ABSTRACT
BACKGROUND: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear. METHODS: We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16-20 weeks. RESULTS: DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs. CONCLUSION: We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.
Subject(s)
Atherosclerosis , Insulin Resistance , Plaque, Atherosclerotic , Animals , Humans , Mice , Atherosclerosis/genetics , Atherosclerosis/prevention & control , Cholesterol , Disease Models, Animal , Inflammation/genetics , Inflammation/metabolism , Matrix Metalloproteinase 12/genetics , Mice, Inbred C57BL , Mice, Knockout , Proteomics , Receptors, LDL/geneticsABSTRACT
BACKGROUND: Suture anchors (SAs) made of human allogenic mineralized cortical bone matrix are among the newest developments in orthopaedic and trauma surgery. Biomechanical properties of an allogenic mineralized suture anchor (AMSA) are not investigated until now. The primary objective was the biomechanical investigation of AMSA and comparing it to a metallic suture anchor (MSA) and a bioabsorbable suture anchor (BSA) placed at the greater tuberosity of the humeral head of cadaver humeri. Additionally, we assessed the biomechanical properties of the SAs with bone microarchitecture parameters. METHODS: First, bone microarchitecture of 12 fresh frozen human cadaver humeri from six donors was analyzed by high-resolution peripheral quantitative computed tomography. In total, 18 AMSAs, 9 MSAs, and 9 BSAs were implanted at a 60° angle. All three SA systems were systematically implanted alternating in three positions within the greater tuberosity (position 1: anterior, position 2: central, position 3: posterior) with a distance of 15 mm to each other. Biomechanical load to failure was measured in a uniaxial direction at 135°. RESULTS: Mean age of all specimens was 53.6 ± 9.1 years. For all bone microarchitecture measurements, linear regression slope estimates were negative which implies decreasing values with increasing age of specimens. Positioning of all three SA systems at the greater tuberosity was equally distributed (p = 0.827). Mean load to failure rates were higher for AMSA compared to MSA and BSA without reaching statistical significance between the groups (p = 0.427). Anchor displacement was comparable for all three SA systems, while there were significant differences regarding failure mode between all three SA systems (p < 0.001). Maximum load to failure was reached in all cases for AMSA, in 44.4% for MSA, and in 55.6% for BSA. Suture tear was observed in 55.6% for MSA and in 22.2% for BSA. Anchor breakage was solely seen for BSA (22.2%). No correlations were observed between bone microarchitecture parameters and load to failure rates of all three suture anchor systems. CONCLUSIONS: The AMSA showed promising biomechanical properties for initial fixation strength for RCR. Since reduced BMD is an important issue for patients with chronic rotator cuff lesions, the AMSA is an interesting alternative to MSA and BSA. Also, the AMSA could improve healing of the enthesis.
Subject(s)
Rotator Cuff Injuries , Suture Anchors , Adult , Amsacrine , Biomechanical Phenomena , Cadaver , Cortical Bone , Humans , Middle Aged , Rotator Cuff/diagnostic imaging , Rotator Cuff/surgery , Rotator Cuff Injuries/diagnostic imaging , Rotator Cuff Injuries/surgery , Suture TechniquesABSTRACT
BACKGROUND: Arterial compliance assists the cardiovascular system with three key roles: (i) storing up to 50% of the stroke volume; (ii) ensuring blood flow during diastole; (iii) dampening pressure oscillations through arterial distension. In mock circulation loops (MCLs), arterial compliance was simulated either with membrane, spring, or Windkessel chambers. Although they have been shown to be suitable for cardiac device testing, their passive behavior can limit stress-based testing of arteries. Here we present an active compliance chamber with a feedback control of variable compliance as part of an MCL designed for biomechanical evaluation of arteries under physiological waveforms. MATERIALS AND METHODS: The chamber encloses a piston that changes the volume via a cascaded controller when there is a difference between the real-time pressure and the physiological reference pressure with the aim to equilibrate both pressures. RESULTS: The experimental results showed repeatable physiological waveforms of aortic pressure in health (80-120 mm Hg), systemic hypertension (90-153 mm Hg), and heart failure reduced ejection fraction (78-108 mm Hg). Statistical validation (n = 20) of the function of the chamber is presented against compared raw data. CONCLUSION: We demonstrate that the active compliance chamber can track the actual pressure of the MCL and balance it in real time (every millisecond) with the reference values in order to shape the given pressure waveform. The active compliance chamber is an advanced tool for MCL applications for biomechanical examination of stented arteries and for preclinical evaluation of vascular implants.
