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

描述(申请人提供)：目前，市场上只有一种药物疗法可用于治疗糖尿病、腿部、压疮和烧伤造成的无法愈合的伤口。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不必要的副作用的可能性。为了将这些技术推广到临床，需要克服与治疗相关浓度的材料的毒性问题。使用无毒和生物相容的发色团(核黄素或亚甲基蓝)，这项提议旨在设计纤维蛋白支架，通过可见光驱动释放生长因子，用于治疗慢性皮肤伤口。这项提案的发现将通过促进和加速愈合来帮助慢性伤口的临床治疗，并最终使大量患者受益。创新：这项提议的新颖性在于选择核黄素或亚甲基蓝作为发色团，通过可见光驱动高光触发生物活性分子的释放。目前，核黄素作为第二类光引发剂用于水凝胶聚合，而亚甲基蓝在欧洲用于光灭活技术。这项研究将首次使用这些发色团作为按需交付技术的工具。这一建议的另一个独特之处是将传统上对刺激不敏感的纤维蛋白与DNA捆绑在一起。用可见光照射发色团会产生热量，使DNA纽带解杂化，引发释放。我们正在设计一种光热敏感的按需给药系统，该系统使用的材料曾在FDA批准的设备中使用过。方法：这个项目的目标是开发一种治疗慢性伤口的方法，通过可见光将生长因子从纤维蛋白支架上按需和局部释放到不可愈合的皮肤伤口上。 光驱动。这是通过将纤维蛋白与DNA纽带功能化来实现的，DNA纽带在加热时去杂交，从而创建了一种在生色团存在的情况下对可见光照射敏感的系统。目的1：光温响应型纤维蛋白支架释放PDGF、转化生长因子-β或血管内皮生长因子的特性。目的：在糖尿病小鼠创面愈合模型中，评价光热响应型纤维蛋白支架在全层活检创面中的体内疗效和生物相容性。预期结果：特定目标的成功完成实现了以下目标：1)明确了我们实验室开发的可见韧带驱动输送系统的临床应用，并展示了作为一种潜在的慢性皮肤伤口治疗方案的成功；2)通过重复地实现更完全的愈合，比目前可用的治疗方案更能促进慢性伤口的愈合；以及3)证明了按需从输送载体中释放生长因子的优势超过了连续释放方案。

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.