Devices for Treating Inflammatory Bone Loss in an Oral Environment

描述（由申请人提供）：在牙周和口腔外科文献中经常描述感染与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”松动中发挥作用。在这种情况下，“感染”一词不是指暴发性的急性过程，而是指以底物定植为特征的亚临床的惰性感染。在这些条件下，微生物污染物启动合成强效促炎细胞因子的局部细胞。这些初级介质反过来刺激二级介质的产生，从而放大炎症反应。最终的结果是组织降解酶的分泌和最终的破骨细胞骨再吸收。在这个项目中，一个多学科的团队将通过攻击微生物污染、炎症、组织破坏和阻碍组织修复的问题，开发主动的、多功能的局部骨再生设备，用于口腔微生物受损部位。在目标1中，将开发一种用于顺序递送多种生物分子的控制释放系统。关于该Aim，假设该设备可以定制，以提供抗菌，抗炎，抗代谢和合成代谢化合物，具有离散的特征，确保适当的生物活性。在Aim 2中，将研究从Aim 1中选择的设备在体外控制微生物负荷和炎症、抑制骨吸收和促进骨形成的能力，并研究材料降解和药物释放与体内研究结果的相关性。据推测，从器械中释放的生物分子会杀死口腔微生物，降低破骨细胞的分化/活性，并增加成骨细胞的分化/活性。在Aim 3中，完整的设备提供单独的，顺序的，联合的和同时的药物释放谱，将使用犬种植体周围炎模型测试其体内生物活性。假设用一个统一的装置对疾病过程的不同阶段进行顺序治疗将比只治疗其中一个组成部分的常见方法更有效。这些研究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事件链，并将推动生物医学设备开发领域朝着更有效的方式来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会引发一系列局部组织反应，最终导致支撑结构的丧失。这种组织破坏是许多疾病的核心，包括感染牙齿、骨骼、牙种植体和关节种植体。该项目将开发多功能、单一、可控释放装置，阻止有害过程，并刺激受细菌损害部位的局部组织修复。

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.