Subject(s)
Arteries/physiology , Blood Pressure/physiology , Models, Cardiovascular , Cardiovascular Physiological Phenomena , Compliance , Hemodynamics , HumansABSTRACT
BACKGROUND: Esophageal biomechanical studies are important to understand structural changes resulting from stretches during repair of esophageal atresias as well as to obtain values to compare with the biomechanics of tissue-engineered esophagus in the future. This study aimed to investigate light microscopic changes after uniaxial stretching of the ovine esophagus. METHODS: In vitro uniaxial stretching was performed on esophagi (n = 20) of 1-month-old lambs within 4-6 h post-mortem. Esophagi were divided into 5 groups: control and stretched (1.1, 1.2, 1.3 and 1.4). Force and lengthening were measured with 5 cycles performed on every specimen using a PBS organ bath at 37 °C. Histological studies were performed on the 5 groups. RESULTS: Low forces of ~ 2 N (N) were sufficient for a 1.2-1.25 stretch in the 1st cycle, whereas a three times higher force (~ 6 N) was needed for a stretch of 1.3. In the 2nd to 5th cycle, the tissue weakened and a force of ~ 3 N was sufficient for a stretch of 1.3. Histologically, in the 1.3-1.4 stretch groups, rupture of muscle fibers and capillaries were observed, respectively. Changes in mucosa and collagen fibers could not be observed. CONCLUSIONS: These results offer norm values from the native esophagus to compare with the biomechanics of future tissue-engineered esophagus. Esophageal stretching > 1.3 leads to tears in muscle fibers and to rupture of capillaries. These findings can explain the decrease in microcirculation and scarring in mobilized tissue and possibly offer clues to impaired motility in esophagus atresias repaired under excessive tension.
Subject(s)
Esophageal Atresia , Tissue Engineering , Animals , Biomechanical Phenomena , Esophageal Atresia/surgery , Humans , Mucous Membrane , Sheep , Tissue Engineering/methodsABSTRACT
Computational biomechanics plays an important role in biomedical engineering: using modeling to understand pathophysiology, treatment and device design. While experimental evidence indicates that the mechanical response of most tissues is viscoelastic, current biomechanical models in the computational community often assume hyperelastic material models. Fractional viscoelastic constitutive models have been successfully used in literature to capture viscoelastic material response; however, the translation of these models into computational platforms remains limited. Many experimentally derived viscoelastic constitutive models are not suitable for three-dimensional simulations. Furthermore, the use of fractional derivatives can be computationally prohibitive, with a number of current numerical approximations having a computational cost that is ðª ( N T 2 ) and a storage cost that is ðª(NT ) (NT denotes the number of time steps). In this paper, we present a novel numerical approximation to the Caputo derivative which exploits a recurrence relation similar to those used to discretize classic temporal derivatives, giving a computational cost that is ðª(NT ) and a storage cost that is fixed over time. The approximation is optimized for numerical applications, and an error estimate is presented to demonstrate the efficacy of the method. The method, integrated into a finite element solid mechanics framework, is shown to be unconditionally stable in the linear viscoelastic case. It was then integrated into a computational biomechanical framework, with several numerical examples verifying the accuracy and computational efficiency of the method, including in an analytic test, in an analytic fractional differential equation, as well as in a computational biomechanical model problem.
ABSTRACT
Cardiovascular diseases are the leading cause of death worldwide and include, among others, critical conditions of the aortic wall. Importantly, such critical conditions require effective diagnosis and treatment, which are not yet accurate enough. However, they could be significantly strengthened with predictive material models of the aortic wall. In particular, such predictive models could support surgical decisions, preoperative planning, and estimation of postoperative tissue remodeling. However, developing a predictive model requires experimental data showing both structural parameters and mechanical behavior. Such experimental data can be obtained using multimodal experiments. This review therefore discusses the current approaches to multimodal experiments. Importantly, the strength of the aortic wall is determined primarily by its passive components, i.e., mainly collagen, elastin, and proteoglycans. Therefore, this review focuses on multimodal experiments that relate the passive mechanical behavior of the human aortic wall to the structure and organization of its passive components. In particular, the multimodal experiments are classified according to the expected results. Multiple examples are provided for each experimental class and summarized with highlighted advantages and disadvantages of the method. Finally, future directions of multimodal experiments are envisioned and evaluated. STATEMENT OF SIGNIFICANCE: Multimodal experiments are innovative approaches that have gained interest very quickly, but also recently. This review presents therefore a first clear summary of groundbreaking research in the field of multimodal experiments. The benefits and limitations of various types of multimodal experiments are thoroughly discussed, and a comprehensive overview of possible results is provided. Although this review focuses on multimodal experiments performed on human aortic tissues, the methods used and described are not limited to human aortic tissues but can be extended to other soft materials.
