Growth factor delivery using light-sensitive fibrin to treat chronic wounds

描述（由申请人提供）：目前，市场上只有一种药物治疗方法可用于治疗糖尿病，腿部，压疮和烧伤引起的未愈合伤口。然而，它有有害的副作用和有限的成功。这些限制可以通过按需递送技术来克服，这些技术可以提高疗效并减少治疗分子产生不必要副作用的可能性。为了将这些技术应用于临床，需要克服材料在治疗相关浓度下的毒性问题。使用无毒和生物相容性的发色团（核黄素或亚甲基蓝），该提案旨在设计纤维蛋白支架，通过可见光驱动释放生长因子，用于慢性皮肤伤口的治疗。这项研究结果将有助于慢性伤口的临床治疗，促进和加速愈合，并最终使大量患者受益。创新：该方案的新颖之处在于选择核黄素或亚甲基蓝作为发色团，通过可见光激活高光触发生物活性分子的释放。目前，核黄素被用作水凝胶聚合的II型光引发剂，而亚甲基蓝在欧洲被用于光失活技术。这项研究将首次使用这些发色团作为按需递送技术的工具。该方案的另一个独特之处在于将传统上对刺激不敏感的纤维蛋白与DNA链功能化。用可见光照射发色团会产生热量，使DNA链去杂化并触发释放。我们正在设计一种光热敏药物按需输送系统，其材料在FDA批准的设备中具有使用历史。方法：该项目的目标是通过纤维蛋白支架实现生长因子的按需和局部释放，通过可见途径释放到未愈合的皮肤伤口，从而开发一种治疗慢性伤口的方法

DESCRIPTION (provided by applicant): 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.