Hybrid Synthetic and Biologic Shear Thinning Hydrogels for Diabetic Wound Healing

项目概要/摘要 不愈合的皮肤伤口是世界范围内发病率的主要来源，并且由于 医疗保健费用的增加、人口老龄化和糖尿病发病率的上升。皮肤不愈合 近25%的糖尿病患者发生伤口，约6%的糖尿病患者因伤口相关原因住院。 治疗，如果不成功，可能导致截肢或死亡。虽然更先进的治疗方法 所需的尖端多组分技术，如水凝胶或装载细胞的支架 和/或药物尚未达到临床效果。新候选治疗的失败通常是由于组织差 整合、药物释放曲线不足和递送时生物（细胞或生长因子）活性的丧失 进入以高浓度细胞因子、蛋白酶和 细胞毒性活性氧（ROS）。 目前项目的总体目标是开发和应用下一代剪切稀化和ROS 清除水凝胶，其包含ROS响应性纳米颗粒（NP）和透明质酸（HA）的混合物， 天然细胞外基质成分。将实现剪切稀化水凝胶的机械性能 通过基于金刚烷（AD）和β-环糊精（CD）的主客体化学，其形成可逆的， 机械稳定包合物。NP将用AD进行表面官能化，并且HA聚合物将 用CD改性;当这两种组分混合时，它们形成剪切稀化溶液， 愈合以在组织缺损内形成稳定的水凝胶。包括HA组件是因为其先例 为了在伤口愈合装置/敷料中有效使用，而NP被设计成具有ROS反应性（使得 它固有抗氧化剂）。纳米颗粒也可以在水凝胶形成之前“预加载”药物，从而提供药物释放。 药物持续释放到伤口部位的机制。 本项目的第一个目标是通过调整聚合物的浓度来优化所提出的NP/HA水凝胶系统。 分子量和AD/CD修饰密度。第二个目的 将涉及在体内测试先导候选水凝胶以评估组织反应，持续模型药物释放， 和ROS清除/保护装载到装置中的治疗性干细胞。第三个目标，我们将 将领先的NP/HA水凝胶配方与HA基临床对照材料单独进行愈合获益比较 与干细胞或激活促愈合转录的小分子药物联合使用 因子HIF 1 α。这些研究旨在建立临床疗效的概念验证，将于 极端挑战（缺血和遗传驱动的增强的ROS表型）糖尿病伤口模型。我们 包括生物工程师、化学家、伤口愈合专家和干细胞专家在内的多学科团队已准备就绪 以实现建立新的伤口愈合平台的目标。

PROJECT SUMMARY/ABSTRACT Nonhealing skin wounds are a major source of morbidity worldwide and becoming more of a burden due to an increase in health care costs, an aging population, and growing incidence of diabetes. Non-healing skin wounds occur in nearly 25% of diabetic patients, and ~6% are admitted to the hospital for wound-related treatment, which if not successful, can lead to limb amputation or death. While more advanced treatments are needed, cutting edge, multi-component technologies such as hydrogels or scaffolds loaded either with cells and/or drugs have not achieved clinical impact. Failure of new candidate treatments is often due to poor tissue integration, insufficient drug release profiles, and loss of biological (cell or growth factor) activity upon delivery into a hostile wound microenvironment characterized by high concentrations of cytokines, proteases, and cytotoxic reactive oxygen species (ROS). The overall goal of the current project is to develop and apply a next generation, shear-thinning, and ROS scavenging hydrogel that comprises a hybrid of ROS responsive nanoparticles (NPs) and hyaluronic acid (HA), a natural extracellular matrix component. The shear thinning hydrogel mechanical properties will be achieved through guest-host chemistry based on adamantane (AD) and beta-cyclodextrin (CD), which form reversible, mechanically-stabilizing inclusion complexes. NPs will be surface functionalized with AD, and HA polymers will be modified with CD; when these two components are mixed, they form shear-thinning solutions that rapidly self- heal to form stable hydrogels within the tissue defect. The HA component is included because of its precedent for efficacious use in wound healing devices/dressings, while the NP is designed to have ROS reactivity (making it inherently antioxidant). The NPs can also be “pre-loaded” with drugs prior to hydrogel formation, providing a mechanism for sustained drug release to the wound site. The first aim of this project will be to optimize the proposed NP/HA hydrogel system by tuning polymer molecular weight and AD/CD modification density on the NP and HA components, respectively. The second aim will involve testing of lead candidate hydrogels in vivo to assess tissue response, sustained model drug release, and ROS scavenging / protection of therapeutic stem cells loaded into the device. In the third aim, we will compare the leading NP/HA hydrogel formulation to a HA-based, clinical control material for healing benefit alone on in combination with either stem cells or a small molecule drug that activates the pro-healing transcription factor HIF1alpha. These studies, designed to establish proof of concept for clinical efficacy, will be completed in extremely challenged (ischemic and genetically-driven enhanced ROS phenotype) diabetic wound models. Our multidisciplinary team, including a bioengineer, chemist, wound healing expert, and stem cell expert, is poised to achieve the proposed goals toward establishing a new wound healing platform.