"A Two-Stage High-Fidelity, Anti-Infective Approach to Craniofacial Repair in Novel Ovine Model"

“新型绵羊模型中的两阶段高保真、抗感染颅面修复方法”

• 批准号: 9750093
• 负责人: Emma Watson
• 金额: $ 4.41万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750093
• 关键词: 3D Print; Address; Affect; Animal Model; Animal Testing; Animals; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Autologous Transplantation; Bacteria; Bacterial Infections; Biocompatible Materials; Biomedical Engineering; Bioreactors; Blood; Bone Growth; Bone Regeneration; Bone Tissue; Bone Transplantation; Ceramics; Clinical; Communication; Complex; Congenital Abnormality; Craniofacial Abnormalities; Custom; Defect; Development; Dimensions; Disease; Distal; Distant; Ensure; Esthetics; Evaluation; Excision; Fellowship; Focal Infection; Geometry; Goals; Growth; Harvest; Heart Rate; High Pressure Liquid Chromatography; Histology; Hydroxyapatites; Immune response; Implant; Incidence; Infection; Inflammation; Investigation; Kinetics; Knowledge; Lead; Literature; Maintenance; Mandible; Mechanics; Methods; Minimum Inhibitory Concentration measurement; Modeling; Molds; Monitor; Morbidity - disease rate; Mucous Membrane; Oral; Oral cavity; Organ Transplantation; Outcome; Patients; Periosteum; Pharmaceutical Preparations; Polymerase Chain Reaction; Polymers; Polymethyl Methacrylate; Porosity; Property; Publishing; Repair Complex; Research; Shapes; Sinus; Site; Skin; Specific qualifier value; Surgeon; Swab; System; Temperature; Testing; Therapeutic; Thinness; Time; Tissue Donors; Tissue Engineering; Tissues; Trauma; Validation; Work; base; bone; bone engineering; cell type; combat; commercialization; craniofacial; craniofacial bone; craniofacial complex; craniofacial repair; craniofacial tissue; cytokine; design; healing; implantation; improved; in vivo; inflammatory marker; long bone; maxillofacial; mechanical properties; member; novel; novel strategies; reconstruction; repaired; response; rib bone structure; scaffold; soft tissue; tissue repair; tomography; tool; tumor

Project Summary/Abstract The rationale for this project is based on the need for improved strategies for functional and aesthetic reconstruction of craniofacial defects caused by trauma, tumor removal, infection, congenital malformations, or other diseases. Due to many tissue types in close proximity and a nearby bacteria-filled oral cavity, repair of craniofacial tissue is complex. Therefore, the objective of this study is to develop novel approaches and to improve upon existing strategies for craniofacial bone tissue repair by utilizing a scaffold to promote soft tissue healing and space maintenance of the defect, local antibiotic release to combat infection, and tissue growth of specified geometry at a distant site within the body to eliminate donor-site morbidity associated with autograft for repair. The proposed research will test the fundamental hypothesis that local release of antibiotics will eliminate local infection, restore soft tissue healing at the defect site, and allow robust bone growth at a distal site. The proposed research will be accomplished through two specific aims: 1) To manufacture and characterize properties of space maintainers utilizing different antibiotic-loading methods to understand kinetics of antibiotic release and to ensure mechanical properties are adequate for mandibular implantation and 2) To evaluate the effects of an antibiotic-releasing space maintainer on mandibular infection in an in vivo large animal model while bone is grown adjacent to rib periosteum in a 3D printed bioreactor. The space maintainers will be evaluated via mechanical testing (compression, 4-point bending, screw pull-out) and microcomputed tomography (microCT) (for pore size and porosity). The released antibiotic concentration will be evaluated via high performance liquid chromatography (HPLC). Bacteria will be utilized to determine minimum inhibitory concentration of antibiotic. In order to evaluate the effects of the space maintainer in vivo, the mandibular site will be swabbed (for identification, testing of potential antibiotic resistance) and will be analyzed by microCT for bone growth and histology for tissue and cell types. The tissue grown in bioreactors will be analyzed by microCT and by histology for bone growth, with quantitative polymerase chain reaction (qPCR), and via compression and screw pull-out testing. Blood drawn at several time points will be utilized to detect systemic markers of infection, oral swabs will be cultured, and vitals (such as heart rate and temperature) will be monitored. Upon completion of these studies, the expected outcomes are the successful fabrication of a space maintainer capable of antibiotic release with robust mechanical properties, the successful utilization of 3D printed bioreactors in a large animal model, and the successful development of a large animal model with sustained, yet localized, mandibular infection. In addition to improving upon existing strategies, this work will broaden our understanding on the interplay between bacteria, immune response, antibiotic delivery, and bone growth. Moreover, the proposed system provides a therapeutic approach for complex defects of large or unusual sizes that cannot utilize traditional autograft tissues due to shape or size constraints.

