Devices for Treating Inflammatory Bone Loss in an Oral Environment

描述（由申请人提供）：牙周和口腔外科文献中经常描述感染和次优再生结果之间的关联。人们也越来越认识到，低水平的细菌污染可以在全关节植入物的“无菌性”松动中发挥作用。在这种情况下，术语“感染”不是指暴发性的急性过程，而是指以底物定殖为特征的亚临床的惰性感染。在这些条件下，微生物污染物通过局部细胞启动强效促炎细胞因子的合成。这些主要介质，反过来，刺激生产的次级介质，放大炎症反应。最终的结果是组织降解酶的分泌，并最终导致骨细胞的骨反应。在该项目中，将使用多学科团队方法开发主动的多功能设备，用于通过攻击微生物污染，炎症，组织破坏和组织修复受阻的问题，在口腔微生物受损的部位进行局部骨再生。在目标1中，将开发用于顺序递送多个生物分子的控制释放系统。关于这一目标，假设可以定制器械以递送具有离散特征的抗菌、抗炎、抗分解代谢和合成代谢化合物，从而确保适当的生物活性。在目标2中，将研究从目标1中选择的器械在体外控制微生物生物负载和炎症以及抑制骨吸收和促进骨形成的能力，并将材料降解和药物释放与体内结果相关联。假设从器械释放的生物分子将杀死口腔微生物，降低骨细胞分化/活性，并增加成骨细胞分化/活性。在目标3中，将使用犬牙周炎-种植体炎模型测试提供单独、顺序、组合和同时药物释放曲线的完整器械的体内生物活性。据推测，使用单一器械对疾病过程的不同阶段进行顺序治疗将比仅治疗其中一种成分的常见方法更有效。这些研究的结果将有助于理解细菌诱导的炎症性骨破坏过程中发生的生物学事件链，并将推动生物医学器械开发领域朝着更有效的方式发展，以增强口腔微生物环境中的骨再生。公共卫生相关性：细菌对天然和合成生物材料的定植引发了一系列局部组织反应，最终导致支持结构的丧失。这种组织破坏是许多疾病的核心，包括感染的牙齿，骨骼，牙科植入物和关节植入物。该项目将开发多功能，单一，控制释放装置，停止有害过程，并刺激局部组织修复的网站受到细菌的损害。

DESCRIPTION (provided by applicant): An association between infection and suboptimal regenerative outcomes has often been described in the periodontal and oral surgical literature. It is also increasingly recognized that low-level bacterial contamination can play a role in "aseptic" loosening of total joint implants. In this context, the term "infection" does not refer to fulminating, acute processes, but to subclinical, indolent infections characterized by colonization of substrates. In these conditions, microbial contaminants initiate synthesis of potent pro-inflammatory cytokines by local cells. These primary mediators, in turn, stimulate production of secondary mediators that amplify the inflammatory response. The end result is secretion of tissue-degrading enzymes and eventually osteoclastic bone resoprtion. In this project, a multidisciplinary team approach will be used to develop proactive, multifunctional devices for localized bone regeneration in sites compromised by oral microbes by attacking the problems of microbial contamination, inflammation, tissue destruction, and hindered tissue repair. In Aim 1, a controlled release system for sequential delivery of multiple biomolecules will be developed. With respect to this Aim, it is hypothesized that the devices can be tailored to deliver antibacterial, anti-inflammatory, anticatabolic, and anabolic compounds with discrete profiles that ensure appropriate bioactivity. In Aim 2, devices selected from Aim 1 will be investigated for their ability to control microbial bioburden and inflammation as well as to inhibit bone resorption and to promote bone formation in vitro, and material degradation and drug release will be correlated with in vivo findings. It is hypothesized that biomolecules released from the devices will kill oral microbes, decrease osteoclastic differentiation/activity, and increase osteoblastic differentiation/activity. In Aim 3, complete devices providing individual, sequential, combined, and simultaneous drug release profiles will be tested for their biological activity in vivo using a canine peri- implantitis model. It is hypothesized that sequential treatment of the different phases of the disease process with a unitary device will be more effective than the common approach of treating only one of the components. The findings of these studies will contribute to understanding of the chain of biological events that occurs during bacterially-induced inflammatory bone destruction, and they will progress the field of biomedical device development toward more effective means for enhancing bone regeneration in an oral microbial environment. PUBLIC HEALTH RELEVANCE: Colonization of natural and synthetic biomaterials by bacteria elicits a cascade of local tissue reactions that ultimately lead to loss of the supportive structures. Such tissue destruction is at the heart of many conditions, including infected teeth, bones, dental implants, and joint implants. This project will develop multifunctional, unitary, controlled release devices that halt the detrimental processes and stimulate localized tissue repair in sites compromised by bacteria.