Hybrid Synthetic and Biologic Shear Thinning Hydrogels for Diabetic Wound Healing

用于糖尿病伤口愈合的混合合成和生物剪切稀化水凝胶

• 批准号: 10005338
• 负责人: Craig Lewis Duvall
• 金额: $ 47.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005338
• 关键词: Acrylamides; Adamantane; Amputation; Antioxidants; Automobile Driving; Behavior; Biocompatible Materials; Biological; Biomechanics; Biomedical Engineering; Body Temperature; Cells; Cessation of life; Chemistry; Chronic; Clinical; Complex; Cyclodextrins; Data; Defect; Devices; Diabetes Mellitus; Diabetic Foot Ulcer; Drug Modelings; Economic Burden; Environment; Enzymes; Excision; Extracellular Matrix; Failure; Fibroblasts; Formulation; Gel; Goals; Granulation Tissue; Growth Factor; Health Care Costs; Healthcare Systems; Hospitals; Hyaluronic Acid; Hybrids; Hydrogels; Hydrophobicity; Image; Immune; Immune response; Impairment; In Vitro; Incidence; Inflammation; Injectable; Injections; Islets of Langerhans; Kinetics; Lead; Length; Leptin; Longevity; Maintenance; Measures; Mechanics; Mediating; Modification; Modulus; Molecular Weight; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organoids; Outcome; Oxidative Stress; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Physiological; Polymers; Porifera; Property; Prunella vulgaris; Rattus; Reaction; Reactive Oxygen Species; Research Design; Series; Site; Source; Sterile coverings; Structure; Sulfides; Surface; Surgical Flaps; Syringes; System; Technology; Temperature; Testing; Therapeutic; Thinness; Tissues; Variant; Water; Work; Wound models; aging population; angiogenesis; base; beta-Cyclodextrins; biomaterial compatibility; clinical efficacy; cytokine; cytotoxic; density; design; diabetic; diabetic patient; diabetic ulcer; diabetic wound healing; drug release profile; experience; healing; hydrophilicity; in vivo; inhibitor/antagonist; lead candidate; limb amputation; mechanical properties; mesenchymal stromal cell; mouse model; multidisciplinary; nanoparticle; next generation; nile red; poly-N-isopropylacrylamide; polycaprolactone; propylene; repaired; response; scaffold; skin wound; small molecule; stem cell therapy; stem cells; success; therapeutic evaluation; transcription factor; wound; wound care; wound closure; wound healing

PROJECT SUMMARY: 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.

项目摘要： 非污染皮肤伤口是全球发病率的主要来源，由于 医疗保健成本，人口老龄化以及糖尿病事件不断增长的增加。非愈合的皮肤 近25％的糖尿病患者发生伤口，约6％被送往医院与伤口有关 如果不成功，可以导致肢体截肢或死亡。虽然更高级的治疗方法是 需要，尖端，多组分技术，例如水凝胶或带有细胞的支架 和/或药物尚未达到临床影响。新候选治疗的失败通常是由于组织不良造成的 分娩后的整合，药物释放曲线不足以及生物学（细胞或生长因子）活性的丧失 以高浓度的细胞因子，蛋白酶和 细胞毒性活性氧（ROS）。 当前项目的总体目标是开发和应用下一代，剪切和ROS 清除水凝胶，包括ROS响应性纳米颗粒（NP）和氢酸（HA）的杂种， 天然细胞外基质组件。将实现剪切薄水凝胶机械性能 通过基于Adamantane（AD）和Beta-Cyclodextrin（CD）的来宾宿主化学，它们形成可逆的， 机械稳定的包容络合物。 NP将通过AD进行表面功能，HA聚合物将 用CD修改；当这两个组件混合在一起时，它们会形成剪切的溶液，这些溶液迅速自我 愈合以在组织缺陷中形成稳定的水凝胶。包括HA组件是因为其先例 为了在伤口愈合设备/敷料中有效使用，而NP的设计为ROS反应性（制作） 它固有地是抗氧化剂）。 NP也可以在水凝胶形成之前“预载”药物，提供 持续药物释放到伤口部位的机制。 该项目的第一个目的是通过调整聚合物来优化拟议的NP/HA水凝胶系统 NP和HA成分的分子量和AD/CD修饰密度分别。第二个目标 将涉及在体内测试铅候选水凝胶以评估组织反应，持续模型药物释放， ROS清除了加载到设备中的治疗干细胞的保护 /保护。在第三个目标中，我们将 将领先的NP/HA水凝胶配方与仅HA基于HA的临床控制材料进行比较 与干细胞或小分子药物结合使用，该药物激活pro-healing转录 因子hif1alpha。这些研究旨在建立临床效率的概念证明，将在 极具挑战性（缺血性和遗传驱动的增强ROS表型）糖尿病伤口模型。我们的 多学科团队，包括生物工程师，化学家，伤口愈合专家和干细胞专家 为了实现建立新的伤口愈合平台的拟议目标。