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.

总结 在慢性伤口中观察到的延迟愈合因持续的微生物感染和非细菌感染而加剧。 消除炎症。此外，耐药性细菌的出现限制了这些抗生素的使用。 用于治疗感染伤口的药剂。增加了慢性伤口治疗的复杂性，感染通常是 不是伤口慢性化的唯一原因糖尿病等潜在疾病使个人易于感染 通过影响宿主免疫应答，包括炎性细胞迁移、细胞信号传导和效应物， 功能因此，理想的伤口愈合治疗剂必须解决宿主免疫应答的损伤，同时还 具有抗菌活性。由于慢性伤口相关截肢和死亡率高， 对于这样一种多作用治疗是迫切的。一氧化氮（NO）是一种内源性信号分子， 由于其固有的抗菌性， 免疫调节功能。我们率先开发了高分子 储存和自发释放溶解形式的NO的NO供体系统（即，不作为气体）， 治疗相关水平。我们现在的目标是开发释放NO的糖胺聚糖生物聚合物（GAG） 作为伤口愈合治疗剂。GAG是天然存在的生物聚合物，其具有免疫调节作用， 已知与伤口愈合生理学有关。我们假设，结合多方面的作用， GAG和NO将允许有效的治疗：1）根除伤口病原体; 2）调节 炎症;和3）促进上皮再生以促进及时的伤口闭合。 本项目的目的是确定GAG分子量，硫酸化模式和NO释放的作用 因为它们与抗菌和促伤口愈合活性有关。在发展一种新的伤口- 愈合疗法，我们将表征细胞增殖，粘附和迁移作为一个功能的NO 使用细胞培养测定和三维人体皮肤组织模型，对有效载荷和GAG结构进行了分析。我们 将使用原代人细胞评估NO释放GAG对先天免疫细胞可塑性的影响 系统.然后，我们将确定最有前途的NO释放GAG衍生物的治疗效果 对抗菌作用、炎症和作为感染和糖尿病的函数的伤口闭合的影响。迭代 将采取一种方法来确定治疗干预的最佳剂量、时间和频率。一 系统生物学方法将用于阐明有效性和失败的机制，这将为临床提供信息。 这些治疗方法的翻译。这项新的研究计划将使我们能够建立在我们以前的 在开发NO释放大分子支架方面取得了成功，但现在专注于伤口愈合。我们 目标是开发一种治疗感染并促进慢性伤口患者伤口愈合的治疗剂。