Establishment and translational evaluation of animal models for skin wound healing: a systematic review

Background: Skin wounds, encompassing acute injuries and chronic refractory ulcers, impose substantial physical and economic burdens globally. While animal models are indispensable for dissecting wound healing pathophysiology and testing therapeutic interventions, the discordance between preclinical findings and clinical outcomes remains a critical challenge. Methods: cutaneous wound models in mice, rats, and rabbits that reported quantitative outcomes (e.g., closure kinetics, histology, molecular markers). Studies lacking separate control groups or sufficient methodological detail were excluded. The methodological quality of included studies was assessed using SYRCLE's risk of bias tool. Results: A total of 129 studies met the inclusion criteria and were synthesized. We systematically categorized and evaluated mainstream models: (1) Acute wounds: Rodent incisional/excisional models facilitate high-throughput screening but are limited by contraction-dominant healing, whereas rabbit ear models better approximate human re-epithelialization. (2) Chronic wounds: Streptozotocin (STZ)-induced diabetic models in mice and rats predominate but often lack the macrovascular complications of human ulcers, necessitating novel composite models incorporating ischemia and biofilm infection. (3) Pathological scarring: Tension-induced models (e.g., suture anchoring, mechanical stretching) are identified as critical for studying mechanotransduction pathways (e.g., YAP/TAZ) absent in traditional unstressed models. Furthermore, our review identifies a pervasive male bias in study design. We highlight that sex steroids critically modulate inflammation and angiogenesis-with estrogen typically promoting and androgens delaying repair-necessitating the inclusion of both sexes or specific hormone-depleted models (e.g., ovariectomized females) to improve clinical predictive value. Conclusion: No single animal model perfectly recapitulates human cutaneous repair. Based on the synthesis of 129 studies, we propose a hierarchical translational framework: utilizing genetically tractable mice for mechanistic discovery, rats for longitudinal pharmacological screening, and rabbits or porcine models for the validation of scar quality and epithelial closure prior to clinical trials.