Introduction: Diabetic Foot Ulcers (DFU) continue to present a formidable challenge in terms of morbidity and healthcare costs. Increasing evidence ascertains the important role of Matrix Metallo-Proteinases (MMPs) and their tissue inhibitors TIMPS in wound healing. Imbalance of MMPs in the DFU microenvironment has been associated with poor wound healing. Current research is directed toward therapeutic agents that could redress the imbalance of MMPs / TIMPs. Polyhydrated Ionogens (PHIs) formulation is based on metallic ions and citric acid. PHI application aims to positively restore MMP ratios within chronic wounds. This initial multicenter pilot study aimed to investigate the efficacy of the PHI formulation in achieving stable wound closure in recalcitrant DFUs. Methods: Twenty-nine patients with therapy resistant DFUs of at least 2 cm2 and 3 months duration were treated with PHI formulation in an acetate carrier dressing. Wound debridement, digital imaging, and wound perimeter tracing were performed weekly. Serum samples and punch biopsies were taken from random ulcers for quantitative MMP/TIMP analysis at three time points to assess feasibility of this method. Patient satisfaction was assessed with a questionnaire. Results: Stable wound closure with high patient satisfaction was achieved in 15 (75%) DFUs. MMP/TIMP ratios within different healing phases were delineated. Discussion: This pilot study’s encouraging results prompt us to further investigate the PHI efficacy in DFU treatment in a Web-based, multicenter, randomized controlled trial.