Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Biomedical Engineering

First Advisor

Edward A. Sander

Abstract

Many physiological and pathological processes, such as wound healing and tissue remodeling, are heavily influenced by continuous mechanical cell-cell and cell-ECM communication. Abnormalities that may compromise the biomechanical communication between the cells and the ECM can have significant repercussions on these physiological and pathological processes. The state of the mechanical environment and the reciprocal communication of mechanical signals between the ECM and the cell during wound healing and aged dermal tissue regeneration may be key in controlling the quality of the structure and physical properties of regenerated tissue.

This dissertation encompasses a series of studies developed for characterizing the effects of mechanical cues on altering and controlling tissue remodeling, and regeneration in the context of controlling scar formation during wound healing, and the maintenance and regeneration of the dermal extracellular matrix (ECM) during aging. In order to achieve this goal, in vitro models that contained some features of the provisional ECM, and the ECM of the dermis were developed and subjected to an array of quantifiable mechanical cues. Wound models were studied with different mechanical boundary conditions, and found to exhibit differences in initial short-term structural remodeling that lead to significant differences in the long-term synthesis of collagen after four weeks in culture. Dermal models seeded with fibroblasts from individuals of different ages were treated with a hyaluronic acid (HA)-based dermal filler. Changes in the mechanical environment of the dermal models caused by swelling of the hydrophilc HA, resulted in changes in the expression of mechanosensitive, and ECM remodeling genes, essential for the maintenance and regeneration of dermal tissue. Taken together, these data provide new insights on the role of mechanical signals in directing tissue remodeling.

Public Abstract

The integrity, composition and function of cutaneous tissue is highly dependent on the physical interactions that occur between fibroblasts and the composite of proteins that make up the structural frame-work of said tissue. Many physiological and pathological processes depend on the ability of the fibroblast to sense mechanical cues from its environment and respond by altering its tissue remodeling capabilities in order to maintain equilibrium and the structural integrity of tissue.

This dissertation describes a series of studies that were developed for characterizing the effects of different mechanical cues on altering tissue remodeling, regeneration and repair in the context of controlling scar formation during wound healing and the maintenance and regeneration of the aged dermis. To achieve this goal, in vitro models of the wound and the extracellular matric (ECM) of the dermis were developed and were subjected to an array of quantifiably mechanical cues. Wound models were subjected to different physical constraints and were found to exhibit differences in initial short-term structural remodeling that lead to significant differences in the long-term synthesis of collagen after four weeks in culture. Dermal models seeded with fibroblasts from individuals of different ages were treated with a hyaluronic acid (HA)-based dermal filler. Changes in the mechanical environment of the dermal models caused by swelling of the hydrophilc HA, resulted in changes in the expression of mechanosensitive, and ECM remodeling genes, essential for the maintenance and regeneration of dermal tissue. Taken together, these data provide new insights on the role of mechanical signals in directing tissue remodeling.

Keywords

publicabstract, Aging, ECM remodeling, Fibroblast-ECM interactions, In vitro tissue models, Multi-scale mechanical interactions, Wound healing

Pages

xiv, 121

Bibliography

99-107

Copyright

Copyright 2016 Aribet Marie De Jesus

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