Currently, there is only one drug therapy treatment available on the market to treat non- healing wounds caused by diabetic, leg, and pressure ulcers and burns. However, it has harmful side effects and limited success. These limitations can be overcome by delivery-on-demand technologies which improve the efficacy and reduce the potential for unwanted side effects of therapeutic molecules. To advance these technologies to the clinic problems with the toxicity of the materials at therapeutically relevant concentration need to be overcome. Using non-toxic and biocompatible chromophores (riboflavin or methylene blue), this proposal aims to engineer fibrin scaffolds that release growth factors by visible light actuation for the treatment of chronic skin wounds. The findings from this proposal will aid in the clinical treatment of chronic wounds by promoting and accelerating healing and ultimately benefit a large patient population. Innovation: The novelty of this proposal is highlighted by the choice of either riboflavin or methylene blue as the chromophore to trigger the release of biologically active molecules through visible light actuation highlights. Currently, riboflavin is as a type II photo-initiator for hydrogel polymerizations while methylene blue is use in Europe for photo-inactivation technologies. This study will be the first to use these chromophores as a tool for delivery-on-demand technologies. Another unique feature of this proposal is the functionalization of traditionally non-stimuli-sensitive fibrin with DNA tethers. Irradiating the chromophores with visible light generates heat and de-hybridizes the DNA tethers and triggers release. We are engineering a photothermally sensitive drug delivery-on-demand system out of materials with a history of use in FDA approved devices. Approach: It is the objective of this project to develop a treatment for chronic wounds by achieving an on-demand and localized release of growth factor from fibrin scaffolds to non-healing skin wounds via visible light actuation. This is achieved by functionalizing fibrin with DNA tethers which de-hybridize upon heating and thereby creates a system that is sensitive to visible light irradiation in the presence of chromophores.
Aim 1 : Characterization of PDGF, TGF-B or VEGF release from the photothermally responsive fibrin scaffolds.
Aim 2 : Assessment of the in vivo efficacy and biocompatibility of the photothermally responsive fibrin scaffold in full- thickness biopsy wounds in a diabetic mouse wound healing model. Expected Outcome: The successful completion of the specific aims accomplishes the following: 1) defines a clinical application for the visible ligt-actuated delivery system developed by our lab and demonstrates success as a potential treatment option for chronic skin wounds;2) enhances the healing of chronic wounds over currently available treatment options by reproducibly achieving more complete healing;and 3) demonstrates the advantage of having on-demand release of growth factors from delivery vehicles over continuous release profiles.
We have developed a novel strategy for the on-demand release of biologically active molecules via visible light actuation by incorporating non-toxic, biocompatible chromophores - either riboflavin or methylene blue - to generate heat and act upon a photothermally responsive carrier. This proposal aims to optimize our system for treatment of chronic skin wounds. Fibrin scaffolds, which are an ideal choice for treating chronic wounds but are not photothermally responsive, are functionalized with heat-liable DNA tethers for the on-demand delivery of platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), or transforming growth factor-beta (TGF-).
|Linsley, Chase S; Wu, Benjamin M (2017) Recent advances in light-responsive on-demand drug-delivery systems. Ther Deliv 8:89-107|
|Linsley, Chase S; Quach, Viola Y; Agrawal, Gaurav et al. (2015) Visible light and near-infrared-responsive chromophores for drug delivery-on-demand applications. Drug Deliv Transl Res 5:611-24|