The overall goal of my thesis is to develop molecules to induce wound healing in an otherwise non-healing, diabetic wound by adjusting the microenvironment within the wound. To do this we utilized protein engineering strategies to target the exposed collagen in a cutaneous wound to ensure localization of protein constructs, we also took advantage of cellular deficits within the wound and systemically delivered appropriate soluble signals to the wound, and finally we as utilized a polymerized form of butyrate to disrupt the nonfunctional microenvironment by means of other dysfunctional pathways. In Chapter 1, I introduce the groundwork for why a diabetic wound becomes chronic and non-healing. I discuss the key differences between healthy, healing wounds and diabetic, non-healing wounds, these differences span soluble signals, cellular populations and geneexpression levels. I discuss the current standard of care used to treat diabetic wounds and the clinical shortcomings of these standards of care. Finally, I introduce new and emerging strategies being used to heal diabetic wounds. Non-healing diabetic wounds are complex and multifaceted, many immune cells play a specific and crucial role in moving the wound towards healing. This allows us the opportunity to view the wound through many different lenses, represented by key cellular players of the wound healing process. In Chapter 2, I look at the wound through a macrophage focused lens and expand upon previously developed cytokine engineering techniques utilized in the laboratory to target exposed collagen with a cytokine payload, interleukin-4 (IL-4). We characterize the protein through bioactivity and macrophage polarization assays and determine our construct is biologically active and capable of pushing macrophages towards a pro-regenerative phenotype in vitro. I then move into efficacy studies using the well-established Type 2 diabetic murine model for non-healing diabetic wounds where CBD-SAIL-4 shows to promote wound closure. Finally, I describe the mechanism through which CBDSA-IL-4 promotes wound closure by characterizing the soluble signal changes in the wound microenvironment and subsequent cellular changes that occur after topical administration of our construct. In Chapter 3, I expand the approach to treat non-healing, diabetic wound through a different cellular lens focusing instead on dendritic cells and the role they carry in wound healing. We again use the Type 2 diabetic, db/db, mouse model to assess the efficacy of systemically administered Flt3L therapy in wound healing. Finally, we quantify the cellular changes within the wound to understand how Flt3L improves wound closure of chronic cutaneous wounds. In Chapter 4, we utilize a polymer, instead of a protein, to again manipulate the microenvironment of a non-healing diabetic wound and induce changes toward pro-regenerative signals. We characterize the changes in soluble signals in the wound after topical administration of pManButyrate. We test the efficacy of pManButyrate as a therapeutic for wound healing in the Type 2 diabetic, db/db, mouse model and show improved closure after topical administration. In Chapter 5, I discuss limitations, conclusions and future directions of this work within the context of both diabetic wound healing and other forms of non-healing wounds.