Tissue-engineered trachea composites for long-segment airway replacement

用于长段气道置换的组织工程气管复合材料

• 批准号: 10179870
• 负责人: Tendy Chiang
• 金额: $ 74.13万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10179870
• 关键词: 3-Dimensional; Address; Adolescent; Air Movements; Animal Model; Animals; Attenuated; Autologous; Autologous Transplantation; Biochemical; Biocompatible Materials; Biological; Biomechanics; Biophysics; Biopsy; Bronchi; Bronchoscopy; Caliber; Cartilage; Cells; Child; Childhood; Chondrocytes; Chondrogenesis; Clinical; Clinical Management; Complex; Congenital Abnormality; Cues; Data; Defect; Detection; Development; Diagnostic radiologic examination; Dimensions; Disease; Epithelial; Epithelial Cells; Expression Profiling; Extracellular Matrix; Generations; Growth; Host Defense; Image; Immunofluorescence Immunologic; Implant; Infection; Inflammation; Injury; Intervention; Liquid substance; Maintenance; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mechanics; Mediating; Modeling; Modification; Mucociliary Clearance; Mus; Natural regeneration; Operative Surgical Procedures; Organ; Outcome; Patients; Performance; Population; Production; Public Health; Radial; Role; Source; Splint Device; Stents; Surface; Techniques; Testing; Time; Tissue Engineering; Tissue Preservation; Tissues; Trachea; Tracheal Diseases; Translations; Trauma; Work; airway epithelium; airway obstruction; biomaterial compatibility; cartilaginous; clinical translation; conditional knockout; epithelium regeneration; extracellular; implantation; improved; innovation; lamb model; mechanical properties; migration; mouse model; nanofiber; preservation; progenitor; protein expression; reconstruction; repaired; replacement tissue; restoration; shear stress; sheep model; stem

PROJECT SUMMARY / ABSTRACT Pediatric long-segment airway defects are caused by congenital malformations or result from trauma, infection, or malignancy. Although rare, these defects are often fatal. There is currently no established surgical technique to repair long-segment tracheal defects and the reconstructive options remain heroic. Tissue engineering has the potential to replace failed tissue with a normal, living organ. Despite its potential, clinical outcomes of tissue engineered tracheal grafts (TETG) have been poor. The main barriers to translation of tracheal replacement are graft collapse and delayed epithelialization. We assessed the performance of decellularized TETG (dcTETG) in our mouse model of orthotopic tracheal replacement. We identified that decellularized TETG can regenerate, restoring a functional surface airway epithelium (SAE), however outcomes are limited due to graft collapse. Using resorbable biomaterials to stabilize dcTETG, we created a Composite TETG (CTETG). We hypothesize the CTETG can improve overall survival in long-segment tracheal replacement, attenuate graft collapse, promote extracellular matrix (ECM production) and SAE differentiation. To test this hypothesis, we will first assess how CTETG promotes ECM regeneration in the tracheal cartilage. In our first aim, we will implant dcTETG and CTETG in a mouse model of tracheal replacement and quantify ECM production and mechanical properties. Using a conditional knock-out of chondrocyte-mediated ECM production, we will then assess the impact on graft chondrocytes on ECM production. In our second aim, we will define how SAE differentiation is promoted by CTETG. We hypothesize that modification of graft dimensions with splinting reduces wall shear stress (WSS) resulting in improved epithelial differentiation. To test the effect of WSS on SAE differentiation, we will implant dcTETG and CTETG of normal and small diameter, thus increasing WSS by reducing graft radius. To quantify WSS, we will use computational fluid dynamics (CFD) to topographically map WSS through the TETG and correlate these values with quantitative immunofluorescence of neo-epithelium. Finally, we will validate CTETG performance in an ovine model of tracheal replacement in our third aim. Using routine radiographic and endoscopic surveillance, we will quantify animal survival, clinical manifestations, graft dimensions, and graft regeneration. This proposal advances the field of airway tissue engineering through the development of a composite tissue engineered tracheal graft and defining the mechanical factors contributing to graft regeneration.

项目概要/摘要 小儿长段气道缺陷是由先天畸形或外伤造成的， 感染或恶性肿瘤。尽管很少见，但这些缺陷往往是致命的。目前尚无成熟的手术方法 修复长段气管缺损的技术和重建方案仍然是英勇的。组织 工程学有潜力用正常的活器官替代失效的组织。尽管其潜力巨大，但临床 组织工程气管移植物（TETG）的效果一直很差。 气管置换术转化的主要障碍是移植物塌陷和上皮化延迟。 我们评估了脱细胞 TETG (dcTETG) 在小鼠原位气管模型中的性能 替代品。我们发现脱细胞 TETG 可以再生，恢复功能性表面气道 上皮细胞（SAE），但由于移植物塌陷，结果有限。使用可吸收生物材料来稳定 dcTETG，我们创建了复合 TETG (CTETG)。我们假设 CTETG 可以提高患者的总体生存率 长段气管置换术，减轻移植物塌陷，促进细胞外基质（ECM 产生）和 SAE 分化。 为了检验这一假设，我们将首先评估 CTETG 如何促进气管中的 ECM 再生 软骨。在我们的第一个目标中，我们将在气管置换小鼠模型中植入 dcTETG 和 CTETG 量化 ECM 生产和机械性能。使用软骨细胞介导的条件敲除 ECM 生产，然后我们将评估移植软骨细胞对 ECM 生产的影响。在我们的第二个目标中， 我们将定义 CTETG 如何促进 SAE 分化。我们假设移植物的修饰 带夹板的尺寸可减少壁剪切应力（WSS），从而改善上皮分化。测试 WSS对SAE分化的影响，我们将植入正常直径和小直径的dcTETG和CTETG， 从而通过减小移植物半径来增加 WSS。为了量化 WSS，我们将使用计算流体动力学 (CFD) 通过 TETG 绘制 WSS 地形图，并将这些值与定量免疫荧光相关联 新上皮。最后，我们将在我们的气管置换羊模型中验证 CTETG 的性能 第三个目标。使用常规放射线和内窥镜监测，我们将量化动物生存、临床 表现、移植物尺寸和移植物再生。 该提案通过开发复合材料推进了气道组织工程领域的发展 组织工程气管移植物并确定有助于移植物再生的机械因素。