maps of local aortic dilatation and distensibility for multiple TAA risk factors. We evaluate the performance of the surrogate model for insult distributions varying from fusiform (analytically defined) to complex (randomly generated). We propose two frameworks, one trained on sparse information and one on full-field greyscale images, to gain insight into a preferred neural operator-based approach. We show that this continuous learning approach can predict the patient-specific insult profile associated with any given dilatation and distensibility map with high accuracy, particularly when based on full-field images. Our findings demonstrate the feasibility of applying DeepONet to support transfer learning of patient-specific inputs to predict TAA progression.

Adverse Local Tissue Reaction Associated With Ceramic-On-Metal Bearing Surface in Primary Total Hip Arthroplasty: Report of Two Cases.

Total hip arthroplasty (THA) is one of the most common and successful surgical procedures worldwide. At the same time, it is constantly evolving, and as a consequence, advances in implant technology have led to significant improvements in the different materials of the acetabular and femoral components. The selection of bearing surfaces and their tribology are critical to achieving a successful outcome. Pseudotumors are important, and usually misdiagnosed, complications associated with hard bearing surfaces such as metal-on-metal couples. They belong to a group of reactions called adverse local tissue reaction, which can occur in the vicinity of any THA. We present 2 cases of adverse local tissue reaction associated with the use of ceramic-on-metal bearings surfaces in 2 primary THAs that were treated with modular component exchange during single-stage revision surgery. Level of Evidence: IV.

[Septic hip arthritis after a closed acetabulum fracture treated conservatively. Case report]. / Artritis séptica de cadera luego de una fractura cerrada de acetábulo tratada en forma conservadora. Reporte de caso.

Necrotizing fasciitis is a life-threatening infection. Inmediate diagnosis and treatment are essential. Acetabulum fractures are a frequent identity in older adults today, associated with low-energy trauma. The indication for surgical or conservative treatment depends on multiple factors such as the age and comorbidities of the patient, the type and location of the fracture, and the socio-economic environment. We described an unusual case of infected hematoma, secondary to a closed acetabulum fracture, which led to septic arthritis of the hip joint.

Las fracturas de acetábulo asociadas a traumatismos de baja energía, son una identidad frecuente hoy en día en los adultos mayores. La indicación del tratamiento quirúrgico o conservador, depende de múltiples factores como la edad y las comorbilidades del paciente, el tipo y localización de la fractura, y el medio socio-económico. Independientemente del tratamiento elegido, ninguno está exento de complicaciones. Se describe a continuación un paciente con una fractura de acetábulo cerrada, de tratamiento conservador, que derivó en artritis séptica de la articulación coxofemoral.

From Transcript to Tissue: Multiscale Modeling from Cell Signaling to Matrix Remodeling.

Tissue-level biomechanical properties and function derive from underlying cell signaling, which regulates mass deposition, organization, and removal. Here, we couple two existing modeling frameworks to capture associated multiscale interactions-one for vessel-level growth and remodeling and one for cell-level signaling-and illustrate utility by simulating aortic remodeling. At the vessel level, we employ a constrained mixture model describing turnover of individual wall constituents (elastin, intramural cells, and collagen), which has proven useful in predicting diverse adaptations as well as disease progression using phenomenological constitutive relations. Nevertheless, we now seek an improved mechanistic understanding of these processes; we replace phenomenological relations in the mixture model with a logic-based signaling model, which yields a system of ordinary differential equations predicting changes in collagen synthesis, matrix metalloproteinases, and cell proliferation in response to altered intramural stress, wall shear stress, and exogenous angiotensin II. This coupled approach promises improved understanding of the role of cell signaling in achieving tissue homeostasis and allows us to model feedback between vessel mechanics and cell signaling. We verify our model predictions against data from the hypertensive murine infrarenal abdominal aorta as well as results from validated phenomenological models, and consider effects of noisy signaling and heterogeneous cell populations.

Complementary roles of mechanotransduction and inflammation in vascular homeostasis.

Arteries are exposed to relentless pulsatile haemodynamic loads, but via mechanical homeostasis they tend to maintain near optimal structure, properties and function over long periods in maturity in health. Numerous insults can compromise such homeostatic tendencies, however, resulting in maladaptations or disease. Chronic inflammation can be counted among the detrimental insults experienced by arteries, yet inflammation can also play important homeostatic roles. In this paper, we present a new theoretical model of complementary mechanobiological and immunobiological control of vascular geometry and composition, and thus properties and function. We motivate and illustrate the model using data for aortic remodelling in a common mouse model of induced hypertension. Predictions match the available data well, noting a need for increased data for further parameter refinement. The overall approach and conclusions are general, however, and help to unify two previously disparate literatures, thus leading to deeper insight into the separate and overlapping roles of mechanobiology and immunobiology in vascular health and disease.