Subject(s)
Aorta , Collagen , Humans , Collagen/chemistry , Stress, Mechanical , Biomechanical PhenomenaABSTRACT
Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors, including cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified yet. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), which are required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, aortic stiffening and disorganization of aortic collagen in the absence of hypercholesterolemia, and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD (VCDD+Hcy) in the absence of hypercholesterolemia. While this treatment did not lead to thickening of aortic wall, intravenous injections of Hcy into rabbits fed VCDD led to massive accumulation of VLDL-triglycerides as well as significant impairment of vascular reactivity of the aorta compared to VCDD alone. In the aorta intravenous Hcy injections into VCDD-fed rabbits led to fragmentation of aortic elastin, accumulation of elastin-specific electron-dense inclusions, collagen disorganization, lipid degradation, and autophagolysosome formation. Furthermore, rabbits from the VCDD+Hcy group exhibited a massive decrease of total protein methylated arginine in blood cells and decreased creatine in blood cells, serum and liver compared to rabbits from the VCDD group. Altogether, we conclude that Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.
Subject(s)
Aorta , Atherosclerosis , Homocysteine , Hypercholesterolemia , Animals , Rabbits , Atherosclerosis/pathology , Atherosclerosis/metabolism , Homocysteine/blood , Aorta/pathology , Aorta/metabolism , Hypercholesterolemia/blood , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Male , Choline/administration & dosage , Disease Models, Animal , Elastin/metabolism , Vitamin B Complex/administration & dosage , Vitamin B Complex/pharmacologyABSTRACT
Esophageal biomechanical studies are being performed to understand structural changes resulting from stretches during repair of esophageal atresias as well as to obtain biomechanical values for tissue-engineered esophagus. The present study offers insights into ultrastructural changes after stretching of the ovine esophagus using uniaxial stretch tests. In vitro uniaxial stretching was performed on esophagi (n = 16) obtained from the abattoir within 4-6 h of 1-month-old lambs. Esophagi were divided into 4 groups (4 esophagi/group): control, Group1 (G1), Group2 (G2), Group3 (G3) stretched to 20%, 30% and 40% of their original length respectively. Force and lengthening were measured with 5 cycles performed on every specimen. Transmission electron microscopic (TEM) studies were performed on the 4 groups. During observational TEM study of the control group there were no significant differences in muscle cell structure or extracellular matrix. In all stretched groups varying degrees of alterations were identified. The degree of damage correlated linearly with the increasing level of stretch. Distance between the cells showed significant difference between the groups (control (µ = 0.41 µm, SD = 0.26), G1 (µ = 1.36 µm, SD = 1.21), G2 (µ = 2.8 µm, SD = 1.83), and G3 (µ = 3.01 µm, SD = 2.06). The diameter of the cells (control µ = 19.87 µm, SD = 3.81; G1 µ = 20.38 µm, SD = 4.45; G2 µ = 21.7 µm, SD = 6.58; G3 µ = 24.48 µm, SD = 6.69) and the distance between myofibrils (control µ = 0.23 µm, SD = 0.08; G1 µ = 0.27 µm, SD = 0.08; G2 µ = 0.4 µm, SD = 0.15; G3 µ = 0.61 µm, SD = 0.2) were significantly different as well ( p < 0.05 was considered to be significant). Esophageal stretching > 30% alters the regular intracellular and extracellular structure of the esophageal muscle and leads to disruption of intra- and extracellular bonds. These findings could provide valuable insights into alterations in the microscopic structure of the esophagus in esophageal atresias repaired under tension as well as the basis for mechanical characterization for tissue engineering of the esophagus.
