Multiscale biomechanical investigation of human aortas

Arteries have a remarkable ability to adapt in response to altered blood flow, diseases, and injury. Altered arterial tissue properties in diseased conditions such as atherosclerosis arise from changes in wall constituents at different length scales. This project proposal is based on the fact that multiscale biomechanical analyses of healthy and diseased arteries and its modeling can be used to understand many pathophysiological processes at different length scales. This also allows the identification of relationships between structural alterations and diseases. In this study aortic tissue imaging and mechanical characterization techniques will be combined at the macro-, micro- and nanoscale to develop and validate next generation multiscale material laws. Realistic biomechanical testing and multi-photon microscopy imaging will be simultaneously used to obtain properties at the micro- and macroscale of healthy and atherosclerotic human aortas. Moreover, the nanostructure of interfibrillar proteoglycans, and of constituents of collagen (e.g., tropocollagen, fibrils), elastin (e.g., tropoelastin, fibrillin), and smooth muscle cells (e.g., myosin, actin) will be determined by three-dimensional transmission electron microscopy. The combination of the obtained data is used for the development of novel material laws which explicitly incorporate nanoscale, microscale and macroscale mechanisms as well as their coupling effects. The novelties of this project are the application and development of experimental methods on different hierarchical scales, and the intelligent combination, integration and validation of experimental techniques to give an explanation for the role of important constituents in arterial mechanics, physiology, and pathology. This approach is a step forward to investigate and understand the development, growth and remodeling principles of biological tissues and their response to pathological conditions. The project approaches well-defined clinical problems from engineering and biological perspectives. The interdisciplinary character of the proposed research project will involve scientists from different research fields, i.e. biomechanics, mechanobiology, ultrastructural analysis, histology, and pathology.

Cardiovascular diseases are the main cause of death not only in Austria but worldwide. Cardiovascular diseases include aortic-related diseases such as atherosclerosis, aneurysm, or aortic dissection. The aorta is the main artery of the human body, which originates directly at the heart and distributes oxygenated blood to all organs. Severe stiffening or rupture of aortas have therefore most tragical consequences. Hence, it is in everyones interest to be aware of its condition. A big issue is that the mechanical properties of the aorta are not fully understood yet. In contrast, a steel construction, e.g., a bridge, can be designed by engineers in a safe way, and a built bridge can be checked regarding its condition and signs for an upcoming failure. This is possible since the mechanical properties of steel are well explored. However, signs indicating an upcoming failure of the aorta are not known. It is, therefore, very important to investigate the mechanical properties of aortas. The project Multiscale Biomechanical Investigation of Human Aortas focused on experiments, which are able to explore changes in the micro- and nanostructure of human aortic tissues caused by different levels of mechanical loadings. One goal was to discover signs in the structure, which could lead to aortic failure. Specifically, we prepared square specimens from the aortic wall and stretched them in the circumferential and axial direction, performing so-called biaxial extension tests, to mimic physiological stretches, i.e., stretches to which the aorta is exposed in the human body. At the same time, we observed the microstructure of the aortic tissue, in particular of the main load-bearing components collagen and elastin fibers, using multi-photon microscopy. Additionally, we looked inside the collagen fibers, i.e., to its nanostructure, using transmission electron microscopy. With this technique, we were able to observe collagen fibrils and proteoglycans, whereas the mechanical function of proteoglycans is still not clear. Based on our experiments, we observed that collagen and elastin fibers were mostly wavy in the unloaded aortas. In some aortas, however, collagen and/or elastin fibers were already straight in the unloaded configuration. Most importantly, aortas with straight collagen fibers were stiff, and stiff aortas are lacking the ability to elastically support the blood flow. Moreover, aortas with straight elastin fibers ruptured during biaxial extension testing, and an aortic wall rupture causes internal bleeding with a high risk of death. The above-stated findings need further validation, nevertheless, they are an important step towards a better understanding of the impact of load onto the micro- and nanostructure of the human aorta. With the mechanical and structural data gained in this project, more detailed computer simulations to study the failure risk and its corresponding failure mechanisms of aortas will be feasible.