Mechanotransduction Mechanisms Research Articles

Mechanical Stimulation on Mesenchymal Stem Cells and Surrounding Microenvironments in Bone Regeneration: Regulations and Applications.

Treatment of bone defects remains a challenge in the clinic. Artificial bone grafts are the most promising alternative to autologous bone grafting. However, one of the limiting factors of artificial bone grafts is the limited means of regulating stem cell differentiation during bone regeneration. As a weight-bearing organ, bone is in a continuous mechanical environment. External mechanical force, a type of biophysical stimulation, plays an essential role in bone regeneration. It is generally accepted that osteocytes are mechanosensitive cells in bone. However, recent studies have shown that mesenchymal stem cells (MSCs) can also respond to mechanical signals. This article reviews the mechanotransduction mechanisms of MSCs, the regulation of mechanical stimulation on microenvironments surrounding MSCs by modulating the immune response, angiogenesis and osteogenesis, and the application of mechanical stimulation of MSCs in bone regeneration. The review provides a deep and extensive understanding of mechanical stimulation mechanisms, and prospects feasible designs of biomaterials for bone regeneration and the potential clinical applications of mechanical stimulation.

Glycocalyx mechanotransduction mechanisms are involved in renal cancer metastasis

Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the tumor glycocalyx leading to activation of cell motility and metastasis. Using a highly metastatic renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule Suberoylanilide Hydroxamic Acid (SAHA) inhibits the heparan sulfate synthesis enzyme N-deacetylase-N-sulfotransferase-1, reduces heparan sulfate in the glycocalyx and suppresses SN12L1 motility in response to interstitial flow. SN12L1 cells implanted in the kidney capsule of SCID mice formed large primary tumors and metastasized to distant organs, but when treated with SAHA metastases were not detected. In another set of experiments, the role of hyaluronic acid was investigated. Hyaluronan synthase 1, a critical enzyme in the synthetic pathway for hyaluronic acid, was knocked down in SN12L1 cells and in vitro experiments revealed inhibition of interstitial flow induced migration. Subsequently these cells were implanted in mouse kidneys and no distant metastases were detected. These findings suggest new therapeutic approaches to the treatment of kidney carcinoma metastasis.

Real-Time Suture Reconstruction in Rat Skin Stretching Experiments With Multiocular Stereo Vision Measurement System

To investigate the effects of skin stretching stress on tissue expansion and its mechanotransduction mechanism, an animal model of skin stretching was established in our previous work. However, the distribution of stress in the skin cannot be precisely determined in real-time, which leads to an imprecise correlation analysis between stress distribution and protein levels of mechanosensitive molecules. To address this problem, a real-time suture reconstruction method with a multi-ocular stereo vision measurement system was developed in this study. The shape of the suture passing through the rat’s skin can be measured in real-time, and the distribution of skin stress can be precisely determined. The key to real-time suture reconstruction is suture-matching in multi-ocular images, therefore a suture-matching method based on the nearest-neighbor rule and region growing was proposed. First, color markers were fixed on the suture nodes and the frame, secondly, pixels in the frame region are sampled, and the frame inner region is segmented by the nearest neighbor rule. Furthermore, the pixels within the color markers in the region were selected as the seed points for growth, and the markers were segmented using a edge and color integrated detection method. Finally, the markers on the frame were fitted to form a reference line, and the distance between each marker on the suture and the reference line was calculated as the matching feature to realize image matching of nodes in the stereo camera. The three-dimensional coordinates of the nodes were calculated based on region growth, and the sutures were reconstructed using a B-spline curve. The experimental results confirmed the feasibility and high robustness of the proposed method, which ensured accurate three-dimensional reconstruction of the suture.

Hemodynamic Forces, Endothelial Mechanotransduction, and Vascular Diseases.