Subject(s)
Esophageal Atresia , Animals , Abattoirs , Extracellular Matrix , Muscle Cells , Sheep , Sheep, Domestic , Tissue EngineeringABSTRACT
Among the three layers of the aortic wall, the media is primarily responsible for its mechanical properties, but the adventitia prevents the aorta from overstretching and rupturing. The role of the adventitia is therefore crucial with regard to aortic wall failure, and understanding the load-induced changes in tissue microstructure is of high importance. Specifically, the focus of this study is on the changes in collagen and elastin microstructure in response to macroscopic equibiaxial loading applied to the aortic adventitia. To observe these changes, multi-photon microscopy imaging and biaxial extension tests were performed simultaneously. In particular, microscopy images were recorded at 0.02 stretch intervals. The microstructural changes of collagen fiber bundles and elastin fibers were quantified with the parameters of orientation, dispersion, diameter, and waviness. The results showed that the adventitial collagen was divided from one into two fiber families under equibiaxial loading conditions. The almost diagonal orientation of the adventitial collagen fiber bundles remained unchanged, but the dispersion was substantially reduced. No clear orientation of the adventitial elastin fibers was observed at any stretch level. The waviness of the adventitial collagen fiber bundles decreased under stretch, but the adventitial elastin fibers showed no change. These original findings highlight differences between the medial and adventitial layers and provide insight into the stretching process of the aortic wall. STATEMENT OF SIGNIFICANCE: To provide accurate and reliable material models, it is essential to understand the mechanical behavior of the material and its microstructure. Such understanding can be enhanced with tracking of the microstructural changes caused by mechanical loading of the tissue. This study provides therefore a unique dataset of structural parameters of the human aortic adventitia obtained under equibiaxial loading. The structural parameters describe orientation, dispersion, diameter, and waviness of collagen fiber bundles and elastin fibers. Eventually, the microstructural changes in the human aortic adventitia are compared with the microstructural changes in the human aortic media from a previous study. This comparison reveals the cutting-edge findings on the differences in the response to the loading between these two human aortic layers.
Subject(s)
Adventitia , Elastin , Humans , Elastin/chemistry , Microscopy , Aorta , Collagen , Stress, Mechanical , Biomechanical PhenomenaABSTRACT
The ascending thoracic aortic aneurysm (ATAA) is a permanent dilatation of the vessel with a high risk of adverse events, and shows heterogeneous properties. To investigate regional differences in the biomechanical properties of ATAAs, tissue samples were collected from 10 patients with tricuspid aortic valve phenotype and specimens from minor, anterior, major, and posterior regions were subjected to multi-ratio planar biaxial extension tests and second-harmonic generation (SHG) imaging. Using the data, parameters of a microstructure-motivated constitutive model were obtained considering fiber dispersion. SHG imaging showed disruptions in the organization of the layers. Structural and material parameters did not differ significantly between regions. The non-symmetric fiber dispersion model proposed by Holzapfel et al. [25] was used to fit the data. The mean angle of collagen fibers was negatively correlated between minor and anterior regions, and the parameter associated with collagen fiber stiffness was positively correlated between minor and major regions. Furthermore, correlations were found between the stiffness of the ground matrix and the mean fiber angle, and between the parameter associated with the collagen fiber stiffness and the out-of-plane dispersion parameter in the posterior and minor regions, respectively. The experimental data collected in this study contribute to the biomechanical data available in the literature on human ATAAs. Region-specific parameters for the constitutive models are fundamental to improve the current risk stratification strategies, which are mainly based on aortic size. Such investigations can facilitate the development of more advanced finite element models capable of capturing the regional heterogeneity of pathological tissues. STATEMENT OF SIGNIFICANCE: Tissue samples of human ascending thoracic aortic aneurysms (ATAA) were collected. Samples from four regions underwent multi-ratio planar biaxial extension tests and second-harmonic generation imaging. Region-specific parameters of a microstructure-motivated model considering fiber dispersion were obtained. Structural and material parameters did not differ significantly between regions, however, the mean fiber angle was negatively correlated between minor and anterior regions, and the parameter associated with collagen fiber stiffness was positively correlated between minor and major regions. Furthermore, correlations were found between the stiffness of the ground matrix and the mean fiber angle, and between the parameter associated with the collagen fiber stiffness and the out-of-plane dispersion parameter in the posterior and minor regions, respectively. This study provides a unique set of mechanical and structural data, supporting the microstructural influence on the tissue response. It may facilitate the development of better finite element models capable of capturing the regional tissue heterogeneity.
