Nanolayer Assemblies for Temporal Cytokine Therapy in Diabetic Ulcer Healing

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DESCRIPTION (provided by applicant): Chronic wounds disproportionately affect diabetic individuals compared to the general population. One in four diabetic individuals are predicted to develop a chronic wound during their lifetime, with a recurrence rate close to 70%. Many chronic wounds progress in severity, with 12% of recurrent chronic wounds resulting in amputation. While growth factor therapy has demonstrated a limited ability to promote wound healing, the current therapeutic modalities do not accurately recreate the natural wound healing process. The objective of this project is to develop new therapeutic wound dressings that more accurately recreate the natural wound healing dynamics seen in vivo. The central hypothesis of this proposal is that layer-by-layer (LbL) technology can be used to create stratified electrostatic assemblies that temporally modulate local cytokine levels in chronic wounds and stimulate the healing process. To test this hypothesis, Aim 1 will develop 'affinity polymers' that specifically bind cytokines to enable tuning of the temporal release profile. LbL constructs will be subsequently fabricated that possess two different therapeutic strategies: (1) the release of vascular endothelial growth factor (VEGF) followed by the release of platelet derived growth factor (PDGF) to promote angiogenesis and reepithelialization, and (2) the sustained release of CX3CL1 to recruit therapeutic cells to the wound bed. In vitro characterization will be used to optimize the cytokine loading, release profile, and biological activity of the dressings. Following dressing development, Aim 2 will examine the ability of temporally modulated cytokine delivery to promote wound healing in a diabetic mouse model. Collectively, these aims will uncover new insights into the ability to promote chronic wound healing via the synergistic signaling that arise from coordinated cytokine delivery. This work will subsequently lay the foundation for developing a new clinical strategy for treating patients suffering from chronic wounds.