Cells in the tissues and organs of a living body are subjected to mechanical forces, such as pressure, friction, and tension from their surrounding environment. Cells are equipped with a mechanotransduction mechanism by which they perceive mechanical forces and transmit information into the cell interior, thereby causing physiological or pathogenetic mechano-responses. Endothelial cells (ECs) lining the inner surface of blood vessels are constantly exposed to shear stress caused by blood flow and a cyclic strain caused by intravascular pressure. A number of studies have shown that ECs are sensitive to changes in these hemodynamic forces and alter their morphology and function, sometimes by modifying gene expression. The mechanism of endothelial mechanotransduction has been elucidated, and the plasma membrane has recently been shown to act as a mechanosensor. The lipid order and cholesterol content of plasma membranes change immediately upon the exposure of ECs to hemodynamic forces, resulting in a change in membrane fluidity. These changes in a plasma membrane's physical properties affect the conformation and function of various ion channels, receptors, and microdomains (such as caveolae and primary cilia), thereby activating a wide variety of downstream signaling pathways. Such endothelial mechanotransduction works to maintain circulatory homeostasis; however, errors in endothelial mechanotransduction can cause abnormalities in vascular physiological function, leading to the initiation and progression of various vascular diseases, such as hypertension, thrombosis, aneurysms, and atherosclerosis. Recent advances in detailed imaging technology and computational fluid dynamics analysis have enabled us to evaluate the hemodynamic forces acting on vascular tissue accurately, contributing greatly to our understanding of vascular mechanotransduction and the pathogenesis of vascular diseases, as well as the development of new therapies for vascular diseases.

Au nanoflower film-based stretchable biosensors for in situ monitoring of superoxide anion release in cell mechanotransduction.

Cell mechanotransduction plays an important role in vascular regulation and disease development. Excessive accumulation of ROS, especially superoxide anion radicals (O2˙-), is closely related to cardiovascular diseases. Lately, NADPH oxidases, which are the major source of O2˙- production in vascular tissues, have been demonstrated to be involved in cardiovascular diseases. Therefore, in situ and real-time monitoring of superoxide anions (O2˙-) is essential for exploring the mechanisms of mechanotransduction associated with NADPH oxidase function in living cells. Here we report a rationally designed ultrasonication-assisted approach for growing Au nanoflower films on a flexible surface, which serves as the desired interface for cysteine and superoxide dismutase (SOD) anchoring to form a flexible and stretchable electrode (SOD/Cys/Au SE). The SOD/Cys/Au SE shows good stretchability, fast electron-transfer rates, and high selectivity to measure O2˙- released from cells during the stretching states. Our strategy provides a basis for developing more sophisticated stretchable biosensing tools to induce and monitor transient biochemical signals during cell mechanotransduction.

Renin cell baroreceptor and arachidonic acid

Juxtaglomerular cells or granular cells synthesize, store, and secrete renin needed for the renin-angiotensin-aldosterone (RAS) to fine tune the maintenance of blood pressure and blood volume. The baroreceptor function of these granular cells may function as a nuclear mechanotransducer to sense and transmit the extracellular physical forces to their chromatin to regulate renin gene expression and secretion. Cell nucleus serves as a sensor and responds to the changes in pressure and stretch that triggers calcium release and cPLA2 (cytosolic phospholipase A2) activation that, in turn, releases arachidonic acid (AA) (and possibly, other unsaturated fatty acids) from the cell membrane lipid pool. AA influences the cytoskeletal system and is involved and regulates exocytosis. AA is the precursor of a variety of products that have a regulatory role in the formation and action of RAS, inflammation, and immune response. These results imply that AA is involved in nuclear mechanotransduction mechanism in the baroreceptor function of granular cells and in the regulation of synthesis and secretion of renin.

Biophysical Approaches for Applying and Measuring Biological Forces.

