MICRO-MECHANICAL FINGERPRINTS OF BLADDER IN HEALTH AND DISEASE

Tissue mechanics determines tissue homeostasis, disease development and progression. Bladder strongly relies on its mechanical properties to perform its physiological function, but these are poorly unveiled under normal and pathological conditions. In addition, the bladder is a multilayer organ and it is thus needed to understand tissue mechanics at the microscale, spatially resolving the different bladder layers and their contribution to altered tissue mechanics. This thesis aimed to characterize the micromechanical fingerprints of the healthy bladder wall, and to identify modifications associated with the onset and progression of pathological conditions of actinic cystitis and bladder cancer. To do so I used two indentation-based instruments (an Atomic Force Microscope and a nanoindenter) and compared the micromechanical maps with a comprehensive histological analysis. I found that the healthy bladder is a mechanically inhomogeneous tissue, with a gradient of increasing stiffness (in terms of Young’s modulus, YM) from the urothelium to the lamina propria, which gradually decreased when reaching the muscle layer. Stiffening in fibrotic tissues correlated with increased deposition of dense extracellular matrix in the lamina propria. An increase in tissue compliance was observed before the onset and invasion of the tumor. In addition, aiming to establish an experimental approach that would facilitate its application to the clinical environment, I here used Brillouin imaging to investigate healthy and fibrotic bladder, and confront the mechanical information from this non-contact technique to the gold-standard in nanomechanics (indentation-based mechanical tests). While Brillouin imaging reported the same mechanical trend observed by indentation-based mechanical tests when investigating intrinsic mechanical heterogeneities of the bladder wall, a decrease of Brillouin shift in fibrotic bladder was observed contrary to the increased YM measured by indentation-based mechanical tests, thus highlighting different physical phenomena detected by the different techniques and the need to further investigate correlations between both techniques. By providing high resolution micromechanical investigation of each tissue layer of the bladder, I here depicted the intrinsic mechanical heterogeneity of the layers of the healthy bladder as compared with the mechanical properties alterations associated with either actinic cystitis or bladder tumor; and provided an accurate comparison of the gold-standard technique in biomechanics to Brillouin imaging.