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

描述（由申请人提供）：根据疾病控制和预防中心的研究，生物膜被认为会导致大量的人类微生物感染[1]。医院感染是美国第四大死亡原因，每年有超过200万例（或约10%的美国医院患者）。所有此类感染中约60%与植入式医疗器械有关，1992年造成> 45亿美元的医疗费用[2]，每年约有80，000人死亡[3]。涉及生物膜的公认感染包括细菌性心内膜炎、囊性纤维化肺感染、深部伤口愈合、当前龋齿流行、牙周病、阴道病、尿路感染和慢性中耳感染。慢性牙周炎是牙齿支持组织的炎症性疾病，导致牙槽骨吸收和最终牙齿脱落。这种疾病是所有社会的一个主要公共卫生问题，估计影响高达15%的成年齿状人口，严重的形式影响56%。慢性牙周炎的发生和发展与龈下菌斑中的特定革兰氏阴性菌有关。据报道，牙周炎患者治疗（刮治和根面平整）后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，龈下菌斑中牙龈卟啉单胞菌细胞数量的增加已被证明与疾病严重程度相关，如通过附着丧失、牙周袋深度和探诊出血所测量的。引导组织再生（GTR）技术越来越多地用于治疗牙周缺损，或与牙科种植手术结合使用。几项研究表明，放置在牙周病微生物感染部位的屏障膜不能期望最佳的组织再生。因此，组织再生成功的先决条件是无感染的愈合过程。该提案旨在开发生物材料，促进对长期留置生物医学器械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，这些材料还将提供对特定细菌定植的短期防御和长期免疫应答。对于短期即时防御，模型生物材料将释放融合蛋白复合物-人工调理素-旨在增强致病性口腔细菌与单核细胞-巨噬细胞（MX）的偶联;从而促进吞噬作用。对于长期保护，生物材料将抑制抗原呈递细胞（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，并可能刺激直接的天然杀伤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周组织引导再生系统的牙龈卟啉单胞菌（PG）定植的模型微生物系统中建立。 公共卫生相关性：医院感染是美国第四大死亡原因，约60%的此类感染与植入的医疗器械相关。我们的目标是开发组织再生生物材料，也将提供一个短期的防御和终身免疫反应，以特定的细菌感染

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