Nitric oxide-releasing glycosaminoglycans for treating complex wounds

释放一氧化氮的糖胺聚糖用于治疗复杂伤口

• 批准号: 10584269
• 负责人: Mark H Schoenfisch
• 金额: $ 38.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584269
• 关键词: 3-Dimensional; Address; Adhesions; Affect; Amputation; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacterial Antibiotic Resistance; Biological Assay; Biopolymers; Cell Culture Techniques; Cell Proliferation; Cells; Complex; Dermal; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Epithelium; Failure; Frequencies; Future; Gases; Glycosaminoglycans; Goals; Hand; High Prevalence; Human; Immune; Immune response; Impaired healing; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Knowledge; Macrophage; Molecular Weight; Monitor; Morbidity - disease rate; Mus; Nitric Oxide; Nitric Oxide Donors; Non-Insulin-Dependent Diabetes Mellitus; Patients; Pattern; Phenotype; Physiology; Play; Population; Process; Production; Property; Punch Biopsy; Research; Resistance; Role; Series; Signal Transduction; Signaling Molecule; Skin Tissue; Structure; Sulfate; System; Systems Biology; Therapeutic; Therapeutic Intervention; Time; Tissue Model; Tissues; Toxic effect; Treatment Efficacy; Wound Infection; Wound healing therapy; cell motility; chronic wound; clinical translation; diabetic ulcer; efficacy evaluation; immune function; immunoregulation; in vivo; microbial; migration; monocyte; mortality; mouse model; neutrophil; pathogen; programs; resistant strain; response to injury; scaffold; success; therapeutically effective; tissue reconstruction; tissue repair; translational therapeutics; treatment response; two-dimensional; wound; wound closure; wound healing; wound treatment

SUMMARY The delayed healing observed in chronic wounds is exacerbated by persistent microbial infections and non- resolving inflammation. Furthermore, the emergence of antibiotic-resistant bacteria has limited the use of these agents for treating infected wounds. Adding to the complexity of chronic wound treatment, infection is usually not the sole cause of wound chronicity. Underlying diseases such as diabetes leave individuals prone to infection by affecting the host immune responses, including inflammatory cell migration, cell signaling, and effector function. An ideal wound healing therapeutic must thus address the impairment of the host immune response while also possessing antibacterial activity. Due to the high prevalence of chronic wound-related amputations and mortality, the need for such a multi-action therapeutic is urgent. Nitric oxide (NO) is an endogenous signaling molecule that represents an attractive, alternative therapeutic for treating chronic wounds due to its innate antibacterial and immunomodulatory function in human physiology. We have pioneered the development of macromolecular NO donor systems that store and spontaneously release NO in dissolved form (i.e., not as a gas) at therapeutically relevant levels. We now aim to develop NO-releasing glycosaminoglycan biopolymers (GAGs) as wound healing therapeutics. GAGs are naturally occurring biopolymers that are immunomodulatory and known to be involved in wound healing physiology. We hypothesize that combining the multi-faceted roles of GAGs and NO will allow for a therapeutic that effectively: 1) eradicates wound pathogens; 2) modulates inflammation; and, 3) promotes re-epithelialization to facilitate timely wound closure. The objective of this project is to define the roles of GAG molecular weight, sulfation patterns and NO-release properties as they related to antibacterial and pro-wound healing activities. In developing a new class of wound- healing therapeutics, we will characterize cell proliferation, adhesion, and migration as a function of NO payloads and GAG structure using cell culture assays and a three-dimensional human skin tissue model. We will evaluate the effect of NO-releasing GAGs on innate immune cell plasticity using primary human cell systems. We will then determine the therapeutic efficacy of the most promising NO-releasing GAG derivatives on antibacterial action, inflammation, and wound closure as a function of infection and diabetes. An iterative approach will be taken to determine the optimal dose, time, and frequency of therapeutic intervention. A systems biology approach will be used to elucidate mechanisms of efficacy and failure, which will inform clinical translation of these therapeutic approaches. This new research program will allow us to build upon our previous successes in developing NO-releasing macromolecular scaffolds, but now with a focus on wound healing. Our goal is to develop a therapeutic that treats infection and promotes wound healing in populations afflicted by chronic wounds.

概括 持续的微生物感染和非 - 解决炎症。此外，抗生素耐药菌的出现限制了这些 治疗感染伤口的药物。增加了慢性伤口治疗的复杂性，通常是 不是伤口慢性的唯一原因。糖尿病等潜在疾病使人容易感染 通过影响宿主免疫反应，包括炎症细胞迁移，细胞信号和效应子 功能。因此，理想的伤口愈合治疗必须解决宿主免疫反应的损害，同时也必须 具有抗菌活性。由于慢性伤口相关的截肢和死亡率的高患病率，需要 对于这种多动用治疗是紧急的。一氧化氮（NO）是一种内源信号分子，代表 一种有吸引力的替代性治疗，用于治疗慢性伤口，原因是其先天抗菌和 人类生理学中的免疫调节功能。我们开创了大分子的发展 没有以溶解形式释放和自发释放的供体系统（即，不是作为气体） 治疗相关水平。现在，我们旨在开发不释放的糖胺聚糖生物聚合物（插科打） 作为伤口愈合治疗。堵嘴是自然存在的免疫调节的生物聚合物 已知参与伤口愈合生理学。我们假设结合了多方面的角色 插科打and否将允许有效的治疗性：1）消除伤口病原体； 2）调制 炎; 3）促进重新上皮化以促进及时的伤口闭合。 该项目的目的是定义GAG分子量，硫酸化模式和无释放的作用 与抗菌和亲链愈合活动有关的特性。在开发新的伤口 - 治愈治疗剂，我们将表征细胞增殖，粘附和迁移作为NO的函数 使用细胞培养分析和三维人皮肤组织模型的有效载荷和插科打结构。我们 将评估使用原代人类细胞不释放插科打go对先天免疫细胞可塑性的影响 系统。然后，我们将确定最有希望的无释放插入衍生物的治疗功效 关于抗菌作用，炎症和伤口闭合是感染和糖尿病的功能。迭代 将采用方法来确定治疗干预的最佳剂量，时间和频率。一个 系统生物学方法将用于阐明功效和失败机制，这将为临床提供信息 这些治疗方法的翻译。这个新的研究计划将使我们能够在以前的 在开发不释放的大分子支架方面取得了成功，但现在重点是伤口愈合。我们的 目的是开发一种治疗感染并促进慢性伤口折磨人群的伤口愈合的治疗性。