Wound healing is a complex process consisting of three phases: inflammation, proliferation, and remodeling. When this process is disrupted by disease, the outcome can be debilitating or even fatal; dermal injury in diabetic patients and myocardial infarction in patients with heart disease each result in an irresolvable chronic wound that persists for months to years. Animal models are widely used to both understand the underlying mechanisms behind these chronic injuries and to test therapeutics before attempting translation into the clinic. This body of work examines large animal models of wound healing to both improve the efficacy of chronic wound treatments and better understand the healing response in previously uncharacterized large animal models. This dissertation first examines a porcine model of dermal wound healing to test the efficacy of a protein delivery system. This system has previously shown promising results in small animal models, but pigs serve as a more clinically relevant model to test new therapeutics. Therefore, our results provide further evidence that this delivery system is a promising candidate to accelerate wound healing in patients. A diabetic porcine model of wound healing has been proposed as a superior model to the healthy pig. However, the wound environment in this model has not yet been well-described or compared to diabetic ulcers to assess its clinical relevance. Therefore, we evaluated the wound microenvironment in fully aged diabetic pigs to determine its relevance as a preclinical model. Our results indicate that the diabetic porcine model does not exhibit all hallmark behaviors of chronic wounds and that these differences should be considered when designing trials for new therapeutics in these pigs. Finally, we describe a new model of cardiac wound healing in the grass carp (Ctenopharyngodon idella), a large species of fish closely related to the regenerative zebrafish. Grass carp exhibit excessive fibrosis and decreased cardiac function following injury, serving as the first reported fish within the Cyprinid family that exhibits persistent fibrosis rather than functional regeneration. Together, this dissertation characterizes two large animal models of dysregulated wound healing and assesses the efficacy of a protein delivery system to improve this response.