Fundamental Insights into Arterial Remodelling; Strain-Mediated Degradation of Arterial Collagen

Abstract

Maladaptive remodelling of structurally significant collagen fibres in the arterial wall is believed to play a critical role in the development and progression of degenerative arterial disease. A greater understanding of this strain-mediated process may pave the way for improved patient screening, as well as the development of novel medical devices capable of halting or even reversing maladaptive arterial remodelling. The aim of this thesis is to investigate, for the first time, the strain-dependent reorientation and degradation behaviour of arterial collagen, using a combined experimental and numerical approach. To achieve this, structural analysis was first carried out with an optimised, purpose-built small angle light scattering system, to identify the collagen fibre response to strain-dependent degradation. Next, strain dependent degradation rates were determined from stress relaxation experiments in the presence of crude and purified collagenase. This allowed for determination of the tissue level degradation response in arterial dogbone specimens. A complementary computational model was developed, incorporating matrix stiffness and a gradient of collagen fibre crimp to decouple the mechanism behind the strain-dependent degradation data. This model was then used to predict the degradation response of full intact vessels, subjected to physiologically relevant pressures. Finally, the model was applied to an idealised vessel geometry to investigate the role of straindependent degradation in the development of degenerative arterial disease. Structural analysis identified a statistically significant difference in collagen fibre alignment due to strain-dependent degradation. Subsequent mechanical testing identified a unique stress degradation response occurring at the tissue scale, which was not seen in other collagenous tissues. The model was capable of accurately predicting the experimental findings, but only in the presence of three critical components. Namely, the load bearing matrix, its degradation response and the gradient of collagen fibre crimp across the arterial wall. The model also predicted the increased rate of degradation-induced vessel expansion with increasing pressure, which was previously identified experimentally, despite elevated rates of degradation at low pressure. Finally, the model also identified accelerated degradation and subsequent aneurysm growth occurring at a location of initial vessel weakness. These findings highlight the critical role of strain in arterial degradation, particularly in the case of progressive degenerative disease whereby structural integrity may be compromised.