Over the past decades, increasing evidence has indicated that mechanical loads can regulate the morphogenesis, proliferation, migration, and apoptosis of living cells. Investigations of how cells sense mechanical stimuli or the mechanotransduction mechanism is an active field of biomaterials and biophysics. Gaining a further understanding of mechanical regulation and depicting the mechanotransduction network inside cells require advanced experimental techniques and new theories. In this review, the fundamental principles of various experimental approaches that have been developed to characterize various types and magnitudes of forces experienced at the cellular and subcellular levels are summarized. The broad applications of these techniques are introduced with an emphasis on the difficulties in implementing these techniques in special biological systems. The advantages and disadvantages of each technique are discussed, which can guide readers to choose the most suitable technique for their questions. A perspective on future directions in this field is also provided. It is anticipated that technical advancement can be a driving force for the development of mechanobiology.

The Wnt pathway: An important control mechanism in bone's response to mechanical loading.

The conversion of mechanical energy into biochemical changes within living cells is process known as mechanotransduction. Bone is a quintessential tissue for studying the molecular mechanisms of mechanotransduction, as the skeleton's mechanical competence is crucial for vertebrate movement. Bone cell mechanotransduction is facilitated by a number of cell biological pathways, one of the most prominent of which is the Wnt signaling cascade. The Wnt co-receptor Lrp5 has been identified as a crucial protein for mechanical signaling in bone, and modifiers of Lrp5 activity play important roles in mediating signaling efficiency through Lrp5, including sclerostin, Dkk1, and the co-receptor Lrp4. Mechanical regulation of sclerostin is mediated by certain members of the Hdac family. Other mechanisms that influence Wnt signaling-some of which are mechanoresponsive-are coming to light, including R-spondins and their role in organizing the Rnf43/Znrf3 and Lgr4/5/6 complex that liberates Lrp5. While the identity of the key Wnt proteins involved in bone cell mechanical signaling are elusive, the likely pool of key players is narrowing. Identification of Wnt-based molecular targets that can be modulated pharmacologically to make mechanical stimulation (e.g., exercise) more beneficial is an emerging approach to improving skeletal integrity and reducing fracture risk.

Baseline Stiffness Modulates the Non-Linear Response to Stretch of the Extracellular Matrix in Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a progressive disease that disrupts the mechanical homeostasis of the lung extracellular matrix (ECM). These effects are particularly relevant in the lung context, given the dynamic nature of cyclic stretch that the ECM is continuously subjected to during breathing. This work uses an in vivo model of pulmonary fibrosis to characterize the macro- and micromechanical properties of lung ECM subjected to stretch. To that aim, we have compared the micromechanical properties of fibrotic ECM in baseline and under stretch conditions, using a novel combination of Atomic Force Microscopy (AFM) and a stretchable membrane-based chip. At the macroscale, fibrotic ECM displayed strain-hardening, with a stiffness one order of magnitude higher than its healthy counterpart. Conversely, at the microscale, we found a switch in the stretch-induced mechanical behaviour of the lung ECM from strain-hardening at physiological ECM stiffnesses to strain-softening at fibrotic ECM stiffnesses. Similarly, we observed solidification of healthy ECM versus fluidization of fibrotic ECM in response to stretch. Our results suggest that the mechanical behaviour of fibrotic ECM under stretch involves a potential built-in mechanotransduction mechanism that may slow down the progression of PF by steering resident fibroblasts away from a pro-fibrotic profile.

Single Cell Micro-Pillar-Based Characterization of Endothelial and Fibroblast Cell Mechanics

Mechanotransduction, the ability of cells to sense and respond to the mechanical cues from their microenvironment, plays an important role in numerous cellular processes, ranging from cell migration to differentiation. Several techniques have been developed to investigate the underlying mechanisms of mechanotransduction, in particular, force measurement-based techniques. However, we still lack basic single cell quantitative comparison on the mechanical properties of commonly used cell types, such as endothelial and fibroblast cells. Such information is critical to provide a precedent for studying complex tissues and organs that consist of various cell types. In this short communication, we report on the mechanical characterization of the commonly used endothelial and fibroblast cells at the single cell level. Using a micropillar-based assay, we measured the traction force profiles of these cells. Our study showcases differences between the two cell types in their traction force distribution and morphology. The results reported can be used as a reference and to lay the groundwork for future analysis of numerous disease models involving these cells.

