Passariello, Roberta (2024) An immunocompetent 3D-Human Dermal Equivalent model to unravel the complexities of wound healing and scar formation. [Tesi di dottorato]

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Abstract

The skin isolates and protects the body from external agents, and in case of injury, it initiates a natural biological phenomenon, known as wound healing, during which the body blocks the bleeding, heals, and closes the wound. The damaged tissue is then rebuilt, and the injury is repaired. It is during the repair process of such injuries that the mechanism of formation of a crippling scar occurs. In this phase, it may occur that the fibrous connective tissue, which fills empty spaces, follows the pattern of the tissue but in a disorganized way and loses elasticity. Fibrotic tissue formation is characterized by excessive growth and hardening of various tissues due to the disproportionate deposition of components of the ECM, especially type I collagen. Of the latter, a microscopically reticulated network is created, which not only causes a mechanical restriction, but also the thickened tissue is weak and hypoxic. The diversity of the lesion produces different scars. Some are not even noticeable and do not cause discomfort, while others can be painful, unsightly, real disfigurements, and therefore disabling to the point of causing relational problems, especially if they affect the face. Other scars can create movement limitations and adhesions. The entire biological complex process is strongly influenced and regulated by the inflammatory response triggered by both tissue-resident and circulating cells of the immune system. Although inflammation occurs almost immediately after the injury, this strictly regulates the final stages of healing. In particular, the mediators released by M2 macrophages stimulate fibroblasts towards the production of scar tissue and, consequently, give shape to the final repair result. Hence, the manipulation of immune elements emerges as an appealing strategy in the field of regenerative medicine, as the widespread efficacy of stem cell and growth factor interventions in clinical settings remains to be conclusively demonstrated. To accomplish these tasks, this study employs innovative 3D-HDE models to delve into the detailed mechanisms of wound healing and scar formation. By producing controlled injuries in these models, we aim to comprehensively analyse cellular responses and ECM dynamics during the wound closure process. The focus is on understanding the intricate interplay between fibroblasts and the ECM, crucial for guiding the wound repair process. Additionally, our investigation extends to exploring microenvironmental changes and matrix remodelling in response to simulated immunocompetence, emphasizing the integration of endogenous matrices with immune system components, especially M2 macrophages. Our research has demonstrated that the 3D-HDE models replicate some aspects of the complexity of the human dermis, offering a valuable platform for simulating and studying wound healing and scar formation processes. The comprehensive analysis of cellular and matrix-level interactions has allowed us to identify the specific molecular and cellular events that lead to the formation of scars.

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