Biofabrication of Immunocompetent 3D Skin Tissue Equivalents to Model Skin Wound Healing and Fibrosis

Authors

• YW Lim
• H Zarkoob
• MJ Song
• M Ferrer

Abstract

Wound healing is a dynamic and tightly coordinated process to maintain the structural and functional integrities of the skin. Injury to the skin initiates a cascade of events including inflammation, proliferation, and tissue remodeling. Dysregulation in these mechanisms can lead to the formation of non-healing chronic wounds, affecting around 5.7 million people in the United States alone. Therefore, there is an urgent need to understand the pathophysiology of wound healing to develop effective therapies. Macrophages are key immune regulators that play distinct roles to ensure proper wound healing and tissue regeneration. Throughout these tightly regulated processes, M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages secrete cytokines and chemokines that modulate fibroblast proliferation, activation, as well as collagen production. Our group has previously developed three-dimensional (3D) skin tissue equivalents that closely mimic human skin tissue and model inflammatory skin diseases. Here, we introduced human macrophages derived from peripheral monocytes into our 3D skin tissue model to generate an immune-competent skin tissue. The addition of macrophages into our 3D skin tissue upregulates the production of cytokines and chemokines that carries immunomodulatory effects on other cell types in the skin and modulate tissue remodeling. Furthermore, we validate that macrophages incorporated into the dermis can respond to bacterial and viral stimuli. Lastly, the introduction of M2 macrophages in our 3D skin tissue increases collagen deposition in the skin dermis layer upon TGFβ1 treatment, mimicking a skin fibrosis phenotype. This immunocompetent 3D skin model will be a powerful platform for pre-clinical testing for immune-modulated skin diseases.

Scientific Focus Area: Biomedical Engineering and Biophysics

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