Nitric oxide-releasing hyaluronic acid therapeutics for treating periodontal disease

释放一氧化氮的透明质酸疗法用于治疗牙周病

• 批准号: 10657158
• 负责人: Mark H Schoenfisch
• 金额: $ 46.38万
• 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: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657158
• 关键词: Affect; Anti-Bacterial Agents; Anti-Inflammatory Agents; Autoimmunity; Biopolymers; Calculi; Cardiovascular Diseases; Cell Culture System; Cells; Chronic; Clinical; Complex; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Dose; Drug Delivery Systems; Epithelial Cells; Excision; Failure; Fibroblasts; Formulation; Frequencies; Gingiva; Glycosaminoglycans; Goals; Health; Homeostasis; Human; Hyaluronic Acid; Immune System Diseases; Immune system; Immunity; Individual; Inflammation; Integration Host Factors; Intervention; Kinetics; Ligature; Macrophage; Mammalian Cell; Mechanics; Microbial Biofilms; Modeling; Mucous Membrane; Nitric Oxide; Nitric Oxide Donors; Oral; Osteoclasts; Periodontal Diseases; Periodontal Pocket; Periodontitis; Phase; Play; Primary Cell Cultures; Property; Refractory; Research; Resolution; Risk Factors; Role; Series; Structure; Surface; System; Systemic disease; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Tissue Model; Tissues; Toxic effect; Treatment Efficacy; antimicrobial; cytotoxicity; dental biofilm; dysbiosis; effective therapy; efficacy evaluation; healing; human model; immune function; immunoregulation; improved; in vivo; in vivo evaluation; innate immune function; macromolecule; microbial; mouse model; nanomaterials; nanoparticle; neutrophil; oral cavity epithelium; patient population; perpetrators; preservation; prevent; programs; subgingival biofilm; systemic inflammatory response; therapeutic evaluation; translational therapeutics; wound healing

SUMMARY Microbial plaque biofilms that form at and below the gum line are the perpetrators of periodontal diseases, which are a class of diseases associated with non-resolving inflammation that results in soft and hard tissue destruction. Periodontitis is characterized by an unending cycle of chronic inflammation which leads to tissue destruction and prevents wound healing but cannot control the biofilms microbial dysbiosis. Under conditions of systemic inflammation, these host factors are amplified leading to more severe and refractory periodontal disease conditions. As such, periodontal diseases are affected by and can be risk factors for a number of systemic health issues such as diabetes. Current treatment of periodontitis involves mechanical removal of supra- and sub-gingival bacterial plaque and calculus and is often accompanied by the use of locally administered adjunctive therapies aimed at restoring microbial homeostasis. Current adjunctive therapies do not address the need to break the unending cycle of chronic inflammation and restore tissue homeostasis. Thus, there is a profound need to develop an adjunctive therapeutic that: a) possesses broad-spectrum activity against biofilms with minimal toxicity to mammalian cells; b) provides anti-inflammatory activity; and, c) promotes tissue healing. Due to its antibacterial and immunomodulatory functions, nitric oxide (NO) is an attractive adjunctive agent in the treatment of periodontal diseases. In the proposed research program, we will synthesize, characterize and evaluate nitric oxide-releasing hyaluronic acid (HA) as a multi-action NO-release system. Upon release, the NO will serve as a broad-spectrum antibacterial and pro-wound healing agent. The macromolecule that remains (HA) will then further serve to mitigate immunmodulation and wound healing. We will evaluate the efficacy and associated mechanisms of this multi-action therapeutic (e.g., NO: antibacterial, HA and NO: immunomodulatory, and NO and HA: pro-wound healing). We propose this approach will reduce the frequency of and/or augment clinical interventions and promote improved resolution of disease. We aim to: 1) synthesize nitric oxide-releasing hyaluronic acid nanomaterials and formulations, showing the influence of NO- releasing HA on antibacterial and antibiofilm action, mammalian cell cytotoxicity, and inflammation in various oral delivery formulations; 2) delineate the mechanisms modulating microbial dysbiosis, immune dysfunction and tissue-stasis; and, 3) test in vivo therapeutic efficacy in preventing and/or halting periodontal disease progression.

概括 牙龈线及其下方形成的微生物菌斑生物膜是牙周病的罪魁祸首， 这是一类与无法解决的炎症相关的疾病，会导致软组织和硬组织损伤 破坏。牙周炎的特点是慢性炎症的无休止的循环，导致组织 破坏并阻止伤口愈合，但无法控制生物膜微生物失调。有条件的话 在全身炎症的过程中，这些宿主因素会被放大，导致更严重和难治性的牙周病 疾病情况。因此，牙周病受许多系统性疾病的影响，并且可能成为其危险因素。 糖尿病等健康问题。目前牙周炎的治疗包括机械去除牙周病和牙周病。 牙龈下菌斑和牙石，并且通常伴随着局部施用的使用 旨在恢复微生物稳态的辅助疗法。目前的辅助疗法并不能解决这个问题 需要打破慢性炎症的无休止循环并恢复组织稳态。因此，有一个 迫切需要开发一种辅助疗法：a）具有广谱的抗生物膜活性 对哺乳动物细胞的毒性最小； b) 提供抗炎活性； c) 促进组织 康复。 由于其抗菌和免疫调节功能，一氧化氮（NO）是一种有吸引力的辅助剂 牙周疾病的治疗。在拟议的研究计划中，我们将综合、表征和 评估释放一氧化氮的透明质酸 (HA) 作为多作用一氧化氮释放系统。释放后， NO 将作为广谱抗菌剂和促进伤口愈合的剂。残留的大分子 (HA) 随后将进一步减轻免疫调节和伤口愈合。我们将评估效果 以及这种多效治疗的相关机制（例如，NO：抗菌，HA 和 NO： 免疫调节，NO 和 HA：促进伤口愈合）。我们建议这种方法将减少 频率和/或增强临床干预并促进改善疾病的解决。我们的目标是：1) 合成释放一氧化氮的透明质酸纳米材料和制剂，显示NO-的影响 释放 HA 对抗菌和抗生物膜作用、哺乳动物细胞的细胞毒性和各种炎症 口服给药制剂； 2）描绘微生物失调、免疫功能障碍的调节机制 和组织瘀滞； 3) 测试预防和/或阻止牙周病的体内治疗效果 进展。