Subject(s)
Aneurysm, Ascending Aorta , Aortic Aneurysm, Thoracic , Humans , Aortic Aneurysm, Thoracic/pathology , Aorta , Extracellular Matrix/pathology , Collagen , Biomechanical Phenomena , Stress, MechanicalABSTRACT
Residual stress is thought to play a critical role in modulating stress distributions in soft biological tissues and in maintaining the mechanobiological stress environment of cells. Residual stresses in arteries and other tissues are classically assessed through opening angle experiments, which demonstrate the continuous release of residual stresses over hours. These results are then assessed through nonlinear biomechanical models to provide estimates of the residual stresses in the intact state. Although well studied, these analyses typically focus on hyperelastic material models despite significant evidence of viscoelastic phenomena over both short and long timescales. In this work, we extended the state-of-the-art structural tensor model for arterial tissues from Holzapfel and Ogden for fractional viscoelasticity. Models were tuned to capture consistent levels of hysteresis observed in biaxial experiments, while also minimizing the fractional viscoelastic weighting and opening angles to correctly capture opening angle dynamics. Results suggest that a substantial portion of the human abdominal aorta is viscoelastic, but exhibits a low fractional order (i.e. more elastically). Additionally, a significantly larger opening angle in the fully unloaded state is necessary to produce comparable hysteresis in biaxial testing. As a consequence, conventional estimates of residual stress using hyperelastic approaches over-estimate their viscoelastic counterparts by a factor of 2. Thus, a viscoelastic approach, such as the one illustrated in this study, in combination with an additional source of rate-controlled viscoelastic data is necessary to accurately analyze the residual stress distribution in soft biological tissues. STATEMENT OF SIGNIFICANCE: Residual stress plays a crucial role in achieving a homeostatic stress environment in soft biological tissues. However, the analysis of residual stress typically focuses on hyperelastic material models despite evidence of viscoelastic behavior. This work is the first attempt at analyzing the effects of viscoelasticity on residual stress. The application of viscoelasticity was crucial for producing realistic opening dynamics in arteries. The overall residual stresses were estimated to be 50% less than those from using hyperelastic material models, while the opening angles were projected to be 25% more than those measured after 16 hours, suggesting underestimated residual strain. This study highlights the importance viscoelasticity in the analysis of residual stress even in weakly dissipative materials like the human aorta.
Subject(s)
Aorta, Abdominal , Arteries , Biomechanical Phenomena , Elasticity , Humans , Models, Biological , Stress, Mechanical , ViscosityABSTRACT
Understanding the correlation between tissue architecture, health status, and mechanical properties is essential for improving material models and developing tissue engineering scaffolds. Since structural-based material models are state of the art, there is an urgent need for experimentally obtained structural parameters. For this purpose, the medial layer of nine human abdominal aortas was simultaneously subjected to equibiaxial loading and multi-photon microscopy. At each loading interval of 0.02, collagen and elastin fibers were imaged based on their second-harmonic generation signal and two-photon excited autofluorescence, respectively. The structural alterations in the fibers were quantified using the parameters of orientation, diameter, and waviness. The results of the mechanical tests divided the sample cohort into the ruptured and non-ruptured, and stiff and non-stiff groups, which were covered by the findings from histological investigations. The alterations in structural parameters provided an explanation for the observed mechanical behavior. In addition, the waviness parameters of both collagen and elastin fibers showed the potential to serve as indicators of tissue strength. The data provided address deficiencies in current material models and bridge multiscale mechanisms in the aortic media. STATEMENT OF SIGNIFICANCE: Available material models can reproduce, but cannot predict, the mechanical behavior of human aortas. This deficiency could be overcome with the help of experimentally validated structural parameters as provided in this study. Simultaneous multi-photon microscopy and biaxial extension testing revealed the microstructure of human aortic media at different stretch levels. Changes in the arrangement of collagen and elastin fibers were quantified using structural parameters such as orientation, diameter and waviness. For the first time, structural parameters of human aortic tissue under continuous loading conditions have been obtained. In particular, the waviness parameters at the reference configuration have been associated with tissue stiffness, brittleness, and the onset of atherosclerosis.