The 'Yin and Yang' of Cancer Cell Growth and Mechanosensing.

Simple SummaryCells can sense their physical environment, or extracellular matrix (ECM), in a process called ‘mechanosensing’. They do this via adhesion sites which allow them to attach to the ECM and to simultaneously obtain information about its mechanical properties. This mechanical information is converted to biochemical signals that affect cell behavior in various ways. Stiff surroundings tend to promote proliferation of normal cells, whereas soft substrates can lead to their death. Cancer cells, however, can survive on soft substrates, while maintaining increased proliferation on stiff surfaces. This observation is interesting because it suggests that cancer cells potentially ignore negative physical cues, such as a soft ECM, and exploit positive stimuli in the form of a stiff ECM. This brings to mind a ‘yin and yang’ equilibrium which is ever shifting in favor of cancer cell survival and growth. We propose that different rigidities, which cancer cells may encounter in different regions of the body, can lead to modifications in the interactions and adhesions of the cells with the ECM, thus activating signaling pathways that boost cancer cell proliferation. Here, we discuss these interactions through the lens of mechanosensing, and its abnormal function in cancer.In cancer, two unique and seemingly contradictory behaviors are evident: on the one hand, tumors are typically stiffer than the tissues in which they grow, and this high stiffness promotes their malignant progression; on the other hand, cancer cells are anchorage-independent—namely, they can survive and grow in soft environments that do not support cell attachment. How can these two features be consolidated? Recent findings on the mechanisms by which cells test the mechanical properties of their environment provide insight into the role of aberrant mechanosensing in cancer progression. In this review article, we focus on the role of high stiffness on cancer progression, with particular emphasis on tumor growth; we discuss the mechanisms of mechanosensing and mechanotransduction, and their dysregulation in cancerous cells; and we propose that a ‘yin and yang’ type phenomenon exists in the mechanobiology of cancer, whereby a switch in the type of interaction with the extracellular matrix dictates the outcome of the cancer cells.

Bioengineered Models to Study Microenvironmental Regulation of Glioblastoma Metabolism.

Despite extensive research and aggressive therapies, glioblastoma (GBM) remains a central nervous system malignancy with poor prognosis. The varied histopathology of GBM suggests a landscape of differing microenvironments and clonal expansions, which may influence metabolism, driving tumor progression. Indeed, GBM metabolic plasticity in response to differing nutrient supply within these microenvironments has emerged as a key driver of aggressiveness. Additionally, emergent biophysical and biochemical interactions in the tumor microenvironment (TME) are offering new perspectives on GBM metabolism. Perivascular and hypoxic niches exert crucial roles in tumor maintenance and progression, facilitating metabolic relationships between stromal and tumor cells. Alterations in extracellular matrix and its biophysical characteristics, such as rigidity and topography, regulate GBM metabolism through mechanotransductive mechanisms. This review highlights insights gained from deployment of bioengineering models, including engineered cell culture and mathematical models, to study the microenvironmental regulation of GBM metabolism. Bioengineered approaches building upon histopathology measurements may uncover potential therapeutic strategies that target both TME-dependent mechanotransductive and biomolecular drivers of metabolism to tackle this challenging disease. Longer term, a concerted effort integrating in vitro and in silico models predictive of patient therapy response may offer a powerful advance toward tailoring of treatment to patient-specific GBM characteristics.

Treatment-induced shrinking of tumour aggregates: a nonlinear volume-filling chemotactic approach.

