Abstract
(1) Background: Wound healing is a highly coordinated process encompassing hemostasis, inflammation, angiogenesis, keratinocyte migration, collagen deposition, and extracellular matrix remodeling. Successful repair also requires adequate nutrient and oxygen delivery through a well-developed vascular supply. Disruption of these processes can occur through aberrations in diverse biological pathways, including extracellular matrix organization, cellular adhesions, angiogenesis, and immune regulation. (2) Methods: We reviewed mechanisms of impaired tissue repair in monogenic disorders by focusing on three categories-connective tissue, hematological/immunological, and aging-related disorders-to illustrate how single-gene defects disrupt inflammation, cellular proliferation, and matrix remodeling. Additionally, we reviewed various polygenic disorders-chronic kidney disease, diabetes mellitus, hypertension, and obesity-to contrast complex multifactorial pathologies with single-gene defects. (3) Results: This review establishes that genetic impediments, despite their distinct etiologies, monogenic and polygenic disorders share critical downstream failures in the wound healing cascade. While monogenic diseases illustrate direct causal links between specific protein deficits and repair failure, polygenic diseases demonstrate how multifactorial stressors overwhelm the body's regenerative capacity. (4) Conclusions: This review synthesizes current evidence on both monogenic diseases and polygenic contributions to impaired wound healing. These findings highlight that genetic susceptibility is a decisive factor in the ability to restore tissue homeostasis. This underscores the profound impact of genetic background on the efficacy of hemostasis, inflammation, and remodeling.