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[1]，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因，每年有200万例(约占美国住院患者的10%)。在所有此类感染中，大约60%与植入的医疗设备有关，在1992年[2]造成了45亿美元的医疗费用，每年造成约80,000人死亡[3]。公认的涉及生物被膜的感染包括细菌性心内膜炎、囊性纤维化肺部感染、深度伤口愈合、当前的龋齿流行、牙周病、阴道病、尿路感染和慢性中耳感染。慢性牙周炎是一种牙齿支持组织的炎症性疾病，导致牙槽骨吸收，最终导致牙齿脱落。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，其中严重形式影响56%。慢性牙周炎的发生发展与龈下菌斑中的革兰氏阴性菌有关。据报道，牙周炎患者在治疗(洁治和根面平整)后，牙龈下菌斑中持续存在的牙龈卟啉单胞菌与进行性牙槽骨丢失显著相关。此外，根据附着丧失、牙周袋深度和探诊出血的测量，已显示牙龈下菌斑中牙龈假单胞菌细胞数量的增加与疾病严重程度相关。引导组织再生(GTR)技术越来越多地被用于牙周缺陷的治疗，或与牙种植体联合使用。一些研究表明，在被牙周病原体感染的部位放置屏障膜，不能期望获得最佳的组织再生。因此，组织再生成功的先决条件是无感染的愈合过程。这项提议寻求开发生物材料，以促进对长期留置生物医疗设备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，这种材料还将对特定细菌的定植提供短期防御和长期免疫反应。为了短期的即时防御，模型生物材料将释放融合蛋白复合体-人工调色素-旨在加强口腔致病细菌与单核巨噬细胞(MX)的偶联；从而促进吞噬作用。为了长期保护，这种生物材料将转染抗原呈递细胞(特别是树突状细胞-DC)，以产生T和B细胞记忆和抗体表达，并潜在地刺激直接的自然杀伤T细胞反应。这种预防生物材料感染的两层生物学方法将首先建立在牙周组织引导再生系统的牙龈卟啉单胞菌(PG)定植微生物系统中。 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设备有关。我们的目标是开发组织再生生物材料，这种材料还将对特定的细菌感染提供短期防御和终身免疫反应。

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