项目总结/摘要 该项目的基本原理是基于对功能和美学的改进策略的需要 因创伤、肿瘤切除、感染、先天性畸形或 其它疾病由于许多组织类型在附近和附近的细菌充满口腔，修复 颅面组织很复杂因此，本研究的目的是开发新的方法， 通过利用支架促进软组织来改进颅面骨组织修复现有策略 缺损的愈合和空间维持、抵抗感染的局部抗生素释放以及 在体内远端部位的特定几何形状，以消除与自体移植物相关的供体部位发病率， 修复.这项拟议中的研究将检验一个基本假设，即局部释放抗生素将消除 局部感染，恢复缺损部位的软组织愈合，并允许远端部位的骨生长。 本研究将通过两个具体目标来完成：1）制造和表征 利用不同的药物装载方法来了解抗生素动力学的空间保持器的特性 释放并确保机械性能足以用于下颌骨植入; 2）评估 下颌骨间隙保持器对下颌骨感染的影响 在3D打印的生物反应器中邻近肋骨骨膜生长骨。空间维护人员将通过以下方式进行评估： 机械测试（压缩、4点弯曲、螺钉拔出）和微型计算机断层扫描（microCT） (for孔径和孔隙率）。释放的抗生素浓度将通过高效液相色谱法进行评价。 色谱法（HPLC）。将使用细菌测定抗生素的最小抑菌浓度。在 为了评价间隙保持器在体内的效果，将擦拭下颌部位（对于 鉴定、测试潜在的抗生素耐药性），并将通过microCT分析骨生长， 组织和细胞类型的组织学。将通过microCT和组织学分析生物反应器中生长的组织 用于骨生长，采用定量聚合酶链反应（qPCR），并通过加压和螺钉拔出 试验.在几个时间点抽取的血液将用于检测感染的全身标志物，口腔拭子将用于检测感染的全身标志物。 进行培养，并监测生命体征（如心率和体温）。 在完成这些研究后，预期结果是成功制造空间维持器 能够释放抗生素，具有强大的机械性能，成功利用3D打印 生物反应器在大型动物模型，并成功开发了一个大型动物模型，持续，但 局部下颌感染除了改进现有战略外，这项工作还将扩大我们的 了解细菌，免疫反应，抗生素输送和骨生长之间的相互作用。 此外，所提出的系统提供了一种治疗方法，复杂的缺陷，大或不寻常的大小 其由于形状或尺寸的限制而不能利用传统的自体移植组织。

项目成果

A murine model of cutaneous aspergillosis for evaluation of biomaterials-based local delivery therapies.

用于评估基于生物材料的局部递送疗法的皮肤曲霉病小鼠模型。

• DOI: 10.1002/jbm.a.36671
• 发表时间: 2019
• 期刊: Journal of biomedical materials research. Part A
• 作者: Tatara,AlexanderM;Watson,Emma;Albert,NathanielD;Kontoyiannis,PanayiotisD;Kontoyiannis,DimitriosP;Mikos,AntoniosG
• 通讯作者: Mikos,AntoniosG

An Ovine Model of In Vivo Bioreactor-Based Bone Generation.

基于体内生物反应器的骨生成的绵羊模型。

• DOI: 10.1089/ten.tec.2020.0125
• 发表时间: 2020
• 期刊: Tissue engineering. Part C, Methods
• 作者: Watson,Emma;Tatara,AlexanderM;vandenBeucken,JeroenJJP;Jansen,JohnA;Wong,MarkE;Mikos,AntoniosG
• 通讯作者: Mikos,AntoniosG