Motivated by experimental observations in 3D/organoid cultures derived from glioblastoma, we propose a novel mechano-transduction mechanism where the introduction of a chemotherapeutic treatment induces mechanical changes at the cell level. We analyse the influence of these individual mechanical changes on the properties of the aggregates obtained at the population level. We employ a nonlinear volume-filling chemotactic system of partial differential equations, where the elastic properties of the cells are taken into account through the so-called squeezing probability, which depends on the concentration of the treatment in the extracellular microenvironment. We explore two scenarios for the effect of the treatment: first, we suppose that the treatment acts only on the mechanical properties of the cells and, in the second one, we assume it also prevents cell proliferation. We perform a linear stability analysis which enables us to identify the ability of the system to create patterns and fully characterize their size. Moreover, we provide numerical simulations in 1D and 2D that illustrate the shrinking of the aggregates due to the presence of the treatment.

Mechanobiology of Pulmonary Diseases: A Review of Engineering Tools to Understand Lung Mechanotransduction.

Cells within the lung micro-environment are continuously subjected to dynamic mechanical stimuli which are converted into biochemical signaling events in a process known as mechanotransduction. In pulmonary diseases, the abrogated mechanical conditions modify the homeostatic signaling which influences cellular phenotype and disease progression. The use of in vitro models has significantly expanded our understanding of lung mechanotransduction mechanisms. However, our ability to match complex facets of the lung including three-dimensionality, multicellular interactions, and multiple simultaneous forces is limited and it has proven difficult to replicate and control these factors in vitro. The goal of this review is to (a) outline the anatomy of the pulmonary system and the mechanical stimuli that reside therein, (b) describe how disease impacts the mechanical micro-environment of the lung, and (c) summarize how existing in vitro models have contributed to our current understanding of pulmonary mechanotransduction. We also highlight critical needs in the pulmonary mechanotransduction field with an emphasis on next-generation devices that can simulate the complex mechanical and cellular environment of the lung. This review provides a comprehensive basis for understanding the current state of knowledge in pulmonary mechanotransduction and identifying the areas for future research.

Components and Mechanisms of Nuclear Mechanotransduction.

The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene expression. As its largest and stiffest organelle, the nucleus also defines the minimal space requirements of a cell. Internal or external pressures that deform a cell to its physical limits cause a corresponding nuclear deformation. Evidence is consolidating that the nucleus, in addition to its genetic functions, serves as a physical sensing device for critical cell body deformation. Nuclear mechanotransduction allows cells to adapt their acute behaviors, mechanical stability, paracrine signaling, and fate to their physical surroundings. This review summarizes the basic chemical and mechanical properties of nuclear components, and how these properties are thought to be utilized for mechanosensing.

Targeted Remodeling of the Tumor Microenvironment Via Mechanical Stimulation Defines a Novel Therapeutic Strategy in Myeloma Bone Disease

