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State-of-the-art dressings are a multilayer system that can include a collagen cellulose substrate, neonatal foreskin fibroblasts, growth factor containing cream, and a silicone sheet covering for moisture control. Wound healing time can be up to 20 weeks. The future of diabetic wound healing lies in the development of more effective artificial \u201csmart\u201d matrix skin substitutes. This review article will highlight the need for novel smart matrix therapies. These smart matrices will release a multitude of growth factors, cytokines, and bioactive peptide fragments in a temporally and spatially specific, event-driven manner. This timed and focal release of cytokines, enzymes, and pharmacological agents should promote optimal tissue regeneration and repair of full-thickness wounds. Development of these kinds of therapies will require multidisciplinary translational research teams. This review article outlines how current advances in proteomics and genomics can be incorporated into a multidisciplinary translational research approach for developing novel smart matrix dressings for ulcer treatment. 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