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:
- 金额:$ 71.43万
- 依托单位:
- 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:
- 关键词:3-DimensionalAccelerationAddressAdolescentAir MovementsAnimal ModelAnimalsAttenuatedAutologousAutologous TransplantationBiochemicalBiocompatible MaterialsBiologicalBiomechanicsBiophysicsBiopsyBronchiBronchoscopyCartilageCellsChildChildhoodChondrocytesChondrogenesisClinicalClinical ManagementComplexCongenital AbnormalityCuesDataDefectDetectionDevelopmentDiameterDimensionsDiseaseEpithelial CellsEpitheliumExpression ProfilingExtracellular MatrixGenerationsGrowthHost DefenseImageImmunofluorescence ImmunologicImplantInfectionInflammationInjuryInterventionLegal patentLiquid substanceMaintenanceMalignant NeoplasmsMapsMass Spectrum AnalysisMechanicsMediatingModelingModificationMucociliary ClearanceMusNatural regenerationOperative Surgical ProceduresOrganOutcomePatientsPerformancePopulationProductionProliferatingPublic HealthRadialRoleSourceSplint DeviceStentsSurfaceTechniquesTestingTimeTissue EngineeringTissue PreservationTissuesTracheaTracheal DiseasesTraumaWorkairway epitheliumairway obstructionbiomaterial compatibilitycartilaginousclinical translationconditional knockoutefficacy testingepithelium regenerationextracellularimplantationimprovedinnovationlamb modelmechanical propertiesmigrationmouse modelnanofiberpreservationprogenitorprotein expressionradiological imagingrepairedreplacement tissuerespiratory surgeryrestorationshear stresssheep modelstemstress reductiontranslational 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
小儿长段气道缺损是由先天性畸形或创伤引起的,
感染或恶性肿瘤。虽然罕见,但这些缺陷往往是致命的。目前还没有成熟的外科手术
技术修复长段气管缺损和重建的选择仍然是英雄。组织
工程学有可能用正常的活体器官来替代衰竭的组织。尽管它的潜力,临床
组织工程气管移植物(TETG)的结果一直很差。
移植物塌陷和上皮形成延迟是气管置换的主要障碍。
我们评估了脱细胞TETG(dcTETG)在我们的小鼠原位气管模型中的性能,
更换.我们发现脱细胞TETG可以再生,恢复功能性表面气道
上皮(SAE),但由于移植物塌陷,结局有限。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可以改善总生存率,
长段气管置换,减轻移植物塌陷,促进细胞外基质(ECM产生),
SAE区分。
为了验证这一假设,我们将首先评估CTETG如何促进气管中ECM的再生。
软骨在我们的第一个目标中,我们将在气管置换的小鼠模型中植入dcTETG和CTETG,
量化ECM生产和机械性能。使用软骨细胞介导的条件性敲除
ECM的产生,然后我们将评估移植软骨细胞对ECM产生的影响。我们的第二个目标,
我们将定义CTETG如何促进SAE分化。我们假设移植物的修饰
使用夹板固定减小了壁剪切应力(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地形图绘制WSS,并将这些值与定量免疫荧光相关联
新生上皮细胞最后,我们将在我们的研究中验证CTETG在绵羊气管置换模型中的性能。
第三个目标。使用常规放射学和内窥镜监测,我们将量化动物存活率,临床
表现、移植物尺寸和移植物再生。
该建议通过开发复合材料推进了气道组织工程领域
组织工程气管移植物和定义的力学因素有助于移植物再生。
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)
Assemblies of JAG1 and JAG2 determine tracheobronchial cell fate in mucosecretory lung disease.
JAG1和JAG2的组件确定粘膜分泌性肺部疾病中的气管支气管细胞命运。
- DOI:10.1172/jci.insight.157380
- 发表时间:2022-08-08
- 期刊:
- 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
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:
- 影响因子:4.7
- 作者:
- 通讯作者:
Partial decellularization eliminates immunogenicity in tracheal allografts.
部分脱细胞消除了气管同种异体移植物中的免疫原性。
- DOI:10.1002/btm2.10525
- 发表时间:2023-09
- 期刊:
- 影响因子:7.4
- 作者:
- 通讯作者:
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:
- 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
Optimization of Chondrocyte Viability in Partially Decellularized Tracheal Grafts.
- DOI:10.1002/ohn.404
- 发表时间:2023-11
- 期刊:
- 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.
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{{ truncateString('Tendy Chiang', 18)}}的其他基金
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:
10453450 - 财政年份:2021
- 资助金额:
$ 71.43万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 71.43万 - 项目类别:
Mechanisms of regeneration in tissue engineered tracheal grafts
组织工程气管移植物的再生机制
- 批准号:
10207746 - 财政年份:2017
- 资助金额:
$ 71.43万 - 项目类别:
Mechanisms of regeneration in tissue engineered tracheal grafts
组织工程气管移植物的再生机制
- 批准号:
9975214 - 财政年份:2017
- 资助金额:
$ 71.43万 - 项目类别:
Mechanisms of regeneration in tissue engineered tracheal grafts
组织工程气管移植物的再生机制
- 批准号:
9371368 - 财政年份:2017
- 资助金额:
$ 71.43万 - 项目类别:
Mechanisms of regeneration in tissue engineered tracheal grafts
组织工程气管移植物的再生机制
- 批准号:
9527865 - 财政年份:2017
- 资助金额:
$ 71.43万 - 项目类别:
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