In this thesis computational modeling is used to help unravel the mechanisms of key steps in angiogenesis, the formation of new capillaries from existing blood vessels. The first step in... Show moreIn this thesis computational modeling is used to help unravel the mechanisms of key steps in angiogenesis, the formation of new capillaries from existing blood vessels. The first step in angiogenesis is the invasion of new branches into the surrounding tissue by degradation of extracellular matrix proteins, e.g. fibrin. A first model describes how invading sprouts use the so called plasminogen system, which dissolves fibrin matrices. A next model asks how endothelial cells can dynamically switch position during angiogenesis. Based on experimental observations, several authors suggest that dynamic cell shuffling is under strict, genetic control. Our simulations show, however, that shuffling can emerge as a side effect of sprouting. Once a sprout is formed, it needs to hollow to allow blood flow. The mechanisms responsible for this hollowing, or lumen formation, are debated: vacuoles may punch a hole through the cell, or cells might repulse one another. In our simulations, both these hypotheses can work synergistically in lumen formation, suggesting that both hypotheses might work together. In a final chapter, we introduce a workflow to simultaneously test the impact of changes in the value of multiple parameters on the outcome of the type of models used in this thesis. Show less
The primary goal in repairing a peripheral nerve lesion is to guide the outgrowing axon back to its original target organ, which can be done by bridging the defect with an autograft or, more... Show moreThe primary goal in repairing a peripheral nerve lesion is to guide the outgrowing axon back to its original target organ, which can be done by bridging the defect with an autograft or, more experimentally, a synthetic nerve graft. In this thesis an overview is presented of the evaluation methods that are currently used to assess peripheral nerve regeneration and their expediency is discussed. An in vitro electrophysiological evaluation method that charts the electrophysiological properties of the myelinated Aα- and Aβ-nerve fibres was introduced, and it was demonstrated that small differences between grafted nerves could be discriminated. Moreover, the electrophysiological data could be correlated to the morphometrical data, that was likewise broken up into Aα- and Aβ-components. This correlation especially provided new insight in the changes that occur in regenerating nerve fibres. After applying a panel of evaluation methods it was demonstrated that the presence of pores in and biodegradability of synthetic nerve grafts are beneficial to regeneration, evidenced mainly by preferable values of the electrophysiological parameters. Finally the changes that occurred in reinnervated muscles helped to gain insight into the preferential architecture of a synthetic nerve graft. Show less
