Biological Models for Evaluating Hydrogel-Based Formulations in Wound Healing

Abstract

Skin, the largest organ of the human body, serves as a critical physico-chemical barrier against environmental insults and plays essential roles in hydration, thermoregulation, immune defense, and metabolic functions. Wound healing is a complex, multistage biological process involving hemostasis, inflammation, proliferation, and remodeling. Hydrogels have emerged as a promising class of wound dressings due to their high moisture retention, biocompatibility, and ability to mimic the extracellular matrix, thereby supporting accelerated healing and controlled drug delivery. This review provides a comprehensive overview of current hydrogel types-classified by origin, crosslinking mechanisms, and responsiveness to stimuli-and evaluates their use in experimental research on in vitro, ex vivo, and in vivo wound healing models. Furthermore, clinical applications of hydrogels in wound therapy are discussed. Advances in semisynthetic and stimuli-responsive hydrogels, along with improved testing models, offer enhanced therapeutic potential and underscore the need for continued innovation to optimize wound care outcomes and alleviate healthcare burdens.

Keywords: burn wound model; crosslinked hydrogels; full-thickness skin model; hydrogel-based dressings; reconstructed human epithelium; scratch assay; surgical wound model; wound healing models.

Figure 1

The most relevant in vitro wound healing models. Two-dimensional models (left panel), represented by monolayer cultures of fibroblasts/keratinocytes with or without adding other cell types such as endothelial cells (for vasculature) and immune cells (for inflammation studies), and the scratch assay represent useful tools for assessment of wound healing, with multiple advantages, such as high reproducibility, simplicity, and cost-effectiveness, at the expense of limited complexity. Three-dimensional models (right panel), represented by stratified keratinocytes, reconstructed human epithelium (RHE), and full-thickness skin models (FTM), mimic the complexity of skin epidermal layers with or without the dermal layer and add other skin cells, such as endothelial, immune, or neuronal cells, to increase the physiological relevance at the expense of increased costs and enhanced production and assessment difficulties.

Figure 2

Schematic diagram of the design of surgical wound models in vivo for the study of healing efficacy of different types of chemical and physical treatment options. Created with www.BioRender.com, accessed on the 9 July 2025.

Figure 3

Comparative wound healing timeline for different types of in vivo models. All wound models show healing and/or scarring on day 9, except for the diabetic wound. Created with www.BioRender.com, accessed on the 9 July 2025.