Wound pathophysiology and healing dynamics for stem cell-mediated therapeutics in different skin wounds

Abstract

Skin wound healing is a multifaceted and highly regulated biological event, which includes inflammation, cell proliferation, extracellular matrix deposition, neovascularization, and tissue remodeling. The underlying pathophysiological and healing dynamics of skin injuries vary significantly depending on the nature, depth, and etiology of the wound. Full-thickness excisional wounds, acid-induced chemical burns, and cold-induced burn injuries have distinct pathological patterns, each characterized by differential inflammatory cascades, oxidative stress levels, cellular infiltration, vascular compromise, and tissue regeneration dynamics. Understanding this heterogeneity necessitates the development of personalized therapeutic interventions that can address the specific challenges associated with each wound type. This review aims to explore experimental evidence of mesenchymal stem cell (MSC)-based therapies across various wound models and to highlight their therapeutic potential and optimization strategies. MSCs have emerged as promising candidates for regenerative wound therapy due to their multipotency, paracrine activity, and immunomodulatory functions. This review highlights the remarkable potential of MSC-based treatments to accelerate healing, reduce inflammation, and promote scar less tissue regeneration in different experimental models, including full-thickness acid burn wounds, heat burn wounds, cold-induced injuries, and chronic vs acute excisional wounds. The therapeutic efficacy of MSCs has been substantially enhanced through various preconditioning strategies, such as chemical preconditioning with α-terpineol, isorhamnetin, quercetin, and rutin, as well as their incorporation into biocompatible scaffolds and hydrogel matrices. These approaches have improved stem cell viability, survival under hypoxic and oxidative conditions, engraftment efficiency, and functional integration into the host tissue. This review also presents a comparative analysis of the wound healing mechanisms and pathological features associated with different skin injury models while emphasizing the mechanistic role of MSCs in modulating these responses. It further explores the impact of stem cell preconditioning and advanced biomaterial-assisted delivery systems in optimizing regenerative outcomes. Collectively, the findings underscore the necessity for context-specific therapeutic strategies and confirm the translational potential of MSC-based interventions as adaptable, targeted, and clinically viable solutions for complex skin injuries. Moreover, the integration of biomaterials and preconditioning strategies offers promising avenues to overcome current limitations in MSC therapy, ultimately resulting in the advancement of regenerative dermatology.

Keywords: Wound healing; Mesenchymal stem cells; Regenerative medicine; Preconditioning; Biomaterials; Clinical translation

Core Tip: Skin wound healing is a complex process affected by the type and severity of injury. This review provides a comparative overview of the pathophysiology of excisional, thermal, chemical, and cold-induced skin wounds while highlighting mesenchymal stem cell (MSC)-based regenerative strategies. It explains how MSCs modulate inflammation, promote angiogenesis, and support tissue remodeling through paracrine and immunomodulatory mechanisms. Additionally, it emphasizes optimizing MSC therapy via preconditioning (chemical, hypoxic, or genetic) and combining it with biomaterials like hydrogels and scaffolds to improve survival, engraftment, and functional recovery. The review also addresses translational barriers and the need for standardization in clinical applications, underscoring the potential of MSC-based treatments as future-oriented options for complex skin injuries.