Physical and Geometrical Modulation of Human Fibroblast Behaviour
Abstract
This thesis investigates the impact of mechanical stimuli, specifically substratum topography and elastic modulus, on dermal and gingival fibroblast behaviour associated with scarring and regeneration. Scar formation presents a significant issue for implanted biomaterials often leading to device failure. Even though scar formation is a normal end point to adult human dermal wound healing, gingival wounds are capable of tissue regeneration or scarless wound healing. Understanding how these cells respond to environmental cues, including substratum topography and elastic modulus, is central to the development of novel biomaterials for stimulation of tissue regeneration. It was hypothesized that topographic features, with submicron periodicity, will inhibit increased cell contraction and excessive extracellular matrix deposition on materials with a high stiffness.
The first aim quantifies and compares adhesion behaviors of human dermal and gingival fibroblasts on materials patterned with anisotropic sub-micron topographies. I reveal distinct responses between the two cell types including the necessity of integrin β1 in human dermal fibroblast (HDF) contact guidance. The second aim investigates the impact of varying elastic moduli on fibroblast physiology, highlighting differences in adhesion size and composition, F-actin arrangement, myofibroblast differentiation, and extracellular matrix production. The third aim introduces a novel, combined, elastic modulus-varied, topographic cell culture device, incorporating sub-micron topographies into a tunable elastic modulus material for the first time. This device will facilitate the study of how cells integrate mechanical stimuli, offering insights into their effects in vivo, specifically within soft tissue environments.
This work identifies the tissue of origin as a crucial determinant in fibroblast response to topography and elastic moduli, challenging existing theories on adhesion formation, and providing insights into integrin engagement mechanisms. The interplay between topography and elastic modulus is explored, suggesting a potential strategy for reducing fibrotic events related to implanted biomaterials.
Overall, this thesis enhances our understanding of fibroblast responses to microenvironmental cues, emphasizing the importance of tissue-specific considerations in biomaterial design and paving the way for future research in tissue engineering and wound healing.