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: 10668940
• 负责人: Craig Lewis Duvall
• 金额: $ 47.54万
• 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/10668940
• 关键词: Acrylamides; Adamantane; Admission activity; 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; Encapsulated; 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; Ischemia; Islets of Langerhans; Kinetics; Lead; Length; Leptin deficiency; Longevity; Maintenance; Measures; Mechanics; Mediating; Modification; Modulus; Molecular Weight; Morbidity - disease rate; Mus; N-isopropylacrylamide; Non-Insulin-Dependent Diabetes Mellitus; Nucleosome Core Particle; Organoids; Outcome; Oxidative Stress; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Physiological; Polymers; Porifera; Property; Rattus; Reaction; Reactive Oxygen Species; Series; Site; Source; Sterile coverings; Structure; Sulfides; Surface; Syringes; System; Technology; Temperature; Testing; Therapeutic; Thinness; Tissues; Variant; Water; Work; Wound models; aging population; angiogenesis; 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; lead candidate; limb amputation; mechanical properties; mesenchymal stromal cell; mouse model; multidisciplinary; nanoparticle; next generation; nile red; polycaprolactone; propylene; repaired; response; scaffold; skin wound; small molecule; 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.

项目总结： 无法愈合的皮肤创伤是全球发病率的主要来源，并因以下原因而变得更加沉重 医疗费用的增加、人口老龄化和糖尿病发病率的增加。无法愈合的皮肤 近25%的糖尿病患者发生伤口，约6%的患者因伤口相关而入院 如果治疗不成功，可能会导致截肢或死亡。虽然更先进的治疗方法是 所需的尖端多组分技术，如水凝胶或负载细胞的支架 和/或药物未达到临床效果。新的候选治疗方法的失败通常是由于组织不良 整合，药物释放曲线不充分，生物(细胞或生长因子)活性在交付时丧失 进入敌意的伤口微环境，其特征是高浓度的细胞因子，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稀化和ROS 清除水凝胶，包含ROS响应性纳米颗粒(NPs)和透明质酸(HA)的混合物， 天然的细胞外基质成分。剪切变稀的水凝胶具有良好的力学性能 通过金刚烷(AD)和β-环糊精(CD)形成可逆的客体-宿主化学， 机械稳定的包合物。NPS将使用AD进行表面功能化，HA聚合物将 用CD修饰；当这两个组分混合时，它们形成剪切变稀溶液，迅速自 愈合以在组织缺损处形成稳定的水凝胶。包括HA组件是因为它有先例 在伤口愈合设备/敷料中有效使用，而NP被设计为具有ROS反应性(制造 它本身就是抗氧化剂)。在水凝胶形成之前，还可以在纳米粒中预装药物，提供一种 药物持续释放到伤口部位的机制。 该项目的第一个目标将是通过调整聚合物来优化拟议的NP/HA水凝胶体系 NP组分和HA组分的相对分子质量和AD/CD修饰密度。第二个目标 将包括体内主要候选水凝胶的测试，以评估组织反应，持续模型药物释放， 以及装载到设备中的治疗性干细胞的ROS清除/保护。在第三个目标中，我们将 将领先的NP/HA水凝胶配方与以HA为基础的临床对照材料进行比较，仅就愈合益处而言 与干细胞或激活促愈合转录的小分子药物相结合 HIF1α因子。这些研究旨在为临床疗效建立概念证明，将于#年完成。 极具挑战性(缺血和遗传驱动的增强ROS表型)糖尿病创面模型。我们的 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正在蓄势待发。 以实现拟议的目标，建立一个新的伤口愈合平台。