Background: As much as half or more of deep partial-thickness (DPT) burn wounds, regardless of the treatment plan, develop hypertrophic scarring and contracture. And once formed, treatments are only minimally effective.

We propose to determine the effectiveness of pirfenidone (Pf) to diminish fibrotic indices and mitigate scarring in two animal models of DPT burn wound healing. Pf is an orally active, synthetic small molecule that exhibits anti-fibrotic and anti-inflammatory properties, attenuates fibroblast proliferation and collagen deposition in studies in vitro and in animal models, and is approved for the treatment of idiopathic pulmonary fibrosis in Europe, Japan, and the United States. These and other data suggest Pf could modulate the tissue response to injury at multiple stages of wound repair to improve scars resulting from DPT-burn wounds.

Objective/Hypothesis: The Food and Drug Administration (FDA)-approved drug Pf is an anti-inflammatory/anti-fibrosis drug indicated for pulmonary fibrosis that we hypothesize can diminish scarring when applied topically to DPT burn wounds in two animal models. The long-term objective is to learn to effectively use Pf with regard to dosage, formulation, and timing of treatment of burn wounds, such that animal studies will likely translate to the clinic. The objective of this proposal is to evaluate Pf for efficacy in reducing fibrosis and scarring parameters in mouse and porcine models of DPT burn wounds. The dosage formulation and schedule of treatment will be optimized, and molecular markers of inflammation, angiogenesis, wound healing, and fibrosis will be correlated with scar reduction.

Specific Aims: Specific Aim 1: Identify topical formulations of Pf that deliver effective drug concentrations to the dermis of DPT-burn wounds at each phase of healing. Specific Aim 2: Determine the optimal treatment schedule that best diminishes fibrosis indicators in the mouse DPT-burn wound model. Specific Aim 3: Validate the efficacy of Pf to reduce hypertrophic scarring in the Duroc porcine DPT burn model.

Study Design: DPT burns frequently result in hypertrophic scars that can lead to severe functional impairment, psychological morbidity, and costly long-term health care. Current treatment options lack effectiveness. The purpose of this research is to identify dosage formulations and treatment schedules for the FDA-approved drug Pf to evaluate it for use as a topical prophylactic and treatment against fibrotic scarring of DPT burn wounds. Specific Aim 1 identifies topical formulations and doses that effectively deliver Pf to the dermis of DPT burn wounds at each phase of healing and mitigate fibrosis of the closed wounds. Specific Aim 2 optimizes the schedule of topical applications and uses this optimized schedule to determine detailed molecular changes in healing wounds resulting from Pf treatment. Finally, Specific Aim 3 validates the efficacy of Pf to reduce hypertrophic scarring in the Duroc porcine DPT burn model. The successful completion of these three specific aims is expected to produce a lead dosage form and schedule that can be further evaluated for potential development for clinical testing.

Relevance: The predicted outcome is knowledge of the dosage formulation and schedule of application of Pf that effectively reduces scarring. This information would support subsequent studies that could move the drug forward into advanced development as an anti-scarring treatment.