[Denosumab as a treatment for giant cell tumor of bone. Indications, results and side effects]. / Denosumab como tratamiento neoadyuvante del tumor de células gigantes del hueso. Indicaciones, resultados y efectos adversos.

Giant cell tumor of bone is an intermediate, locally aggressive and rarely metastasizing, primary bone neoplasia. In recent years denosumab emerged as a treatment alternative for this pathology. The objective of this work was to analyze its indications as well as the clinical outcomes, side effects and local recurrence rates in patients diagnosed with giant cell tumor of bone, who received denosumab as neoadjuvant treatment. Between 2010 and 2018, 80 patients with giant cell tumor were analyzed, of whom 14 received denosumab as a neoadjuvant treatment. The minimum follow-up was 12 months. In 8 patients it was a primary tumor, while 6 showed tumor recurrence. In all cases, clinical improvement was evident. Thirteen patients presented radiographic changes, and 11 showed complete histological response. A local recurrence was evidenced in 6 of 14 patients, and at least one adverse effect related to denosumab (including tumor malignancy) was identified in 7. Despite being a useful tool for treating giant cell tumor, the use of denosumab is associated with a higher rate of local recurrences and is not free of adverse effects.

El tumor de células gigantes óseo es una neoplasia de agresividad local intermedia, que raramente metastatiza. En los últimos años el denosumab, anticuerpo monoclonal humano, surgió como una alternativa de tratamiento para esta enfermedad, al bloquear el comportamiento lítico tumoral. El objetivo de este trabajo fue determinar sus indicaciones y efectos adversos, analizando también los resultados oncológicos, y las tasas de recurrencia local en pacientes con diagnóstico de tumor de células gigantes óseo que recibieron denosumab como tratamiento neoadyuvante. Entre 2010 y 2018 se analizaron 80 pacientes con tumor de células gigantes, de los cuales 14 recibieron denosumab como tratamiento neoadyuvante. El seguimiento mínimo fue 12 meses. En 8 pacientes se trató de un tumor primario, mientras que 6 fueron pacientes con recidiva tumoral. En todos los casos se evidenció una mejoría clínica. Trece presentaron cambios radiográficos, y 11 respuesta histológica completa. En 6 de 14 pacientes se evidenció una recurrencia local y en 7 se identificó al menos un efecto adverso relacionado con el denosumab (incluyendo una malignización tumoral). A pesar de ser una herramienta útil para el tratamiento del tumor de células gigantes, el uso de denosumab está asociado a mayor tasa de recurrencias locales y no está exento de efectos adversos.

Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice.

Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.

Vascular adaptation in the presence of external support - A modeling study.

Vascular grafts have long been used to replace damaged or diseased vessels with considerable success, but a new approach is emerging where native vessels are merely supported, not replaced. Although external supports have been evaluated in diverse situations - ranging from aneurysmal disease to vein grafts or the Ross operation - optimal supports and procedures remain wanting. In this paper, we present a novel application of a growth and remodeling model well suited for parametrically exploring multiple designs of external supports while accounting for mechanobiological and immunobiological responses of the supported native vessel. These results suggest that a load bearing external support can reduce vessel thickening in response to pressure elevation. Results also suggest that the final adaptive state of the vessel depends on the structural stiffness of the support via a mechano-driven adaptation, although luminal encroachment may be a complication in the presence of chronic inflammation. Finally, the supported vessel can stiffen (structurally and materially) along circumferential and axial directions, which could have implications on overall hemodynamics and thus subsequent vascular remodeling. The proposed framework can provide valuable insights into vascular adaptation in the presence of external support, accelerate rational design, and aid translation of this emerging approach.

Mechanics-driven mechanobiological mechanisms of arterial tortuosity.

Arterial tortuosity manifests in many conditions, including hypertension, genetic mutations predisposing to thoracic aortopathy, and vascular aging. Despite evidence that tortuosity disrupts efficient blood flow and that it may be an important clinical biomarker, underlying mechanisms remain poorly understood but are widely appreciated to be largely biomechanical. Many previous studies suggested that tortuosity may arise via an elastic structural buckling instability, but the novel experimental-computational approach used here suggests that tortuosity arises from mechanosensitive, cell-mediated responses to local aberrations in the microstructural integrity of the arterial wall. In particular, computations informed by multimodality imaging show that aberrations in elastic fiber integrity, collagen alignment, and collagen turnover can lead to a progressive loss of structural stability that entrenches during the development of tortuosity. Interpreted in this way, microstructural defects or irregularities of the arterial wall initiate the condition and hypertension is a confounding factor.