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.

项目概要： 不愈合的皮肤伤口是全世界发病的一个主要来源，并且由于以下原因而变得越来越负担： 医疗保健费用增加、人口老龄化以及糖尿病发病率上升。皮肤无法愈合 近 25% 的糖尿病患者会出现伤口，约 6% 因伤口相关而入院治疗 治疗如果不成功，可能会导致截肢或死亡。虽然更先进的治疗方法正在 所需的尖端多组分技术，例如水凝胶或负载细胞的支架 和/或药物尚未达到临床效果。新候选疗法的失败通常是由于组织不良 整合、药物释放曲线不足以及递送时生物（细胞或生长因子）活性丧失 进入一个以高浓度细胞因子、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）的客体化学，形成可逆的， 机械稳定的包合物。纳米颗粒将通过 AD 进行表面功能化，HA 聚合物将 用CD修改；当这两种成分混合时，它们会形成剪切稀化溶液，并迅速自粘 愈合以在组织缺损内形成稳定的水凝胶。包含 HA 组件是因为它有先例 用于在伤口愈合装置/敷料中有效使用，而 NP 被设计为具有 ROS 反应性（使得 它本质上是抗氧化剂）。纳米颗粒还可以在水凝胶形成之前“预载”药物，从而提供 药物持续释放到伤口部位的机制。 该项目的首要目标是通过调整聚合物来优化所提出的 NP/HA 水凝胶系统 分别对 NP 和 HA 组分进行分子量和 AD/CD 修饰密度。第二个目标 将涉及对主要候选水凝胶进行体内测试，以评估组织反应、持续模型药物释放、 ROS 清除/保护加载到设备中的治疗干细胞。在第三个目标中，我们将 将领先的 NP/HA 水凝胶配方与基于 HA 的临床对照材料进行比较，仅考虑治愈效果 与干细胞或激活促愈合转录的小分子药物结合使用 HIF1α 因子。这些研究旨在建立临床疗效的概念证明，将于 极度困难（缺血和遗传驱动的增强 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，已做好准备 实现建立新伤口愈合平台的拟议目标。