Multivalent Growth Factor Conjugates to Accelerate Wound Neovascularization in El

描述：目前约有480万65岁以上的美国人患有与年龄相关的伤口并发症，每年的支出超过100亿美元。老年人是最有可能接受手术造成手术创伤的年龄段，由于随着年龄的增长皮肤发生变化，他们的皮肤也更容易受到急性皮肤创伤。此外，细胞事件的延迟和损伤的血管生成反应增加了这些伤口愈合所需的时间，进而使患者更容易出现感染、再损伤和慢性伤口发展等并发症。Valitor公司正在开发一种基于蛋白质的疗法，以加速老年人的新生血管并提高伤口愈合率。我们设计我们的疗法是为了补充伤口管理的标准做法，并减少治疗这些缓慢愈合的伤口所需的昂贵的系列努力。我们的专利技术是一种化学拴系工艺，可增强体内生长因子的效力、稳定性和特异性。有了这项技术，我们已经将Sonic Hedgehog(Shh)与透明质酸(HYA)的线性链进行了化学连接，HYA是一种可溶的、生物相容的聚合物。我们可以通过改变Shh：HYA的比例来控制输送到伤口的生长因子的价态，我们已经证明了我们的偶联物的Shh价态可以调节它们的细胞生物活性。将Shh连接到大分子上也可以防止其被蛋白水解酶失活，并增强其在靶组织中的分子稳定性。在第一阶段，我们的总体目标是开发mvShh结合物，通过促进内皮细胞(ECs)的迁移和促进伤口新生血管来改善老年人伤口愈合的机制。在特定的目标#1中，我们将开发mvShh结合物来增强体外培养的内皮细胞的激活和迁移。在特定的目标#2，我们将评估mvShh对内皮细胞迁移和体内新生血管的影响，使用18月龄小鼠的全层切除真皮创伤模型。伤口的大小也将定期测量，直到完全闭合。然后将评估修复组织的抗拉强度。我们的发现将提供有价值的概念验证数据，以指导我们为该项目第二阶段计划的药物治疗的进一步临床前开发。

DESCRIPTION: Approximately 4.8 million Americans over the age of 65 currently suffer from age-related wound complications, with an annual expenditure of over $10 billion annually. The elderly are the most likely age group to undergo procedures resulting in surgical wounds, and due to skin changes that occur with advanced age, their skin is also more prone to acute dermal trauma. In addition, delayed cellular events and impaired angiogenic responses to injury increases the time required for these wounds to heal, and in turn, leaves patients more prone to complications such as infection, re-injury and chronic wound development. Valitor, Inc. is developing a protein-based therapy to accelerate neovascularization and improve the rate of wound healing in aged individuals. We designed our therapy to complement the standard practice of wound management and to reduce the costly serial effort required for treatment of these slowly healing wounds. Our patented technology is a chemical tethering process that provides enhanced potency, stability, and specificity of growth factors in vivo. With this technology, we have chemically conjugated Sonic hedgehog (Shh), an important angiogenic factor previously shown to stimulate neovascularization, to linear chains of hyaluronic acid (HyA), a soluble, biocompatible polymer. We can control the valency of growth factors that are delivered to a wound by varying the ratio of Shh:HyA, and we have demonstrated that the Shh valency of our conjugates can modulate their cellular bioactivity. Conjugating Shh to a large macromolecule may also prevent its deactivation by proteolytic enzymes and enhance its molecular stability in the target tissues. In Phase I, our overall goal is to develop mvShh conjugates that improve the mechanisms of wound healing in older individuals by enhancing the migration of endothelial cells (ECs) and accelerating wound neovascularization. In Specific Aim #1 we will develop mvShh conjugates to enhance endothelial cell activation and migration in vitro. In Specific Aim #2 we will evaluate the effect of mvShh on endothelial cell migration and neovascularization in vivo using a full- thickness excisional dermal wound model in 18-month-old mice. The wound size will also be measured periodically until full closure has been achieved. The tensile strength of the repaired tissue will then be evaluated. Our findings will provide valuable proof-of-concept data to guide further pre-clinical development of our drug therapy, which we have planned for Phase II of this project.