Although the extracellular matrix (ECM) is the key determinant of the mechanical behavior and stability of tissue, remarkably little is known on this tissue component. Most biomedical research on... Show moreAlthough the extracellular matrix (ECM) is the key determinant of the mechanical behavior and stability of tissue, remarkably little is known on this tissue component. Most biomedical research on the human aorta focuses on biochemical analysis of tissues or the properties of specific cells in the aorta. We show that a physics-based approach can yield important complementary insight. By measuring the mechanical response of the ECM by AFM and imaging it with multi-photon microscopy, we show that the spatial organization of the network structure of collagen fibers plays an important role. First we show how aneurysms, a local dilatation of the arterial wall, are caused by profound defects in collagen network. The collagen fibers in het healthy aorta are organized in a loose braiding of collagen ribbons, while the aneurysmatic tissue show dramatically altered collagen architectures with loss of the collagen knitting. Evaluation by AFM shows how this altered network could explain the failure of the tissue. In a follow-up study, we examine the effects of enzymatic digestion of the ECM of the aortic wall. By starting with real tissue and selectively removing different elements, we are able to measure the contribution of the different constituents of the ECM to the mechanical properties of the whole tissue. We also show how the content of neutrophils is able to mimic the observed change in mechanical response from a healthy aorta to an aneurysm. Finally we will show first results on the disease of atherosclerosis, another common vascular disease. The collagen structure of the cap changes during the growth of the atherosclerotic plaque and we discuss its mechanical implications. This study gives key insights in the failure mechanism of two common pathologies and provides biomedical researchers a new, physics-oriented view to organs, with implications for the study of wound healing, myocardial infarction and cancer cell migration. Show less
The aim of this thesis is to evaluate the effect of doxycycline on the proteolytic and inflammatory processes in abdominal aneurysms. This data is essential for the development of pharmaceutical... Show moreThe aim of this thesis is to evaluate the effect of doxycycline on the proteolytic and inflammatory processes in abdominal aneurysms. This data is essential for the development of pharmaceutical strategies for the stabilization of an AAA. Such an approach could reduce the need for elective surgery and endovascular repair. It has repeatedly been shown that AAA progression and rupture is related to the failure of collagen in the aortic wall. Yet the exact mechanism underlying this failure remains unknown. Furthermore, the precise mechanism of activation of collagenases and their inflammatory mediators that are responsible for the collagen turnover of AAA are unknown. In this thesis we attempt to determine how collagen metabolism is balanced in aneurysmal diseases and contribute to the knowledge which collagenases and inflammatory mediators are involved in the destruction of the collagen network in AAA disease. Moreover, we evaluate some of the effects of doxycycline on the proteases and inflammatory mediators in AAA. Analyses showed that doxycycline inhibits specific MMPs and inflammatory pathways that are involved in the collagen balance and aneurysm growth. Together, these observations provide a rationale for a randomized clinical trial studying the effect of doxycycline on aneurysm growth. Show less
