Biological and Biomechanical Effects of Direct Perturbation of Tissue Structure in the Cirrhotic Liver

Abstract

Cirrhosis is the scarring that occurs as the common final stage of chronic liver diseases. Although our understanding of the disease has improved substantially over the past several decades, there has been little progress in the treatment of cirrhosis. Drug development has been unsuccessful largely because it is difficult to reverse profound structural changes with a pharmaceutical approach. Consequently, there is a need for innovative new approaches to the treatment of cirrhosis that can exert greater influence on tissue architecture. This thesis explores three innovative treatment strategies, each aimed at directly perturbing tissue structure through a distinct mechanism.

First, we investigate microinjury perturbation using a fractional laser. This work revealed an exacerbated injury response in the cirrhotic liver. Through investigating the mechanism of this response, we revealed a novel ischemic susceptibility related to the microvascular architecture.

We then investigate lytic perturbation through interstitial infusion of collagenase clostridium histolyticum and mechanical perturbation through shockwave disruption. With both techniques we were able to show significant reductions in fibrosis with minimal toxicity.

Direct perturbation methods have been underexplored in the search for a treatment for cirrhosis and fibrosis of internal organs in general. Our findings highlight the potential of such an approach and may pave the way for new therapeutic options.