Subject(s)
Elastin , Microscopy , Aorta, Abdominal/pathology , Biomechanical Phenomena , Collagen/chemistry , Elastin/chemistry , Humans , Stress, Mechanical , Tunica MediaABSTRACT
An insight into changes of soft biological tissue ultrastructures under loading conditions is essential to understand their response to mechanical stimuli. Therefore, this study offers an approach to investigate the arrangement of collagen fibrils and proteoglycans (PGs), which are located within the mechanically loaded aortic wall. The human aortic samples were either fixed directly with glutaraldehyde in the load-free state or subjected to a planar biaxial extension test prior to fixation. The aortic ultrastructure was recorded using electron tomography. Collagen fibrils and PGs were segmented using convolutional neural networks, particularly the ESPNet model. The 3D ultrastructural reconstructions revealed a complex organization of collagen fibrils and PGs. In particular, we observed that not all PGs are attached to the collagen fibrils, but some fill the spaces between the fibrils with a clear distance to the collagen. The complex organization cannot be fully captured or can be severely misinterpreted in 2D. The approach developed opens up practical possibilities, including the quantification of the spatial relationship between collagen fibrils and PGs as a function of the mechanical load. Such quantification can also be used to compare tissues under different conditions, e.g., healthy and diseased, to improve or develop new material models. STATEMENT OF SIGNIFICANCE: The developed approach enables the 3D reconstruction of collagen fibrils and proteoglycans as they are embedded in the loaded human aortic wall. This methodological pipeline comprises the knowledge of arterial mechanics, imaging with transmission electron microscopy and electron tomography, segmentation of 3D image data sets with convolutional neural networks and finally offers a unique insight into the ultrastructural changes in the aortic tissue caused by mechanical stimuli.
Subject(s)
Imaging, Three-Dimensional , Proteoglycans , Collagen/ultrastructure , Extracellular Matrix , Humans , Microscopy, Electron, TransmissionABSTRACT
Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors, including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in vivo models of atherosclerosis that resemble the human situation. Here, we have developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development, even at low balloon pressure. Our automated system helped to glean vital details of cholesterol-independent changes in the aortic wall of balloon-injured rabbits. We show that deficiency of B vitamins, which are required for homocysteine degradation, leads to atherogenic transformation of the aorta resulting in accumulation of macrophages and lipids, impairment of its biomechanical properties and disorganization of aortic collagen/elastin in the absence of hypercholesterolemia. A combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity compared to any single condition. Our findings suggest that deficiency of B vitamins leads to atherogenic transformation of the aorta even in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence.
Subject(s)
Atherosclerosis , Hypercholesterolemia , Hyperlipidemias , Vitamin B Complex , Animals , Aorta/metabolism , Atherosclerosis/metabolism , Cholesterol , Diet, Atherogenic , Homocysteine/metabolism , Humans , Hypercholesterolemia/metabolism , Hyperlipidemias/metabolism , RabbitsABSTRACT
Arterial mechanics plays an important role in vascular pathophysiology and repair, and advanced imaging can inform constitutive models of vascular behavior. We have measured the mechanical properties of 14 human superficial femoral arteries (SFAs) (age 12-70, mean 48±19 years) using planar biaxial extension, and determined the preferred collagen fiber direction and dispersion using multiphoton microscopy. The collagen fiber direction and dispersion were evaluated using second-harmonic generation imaging and modeled using bivariate von Mises distributions. The microstructures of elastin and collagen were assessed using two-photon fluorescence imaging and conventional bidirectional histology. The mechanical and structural data were used to describe the SFA mechanical behavior using two- and four-fiber family invariant-based constitutive models. Older SFAs were stiffer and mechanically more nonlinear than younger specimens. In the adventitia, collagen fibers were undulated and diagonally-oriented, while in the media, they were straight and circumferentially-oriented. The media was rich in collagen that surrounded the circumferentially-oriented smooth muscle cells, and the elastin was present primarily in the internal and external elastic laminae. Older SFAs had a more circumferential collagen fiber alignment, a decreased circumferential-radial fiber dispersion, but the same circumferential-longitudinal fiber dispersion as younger specimens. Both the two- and the four-fiber family constitutive models were able to capture the experimental data, and the fits were better for the four-fiber family formulation. Our data provide additional details on the SFA intramural structure and inform structurally-based constitutive models.
