Protease Resistant Growth Factor Nanoparticles for Chronic Wound Healing

项目摘要 老年人对慢性伤口非常敏感，如下肢静脉溃疡（VLU）、糖尿病足溃疡 （DFU）和压力性溃疡（PU）。这些伤口很难治疗，通常需要进行激烈的手术干预 例如截肢或游离皮瓣，功能明显丧失。 一种越来越流行的治疗慢性伤口的方法是使用重组生物制剂， 生长因子（GF）。多年来，研究人员的出色工作表明， 在动物中开发的各种临床前伤口模型中的许多GF。尽管取得了这些令人鼓舞的成果， 将GF成功地翻译给人类患者仍然是有限的。我们已经确定，这可以归因于 存在于人类慢性伤口中的高水平蛋白酶的存在，其导致 GF使治疗无效。大多数伤口愈合的动物模型不表现出高蛋白酶水平 因此，在动物身上看起来有希望的治疗方法无法应用于人类。 我们已经开发出创新的纳米颗粒（NP），不仅在伤口部位提供GF， 它由蛋白酶介导降解。我们的工作表明，这些纳米颗粒改善了生长的半衰期， 因子在人类慢性伤口液和伤口愈合的年轻糖尿病小鼠在蛋白酶的存在下。在 根据这项建议，我们打算将这些有前途的NP转化为老年人慢性伤口的愈合。 然而，老年和年轻动物的伤口愈合存在显著差异。因此在 在R21阶段，我们建议在老化伤口中测试NP，在R33阶段，我们将专注于临床前 NP的发展。我们将使用这些数据准备FDA申请，首先在人类研究中重点关注 关于NP对慢性伤口愈合的功效。这个项目将使我们能够把这项有前途的技术 更靠近长椅一侧。作为一种治疗难愈合慢性伤口的新疗法， 降低医疗保健系统中慢性伤口的成本和负担，同时改善患者结局， 生活质量

PROJECT SUMMARY Older adults are extremely susceptible to chronic wounds such as venous leg ulcers (VLUs), diabetic foot ulcers (DFUs) and pressure ulcers (PUs). These wounds are difficult to treat and often drastic operative interventions such as amputations or free flaps with a clear loss of function are necessary. An increasingly popular approach for the treatment of chronic wounds is the use of recombinant biologics such as growth factors (GF). Elegant work by researchers over the years has shown successful healing induced by numerous GFs in various preclinical wound models developed in animals. Despite these promising results, successful translation of GFs to human patients remains limited. We have identified that this can be attributed to the presence of high levels of proteases present in human chronic wounds that result in rapid degradation of the GF rendering the therapy ineffective. Most animals models of wound healing do not exhibit high protease levels and thus therapies that tend to look promising in animals fail to translate to humans. We have developed innovative nanoparticles (NP) that not only deliver the GF at the wound site but also protect it from protease mediated degradation. Our work has shown that these NPs improve the half-life of the growth factor in human chronic wound fluid and wound healing in young diabetic mice in the presence of proteases. In this proposal, we intend to translate these promisinig NPs towards the healing of chronic wounds in the elderly. However, there are significant differences in the wound healing of aged and young animals. Therefore, in the R21 phase we propose to test the NPs in aged wounds and in the R33 stage we will focus on the preclinical development of the NPs. We will use this data to prepare an FDA application for first in human studies focused on efficacy of NPs on the healing of chronic wounds. This project will enable us to bring this promising technology closer to the bench side. As a new therapy for the treatment of difficult to heal chronic wounds, it will significantly reduce the cost and burden of chronic wounds in the health care system while improving patient outcomes and quality of life.