Multiple myeloma (MM) patients develop devastating osteolytic bone disease causing non-healing bone fractures and pain. MM cells in the bone marrow microenvironment stimulate osteoclast activity and inhibit osteoblast and osteocyte function leading to massive bone resorption and therefore destruction. Bones have the capacity to locally adapt to changing loads and for self-repair and remodeling as dramatically seen in athletes during training. In this study we determined if mechanical loading can counterbalance osteolytic bone disease in the presence of established MM. We hypothesized that mechanical stimulation increases bone formation and decreases bone resorption by activating known bone (re)modeling pathways, which are deleteriously altered by MM cells in bone. We performed in vivo cyclic axial compressive tibial loading (Fig. 1) to MOPC315.BM BALB/c injected mice (n=19) with established MM bone disease (Fig. 2, bioluminescence imaging). The bone (re)modeling response to mechanical loading (5d/wk, over 3 wks) was investigated by longitudinal in vivo microCT imaging at days 14, 18, 23, 28 and 33 (Fig. 3, 4). Loading was administered to the left tibia starting 14 days after i.t. injection of left limbs of MOPC315.BM (n=10) and PBS (n=7) mice (left limb: εmax=2000µε determined by strain gauging, right limb was nonloaded). 15 mice served as nonloaded control mice (Fig. 3). We also analyzed a group of loaded, but not injected mice (n=10). MicroCT data (Fig. 3), such as cortical thickness (Ct.Th), cortical bone area (Ct.Ar) of loaded left limbs demonstrate that metaphyseal cortical bone formation was significantly greater and cortical porosity (Ct.Po) was lower compared to nonloaded control limbs. Our data provide for the first time an indication that mechanical loading counteracts MM induced bone loss over time. To further study mechanisms of mechanotransduction we used a small scale cell culture bioreactor system to analyze mechanical stimulation of human mesenchymal stem cells (hMSCs) and the translation of mechanical forces into biochemical signals. The bioreactor system allows for analysis of molecular mechanisms of mechanotransduction using a transcription factor activator protein (AP1) luciferase reporter gene construct. Cyclic stretching of telomerase immortalized hMSCs (hMSC-TERT cells) which were stably transfected by an AP1 construct resulted in stimulation of AP1 activity as measured by luciferase gene expression. We analyzed how MM cells interfere with mechanotransduction when co-cultured with hMSC-TERT cells. Our data show that in presence of MOPC315.BM cells and 2 (MM1S, INA-6) out of 4 human MM cell lines hMSCs can be mechanically stimulated and have osteogenic activity. In contrast the human MM cell lines Amo-1 and U266 inhibit the hMSC-TERT response to mechanical stimulation under these conditions. Biochemical and molecular genetic studies are underway to determine how MM cells in bone alter known bone (re)modeling pathways and which yet unanticipated factors regulate the anabolic response to mechanical loading in the MOPC315.BM model. Our study provides a first fundamental understanding of the mechano-biological mechanisms of anabolic bone adaption during MM bone disease in response to mechanical stimuli. We conclude that mechanical loading in the form of exercise has the potential to be a potent novel anabolic strategy for primary and secondary prevention of MM bone disease. Moreover dissection of the underlying molecular pathways will identify new targets for innovative antimyeloma strategies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mechanobiology of cancerogenesis.

Within the tumour microenvironment, tumour cells are exposed to different mechanical stimuli such as compression stress, cell-cell and cell-extracellular matrix traction forces, interstitial fluid pressure, and shear stress. Cells actively sense and process this information by the mechanism of mechanotransduction to make decisions about their growth, motility, and differentiation. Indeed, the mechanical properties of the tumour microenvironment can deeply influence the behaviour of cancer cells and promote cancerogenesis. During tumour progression, desmoplasia arises and apositive feedback loop between the stiffening extracellular matrix and the properties enabling tumour expansion is established. Tumour cells can use mechanic stimuli to promote proliferation, increase their migratory and invasive potential, and induce therapeutic resistance. Mechanobio-logy is aprogressive multidisciplinary field which studies how mechanical forces influence the behaviour of cells or tissues and may provide some interesting targets for cancer therapy. In this review, we discuss the mechanical properties of cancer cells and describe the tumour promoting effect of the transformed extracellular matrix. We propose that the differences in the mechanobio-logy of cells and extracellular matrix are significant enough to facilitate tumorigenesis and may provide interesting targets for cancer therapy.

The role of osteocytes-specific molecular mechanism in regulation of mechanotransduction - A systematic review.