Subject(s)
Extracellular Matrix , Femoral Artery , Adolescent , Adult , Adventitia , Aged , Biomechanical Phenomena , Child , Collagen , Elastin , Humans , Middle Aged , Stress, Mechanical , Young AdultABSTRACT
Understanding the biomechanics of the heart in health and disease plays an important role in the diagnosis and treatment of heart failure. The use of computational biomechanical models for therapy assessment is paving the way for personalized treatment, and relies on accurate constitutive equations mapping strain to stress. Current state-of-the art constitutive equations account for the nonlinear anisotropic stress-strain response of cardiac muscle using hyperelasticity theory. While providing a solid foundation for understanding the biomechanics of heart tissue, most current laws neglect viscoelastic phenomena observed experimentally. Utilizing experimental data from human myocardium and knowledge of the hierarchical structure of heart muscle, we present a fractional nonlinear anisotropic viscoelastic constitutive model. The model is shown to replicate biaxial stretch, triaxial cyclic shear and triaxial stress relaxation experiments (mean error â¼7.68%), showing improvements compared to its hyperelastic (mean error â¼24%) counterparts. Model sensitivity, fidelity and parameter uniqueness are demonstrated. The model is also compared to rate-dependent biaxial stretch as well as different modes of biaxial stretch, illustrating extensibility of the model to a range of loading phenomena. STATEMENT OF SIGNIFICANCE: The viscoelastic response of human heart tissues has yet to be integrated into common constitutive models describing cardiac mechanics. In this work, a fractional viscoelastic modeling approach is introduced based on the hierarchical structure of heart tissue. From these foundations, the current state-of-the-art biomechanical models of the heart muscle are transformed using fractional viscoelasticity, replicating passive muscle function across multiple experimental tests. Comparisons are drawn with current models to highlight the improvements of this approach and predictive responses show strong qualitative agreement with experimental data. The proposed model presents the first constitutive model aimed at capturing viscoelastic nonlinear response across multiple testing regimes, providing a platform for better understanding the biomechanics of myocardial tissue in health and disease.
Subject(s)
Models, Biological , Myocardium , Anisotropy , Biomechanical Phenomena , Elasticity , Humans , Stress, Mechanical , ViscosityABSTRACT
Specimens of intact wall tubes of human common carotid arteries (CCA), internal carotid arteries (ICA) (n = 11, age 77.6 yr, SD 6.3), and related adventitia and media-intima tubes are mechanically examined. Cyclic, quasi-static extension-inflation tests at different axial stretches are performed on preconditioned tube specimens. Stress-free configurations show significant stress releases in the circumferential direction of the intact CCA and ICA walls and in the axial directions of the intact CCA walls and the CCA and ICA adventitias. All investigated tissues exhibit strong nonlinear, pseudoelastic mechanical behavior with small hysteresis. The "inversion" feature, where the pressure/axial stretch relationship becomes a vertical line, is found only for intact walls. Axial "inversion stretches" are 1.15 (SD 0.06) for CCA and 1.14 (SD 0.06) for ICA, and related external axial forces are 0.43 N (SD 0.15) and 0.30 N (SD 0.22), respectively. Significant negative correlations between age and axial inversion stretches for CCA (r = -0.67, P = 0.03) and ICA (r = -0.29, P = 0.04) are identified. Adventitias are very compliant at low pressures, but change into stiff tubes at high pressures. The burst pressure of the adventitia is beyond 250 kPa. A relatively low burst pressure of approximately 60 kPa is found in the media-intima tubes, in which the pressure/circumferential stretch relationships are almost independent of the axial stretches. Stress analyses indicate a high degree of material anisotropy for all investigated tissues. High circumferential and axial stresses occur in the media-intima tubes at physiological conditions. The obtained data are intended to serve for an improvement of constitutive laws, determination of constitutive parameters, and enhancing our knowledge of the mechanical functions of arteries and their associated layers in specific pathophysiological and clinical problems, such as hypertension and angioplasty with stenting.
