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

基本信息

批准号：
10670906
负责人：
Tendy Chiang
金额：
$ 71.43万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
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/10670906
关键词：
3-Dimensional Acceleration Address Adolescent Air Movements Animal Model Animals Attenuated Autologous Autologous Transplantation Biochemical Biocompatible Materials Biological Biomechanics Biophysics Biopsy Bronchi Bronchoscopy Cartilage Cells Child Childhood Chondrocytes Chondrogenesis Clinical Clinical Management Complex Congenital Abnormality Cues Data Defect Detection Development Diameter Dimensions Disease Epithelial Cells Epithelium Expression Profiling Extracellular Matrix Generations Growth Host Defense Image Immunofluorescence Immunologic Implant Infection Inflammation Injury Intervention Legal patent 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 Proliferating Public Health Radial Role Source Splint Device Stents Surface Techniques Testing Time Tissue Engineering Tissue Preservation Tissues Trachea Tracheal Diseases Trauma Work airway epithelium airway obstruction biomaterial compatibility cartilaginous clinical translation conditional knockout efficacy testing epithelium regeneration extracellular implantation improved innovation lamb model mechanical properties migration mouse model nanofiber preservation progenitor protein expression radiological imaging repaired replacement tissue respiratory surgery restoration shear stress sheep model stem stress reduction translational barrier

项目摘要

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.

项目摘要 /摘要小儿长段气道缺陷是由先天性畸形引起的，或者是由创伤引起的感染或恶性肿瘤。尽管很少见，但这些缺陷通常是致命的。目前没有既定的手术修复长段气管缺陷和重建方案的技术仍然是英勇的。组织工程有可能用正常的生物器官替换失败的组织。尽管具有潜力，但临床组织工程气管移植物（TETG）的结果很差。气管置换翻译的主要障碍是移植物塌陷和上皮化延迟。我们评估了在原位气管的小鼠模型中脱细胞TETG（DCTETG）的性能替代品。我们确定脱细胞TETG可以再生，恢复功能性的表面气道上皮（SAE），但是由于移植物塌陷而限制结果。使用可吸收生物材料稳定 DCTETG，我们创建了一个复合TETG（CTETG）。我们假设CTETG可以改善长段气管置换，衰减移植物塌陷，促进细胞外基质（ECM产生）和 SAE差异化。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，我们将植入DCTETG和CTETG中的气管置换鼠标模型和量化ECM生产和机械性能。使用软骨细胞介导的条件敲除然后，我们将评估对移植软骨细胞对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。我们假设对移植物进行了修改夹板的尺寸减少了壁剪应力（WSS），从而改善了上皮分化。测试 WSS对SAE分化的影响，我们将植入正常和小直径的DCTETG和CTETG，因此，通过减少移植半径来增加WSS。要量化WSS，我们将使用计算流体动力学（CFD）通过TETG映射WSS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替代卵中验证CTETG性能第三目标。使用常规的射线照相和内窥镜监测，我们将量化动物生存，临床表现，移植尺寸和移植物再生。该提案通过复合材料的开发发展了气道组织工程领域组织工程的气管移植物并定义有助于移植再生的机械因素。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tracheostomy in Severe Bronchopulmonary Dysplasia-How to Decide in the Absence of Evidence.

DOI：
10.3390/biomedicines11092572
发表时间：
2023-09-19
期刊：
Biomedicines
影响因子：
4.7
作者：
通讯作者：

Assemblies of JAG1 and JAG2 determine tracheobronchial cell fate in mucosecretory lung disease.

DOI：
10.1172/jci.insight.157380
发表时间：
2022-08-08
期刊：
JCI INSIGHT
影响因子：
8
作者：
Reynolds, Susan D.;Hill, Cynthia L.;Alsudayri, Alfahdah;Lallier, Scott W.;Wijeratne, Saranga;Tan, Zheng Hong;Chiang, Tendy;Cormet-Boyaka, Estelle
通讯作者：
Cormet-Boyaka, Estelle

Optimization of Chondrocyte Viability in Partially Decellularized Tracheal Grafts.

DOI：
10.1002/ohn.404
发表时间：
2023-11
期刊：
OTOLARYNGOLOGY-HEAD AND NECK SURGERY
影响因子：
3.4
作者：
Bergman, Maxwell;Harwood, Jacqueline;Liu, Lumei;Dharmadikhari, Sayali;Shontz, Kimberly M. M.;Chiang, Tendy Y.
通讯作者：
Chiang, Tendy Y.

Tracheal Macrophages During Regeneration and Repair of Long-Segment Airway Defects.

长段气道缺损再生和修复过程中的气管巨噬细胞。

DOI：
10.1002/lary.29698
发表时间：
2022-04
期刊：
The Laryngoscope
影响因子：
0
作者：
Tan ZH;Dharmadhikari S;Liu L;Wolter G;Shontz KM;Reynolds SD;Johnson J;Breuer CK;Chiang T
通讯作者：
Chiang T

Partial decellularization eliminates immunogenicity in tracheal allografts.