BackgroundOsteocytes, composing over 90% of bone cells, are well known for their mechanosensing abilities. Aged osteocytes with impaired morphology and function are less efficient in mechanotransduction which will disrupt bone turnover leading to osteoporosis. The aim of this systematic review is to delineate the mechanotransduction mechanism at different stages in order to explore potential target for therapeutic drugs.MethodsA systematic literature search was performed in PubMed and Web of Science. Original animal, cell and clinical studies with available English full-text were included. Information was extracted from the included studies for review.ResultsThe 26 studies included in this review provided evidence that mechanical loading are sensed by osteocytes via various sensing proteins and transduced to different signaling molecules which later initiate various biochemical responses. Studies have shown that osteocyte plasma membrane and cytoskeletons are emerging key players in initiating mechanotransduction. Bone regulating genes expressions are altered in response to load sensed by osteocytes, but the genes involved different signaling pathways and the spatiotemporal expression pattern had made mechanotransduction mechanism complicated. Most of the included studies described the important role of osteocytes in pathways that regulate mechanosensing and bone remodeling.ConclusionsThis systematic review provides an up-to-date insight to different steps of mechanotransduction. A better understanding of the mechanotransduction mechanism is beneficial in search of new potential treatment for osteoporotic patients. By delineating the unique morphology of osteocytes and their interconnected signaling network new targets can be discovered for drug development.Translational potential of this articleThis systematic review provides an up-to-date sequential overview and highlights the different osteocyte-related pathways and signaling molecules during mechanotransduction. This allows a better understanding of mechanotransduction for future development of new therapeutic interventions to treat patients with impaired mechanosensitivity.

Purinergic P2 Receptors: Novel Mediators of Mechanotransduction.

Mechanosensing and mechanotransduction are vital processes in mechanobiology and play critical roles in regulating cellular behavior and fate. There is increasing evidence that purinergic P2 receptors, members of the purinergic family, play a crucial role in cellular mechanotransduction. Thus, information on the specific mechanism of P2 receptor-mediated mechanotransduction would be valuable. In this review, we focus on purinergic P2 receptor signaling pathways and describe in detail the interaction of P2 receptors with other mechanosensitive molecules, including transient receptor potential channels, integrins, caveolae-associated proteins and hemichannels. In addition, we review the activation of purinergic P2 receptors and the role of various P2 receptors in the regulation of various pathophysiological processes induced by mechanical stimuli.

Multiscale numerical analyses of arterial tissue with embedded elements in the finite strain regime

Multiscale models based on representative volume elements (RVEs) might help unraveling the ways in which macroscopic loadings affect the microstructure of tissues reinforced by collagen fibers, and vice versa. Tissues such as arteries, however, are characterized by a significant collagen dispersion. Therefore, many fibers have to be included in the RVE to achieve a representative geometrical model of the microstructure. For this reason, when the finite element method is employed in the numerical homogenization, fibers are commonly modeled as 1D elements, either by considering a network of trusses or the embedded elements technique. With regard to the latter, there has been little attention in previous works concerning the influence of the chosen multiscale boundary conditions and RVE size. In order to address this issue, the present work combines a sound multiscale framework with the classical embedded elements technique to simulate four increasingly larger RVEs, which resemble the microstructure of the medial layer of the arterial wall. Each RVE is modeled as a ground substance with embedded collagen fibers and subjected to a macroscopic isochoric equibiaxial stretch up to 10%, according to four classical multiscale boundary conditions: Taylor-Voigt, linear boundary displacements, periodic boundary fluctuations and minimally constrained model. Results are evaluated both at the macroscopic level (homogenized response) and the microscopic level (strains in the ground substance and fiber stretches). At the macroscopic level, the homogenized response for the periodic boundary condition seems to converge faster than the other three with increasing RVE size. At the microscopic level, the periodic model is also less prone to concentrated effects at the boundaries of the RVE. Therefore, among the four classical multiscale boundary conditions, the periodic model seems to be better suited to simulate the microstructure of fibrous tissues employing the embedded elements technique. Importantly, the resulting microscopic strain fields are characterized by a considerable degree of inhomogeneity and some values are significantly larger than the macroscopic (imposed) strain. That could help to shed more light on relevant mechanotransduction mechanisms, e.g., cell signaling, that are known to happen in the arterial media and are linked to biological processes such as growth and remodeling. Therefore, the framework herein proposed may serve as a valuable tool for the investigation of microstructural phenomena that happen in arteries, or even other fibrous tissues.