Subject(s)
Carotid Artery, Common/physiology , Carotid Artery, Internal/physiology , Models, Biological , Stress, Physiological/physiology , Aged , Aged, 80 and over , Biomechanical Phenomena , Cadaver , Connective Tissue/physiology , Elasticity/physiology , Female , Humans , Male , Tunica Intima/physiology , Tunica Media/physiologyABSTRACT
An accurate characterization of soft biological tissue properties is essential for a realistic simulation of surgical procedures. Unconfined uniaxial compression tests with specimens affixed to the fixtures are often performed to characterize the stress-stretch curves of soft biological tissues, with which the material parameters can be obtained. However, the constrained boundary condition causes non-uniform deformation during the uniaxial test, posing challenges for accurate measurement of tissue deformation. In this study, we measured the deformation locally at the middle of liver specimens and obtained the corresponding stress-stretch curves. Since the effect of the constrained boundary condition on the local deformation of specimen is minimized, the stress-stretch curves are thus more realistic. Subsequently, we fitted the experimental stress-stretch curves with several constitutive models and found that the first-order Ogden hyperelastic material model was most suitable for characterizing the mechanical properties of porcine liver tissues. To further verify the characterized material properties, we carried out indentation tests on porcine liver specimens and compared the experimental data with computational results by using finite element simulations. A good agreement was achieved. Finally, we constructed computational models of liver tissue with a tumor and investigated the effect of the tumor on the mechanical response of the tissue under indentation. The computational results revealed that the liver specimen with tumor shows a stiffer response if the distance between the tumor and the indenter is small.
Subject(s)
Liver Neoplasms/physiopathology , Liver Neoplasms/surgery , Liver/physiology , Models, Biological , Animals , Biomechanical Phenomena , Compressive Strength , Computer Simulation , Elasticity , Finite Element Analysis , Humans , Imaging, Three-Dimensional , In Vitro Techniques , Liver/anatomy & histology , Liver Neoplasms/diagnosis , Mathematical Concepts , Models, Animal , Stress, Mechanical , Sus scrofa , Tensile StrengthABSTRACT
Vascular damage develops with diverging severity during and after percutaneous coronary intervention with stent placement and is the prevailing stimulus for in-stent restenosis. Previous work has failed to link mechanical data obtained in a realistic in vivo or in vitro environment with data collected during imaging processes. We investigated whether specimens of porcine right coronary arteries soften when indented with a stent strut shaped structure, and if the softening results from damage mechanisms inside the fibrillar collagen structure. To simulate the multiaxial loading scenario of a stented coronary artery, we developed the testing device 'LAESIO' that can measure differences in the stress-stretch behavior of the arterial wall before and after the indentation of a strut-like stamp. The testing protocol was optimized according to preliminary experiments, more specifically equilibrium and relaxation tests. After chemical fixation of the specimens and subsequent tissue clearing, we performed three-dimensional surface and second-harmonic generation scans on the deformed specimens. We analyzed and correlated the mechanical response with structural parameters of high-affected tissue located next to the stamp indentation and low-affected tissue beyond the injured area. The results reveal that damage mechanisms, like tissue compression as well as softening, fiber dispersion, and the lesion extent, are direction-dependent, and the severity of them is linked to the strut orientation, indentation pressure, and position. The findings highlight the need for further investigations by applying the proposed methods to human coronary arteries. Additional data and insights might help to incorporate the observed damage mechanisms into material models for finite element analyses to perform more accurate simulations of stent-implantations.
Subject(s)
Coronary Vessels , Models, Cardiovascular , Animals , Computer Simulation , Humans , Stents , Stress, Mechanical , SwineABSTRACT
The experimental quantification and modeling of the multiaxial mechanical response of polymer membranes of coronary balloon catheters have not yet been carried out. Due to the lack of insights, it is not shown whether isotropic material models can describe the material response of balloon catheter membranes expanded with nominal or higher, supra-nominal pressures. Therefore, for the first time, specimens of commercial polyamide-12 balloon catheters membranes were investigated during uniaxial and biaxial loading scenarios. Furthermore, the influence of kinematic effects on the material response was observed by comparing results from quasi-static and dynamic biaxial extension tests. Novel clamping techniques are described, which allow to test even tiny specimens taken from the balloon membranes. The results of this study reveal the semi-compliant, nonlinear, and viscoelastic character of polyamide-12 balloon catheter membranes. Above nominal pressure, the membranes show a pronounced anisotropic mechanical behavior with a stiffer response in the circumferential direction. The anisotropic feature intensifies with an increasing strain-rate. A modified polynomial model was applied to represent the realistic mechanical response of the balloon catheter membranes during dynamic biaxial extension tests. This study also includes a compact set of constitutive model parameters for the use of the proposed model in future finite element analyses to perform more accurate simulations of expanding balloon catheters.