Periodontal Biomaterials with BITE (Biofilm Immunity via T-cell Enhancement)

描述（由申请人提供）：根据美国疾病控制与预防中心（Centers for Disease Control and Prevention）的数据，生物膜被认为是导致大量人类微生物感染的原因。医院感染是美国第四大死亡原因，每年有200万例（约占美国医院患者的10%）。约60%的此类感染与植入医疗器械有关，1992年造成45亿美元的医疗费用，每年约8万人死亡。众所周知，涉及生物膜的感染包括细菌性心内膜炎、囊性纤维化肺部感染、深部伤口愈合、当前流行的龋齿、牙周病、阴道病、尿路感染和慢性中耳感染。慢性牙周炎是一种牙齿支撑组织的炎症性疾病，导致牙槽骨吸收，最终导致牙齿脱落。该疾病是所有社会的一个主要公共卫生问题，估计影响到15%的成年牙齿人口，严重形式影响到6%。慢性牙周炎的发生和发展与牙龈下菌斑中特定的革兰氏阴性菌有关。据报道，牙周炎患者治疗后牙龈下菌斑中牙龈卟啉单胞菌的持续存在与进行性牙槽骨丢失显著相关。此外，牙龈下菌斑中牙龈卟啉卟啉菌细胞数量的增加已被证明与疾病严重程度相关，通过附着物丧失、牙周袋深度和探诊时出血来测量。引导组织再生（GTR）技术越来越多地被用于治疗牙周缺损，或与牙种植程序相结合。几项研究表明，在被牙周病微生物感染的部位放置屏障膜不能预期最佳的组织再生。因此，组织再生成功的先决条件是无感染的愈合过程。本提案旨在开发生物材料，以促进对长期留置生物医学装置感染的终身免疫保护。在NIDCR的支持下，我们的目标是开发组织再生生物材料，这些材料也将提供针对特定细菌定植的短期防御和长期免疫反应。对于短期的即时防御，模型生物材料将释放融合蛋白复合物-人工调理素-旨在增强口腔致病菌与单核巨噬细胞（MX）的偶联；从而促进吞噬作用。为了获得长期保护，生物材料将转染抗原呈递细胞（特别是树突状细胞- dc），产生T细胞和b细胞记忆和抗体表达，并可能直接刺激天然杀伤T细胞反应。这种预防生物材料感染的双层生物学方法将首先在牙龈卟啉单胞菌（PG）定植牙周组织引导再生系统的模型微生物系统中建立。

DESCRIPTION (provided by applicant): Biofilms are thought to cause a significant amount of all human microbial infections, according to the Centers for Disease Control and Prevention [1]. Nosocomial infections are the fourth leading cause of death in the U.S. with >2 million cases annually (or ~10% of American hospital patients). About 60% of all such infections are associated with an implanted medical device causing >$4.5 billion medical costs in 1992 [2] and ~80,000 deaths annually [3]. Well-recognized infections involving biofilms include bacterial endocarditis, cystic fibrosis lung infections, deep wound healing, the current dental caries epidemic, periodontal disease, vaginosis, urinary tract infections, and chronic middle ear infections. Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth leading to resorption of alveolar bone and eventual tooth loss. The disease is a major public health problem in all societies and is estimated to affect up to 15% of the adult dentate population, with severe forms affecting 5 6%. The development and progression of chronic periodontitis has been associated with specific Gram-negative bacteria in subgingival plaque. Persistence of Porphyromonas gingivalis in subgingival plaque from periodontitis patients after treatment (scaling and root planing) has been reported to be significantly associated with progressive alveolar bone loss. Moreover, an increase in P. gingivalis cell numbers in subgingival plaque has been shown to correlate with disease severity as measured by attachment loss, periodontal pocket depth, and bleeding on probing. Guided tissue regeneration (GTR) techniques are increasingly being used for the treatment of periodontal defects, or in conjunction with dental implant procedures. Several studies have shown that optimal tissue regeneration cannot be expected for barrier membranes placed in sites infected by periodontopathic microorganisms. A prerequisite for tissue regeneration success is therefore an infection-free healing process. This proposal seeks to develop biomaterials that promote a life-long immunity protection against infections of long-term indwelling biomedical devices. Our goal, with NIDCR support, is to develop tissue regenerative biomaterials that will also provide a short- term defense and long-term immune response to specific bacterial colonization. For short-term immediate defense, model biomaterials will release fusion protein complexes - artificial opsonins - designed to enhance the coupling of pathogenic oral bacteria to monocyte-macrophage (MX); thus promoting phagocytosis. For long-term protection, the biomaterial will transfect antigen-presenting cells (specifically dendritic cells - DCs) to produce T- and B-cell memory and antibody expression, and potentially stimulate direct native killer T-cell responses. This two-tiered biological approach to preventing biomaterials infections will first be established in the model microbial system of Porphyromonas gingivalis (PG) colonization of periodontal tissue guided regeneration systems. PUBLIC HEALTH RELEVANCE: Nosocomial infections are the fourth leading cause of death in the U.S. with ~60% of such infections being associated with an implanted medical device. Our goal is to develop tissue regenerative biomaterials that will also provide a short-term defense and life long immune response to specific bacterial infections