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

使用光敏纤维蛋白递送生长因子来治疗慢性伤口

• 批准号: 8638769
• 负责人: BILL TAWIL
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638769
• 关键词: Address; Adverse effects; Area; Becaplermin; Beds; Biocompatible; Biocompatible Materials; Biopsy; Boxing; Burn injury; Cells; Cessation of life; Chronic; Clinic; Clinical; Clinical Treatment; DNA; Decubitus ulcer; Development; Devices; Diabetic mouse; Diabetic ulcer; Dose; Drug Delivery Systems; Electromagnetics; Engineering; Europe; Fibrin; Floods; Growth Factor; Healed; Health; Heating; Human; Hydrogels; In Vitro; Infection; Knowledge; Label; Leg Ulcer; Light; Marketing; Measures; Mechanics; Methylene blue; Modeling; Oligonucleotides; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Photons; Physiological; Platelet-Derived Growth Factor; Recording of previous events; Research; Riboflavin; Signal Transduction; Skin; Skin Ulcer; Source; Stimulus; System; Technology; Temperature; Therapeutic; Therapeutic Effect; Thick; Time; Tissues; Topical application; Toxic effect; Transforming Growth Factor beta; Translations; Tube; Ultrasonography; Ultraviolet Rays; United States Food and Drug Administration; Vascular Endothelial Growth Factors; Visible Radiation; Work; Wound Healing; attenuation; biomaterial compatibility; cancer risk; chromophore; clinical application; healing; improved; in vitro Model; in vivo; innovation; irradiation; magnetic field; novel; novel strategies; patient population; polymerization; prevent; scaffold; spatiotemporal; success; tool; wound

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.

描述（由申请人提供）：目前，市场上只有一种药物治疗可用于治疗糖尿病、腿部和压疮和烧伤引起的不愈合伤口。然而，它具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，该技术提高疗效并降低治疗分子的不希望的副作用的可能性。为了将这些技术推进到临床，需要克服在治疗相关浓度下材料的毒性问题。使用无毒和生物相容的发色团（核黄素或亚甲蓝），该提案旨在工程化纤维蛋白支架，通过可见光驱动释放生长因子，用于治疗慢性皮肤伤口。该提案的研究结果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：选择核黄素或亚甲蓝作为发色团以通过可见光致动亮点触发生物活性分子的释放，突出了该提议的新奇。目前，核黄素作为水凝胶聚合的II型光引发剂，而亚甲蓝在欧洲用于光灭活技术。这项研究将是第一个使用这些发色团作为按需交付技术的工具。该提议的另一个独特特征是用DNA系链使传统上非刺激敏感的纤维蛋白功能化。用可见光照射发色团产生热量并使DNA系链去杂交并触发释放。我们正在设计一种光热敏感的药物按需输送系统，该系统使用的材料在FDA批准的设备中有使用历史。方法：本项目的目的是通过实现生长因子从纤维蛋白支架经可见光局部释放到不愈合的皮肤伤口来开发慢性伤口的治疗方法。 光致动。这是通过用DNA系链官能化纤维蛋白来实现的，DNA系链在加热时去杂交，从而产生在发色团存在下对可见光照射敏感的系统。目的1：光热响应性纤维蛋白支架释放PDGF、TGF-β和VEGF的特性。目标二：在糖尿病小鼠伤口愈合模型中评估光热响应纤维蛋白支架在全层活检伤口中的体内功效和生物相容性。预期结果：具体目标的成功完成实现了以下目标：1）定义了我们实验室开发的可见光驱动输送系统的临床应用，并证明了作为慢性皮肤伤口的潜在治疗选择的成功; 2）通过可重复地实现更完全的愈合，增强了慢性伤口的愈合，超过了目前可用的治疗选择;和3）证明了生长因子从递送载体按需释放超过连续释放曲线的优点。