Preclinical Assessment of a Compliance Matched Biopolymer Vascular Graft
顺应性匹配的生物聚合物血管移植物的临床前评估
基本信息
- 批准号:10731964
- 负责人:
- 金额:$ 12.51万
- 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:2021-12-15 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcuteAdultAnimal ModelAnti-Inflammatory AgentsAortaAutologousBilateralBiomechanicsBiopolymersBioreactorsBlood VesselsBypassCOVID-19 pandemicCardiacCardiac Surgery proceduresCardiovascular DiseasesCause of DeathCd68Cell ProliferationCellsCessation of lifeClinicalClinical ResearchClinical TreatmentCollagenCoronary Artery BypassCustomCytoskeletonDepositionDevelopmentDiameterDiseaseElastinElementsEngineeringExhibitsExposure toExtracellular MatrixFailureFluorescenceGelatinGenerationsHeart DiseasesHyperplasiaImageImplantIn VitroIndividualInfiltrationInterventionLegal patentLocationMacrophageMaintenanceMeasuresMechanicsModelingMyosin Heavy ChainsOrgan TransplantationOutcomePerformancePhenotypePlayProcessProductionProliferatingProtein IsoformsRattusReportingResearchRoleSaphenous VeinSheepSignal TransductionSiteSmooth Muscle MyocytesSprague-Dawley RatsStretchingStromal CellsSystemTGFB1 geneTGFB3 geneTestingThrombosisTimeTissuesTransforming Growth Factor Beta 2Transforming Growth Factor betaTropoelastinUnited StatesVascular DiseasesVascular GraftVascular Smooth MuscleWomanWorkabdominal aortacalponincell motilityconditioningcontrolled releasedosageeffective therapygraft failureimaging systemimprovedin vivointravital imagingmanufacturemechanical propertiesmenmulti-photonmultiphoton imagingparent projectparticlepre-clinicalpre-clinical assessmentpreimplantationpressurerecruitresponsescaffoldsecond harmonicsynergismthree dimensional cell culturetwo-photonvascular smooth muscle cell migrationvascular tissue engineering
项目摘要
PROJECT ABSTRACT
Cardiovascular diseases represent the leading cause of death worldwide and are currently responsible for 32%
of all reported deaths before the start of the COVID-19 pandemic. The increase in cardiovascular disease
prominence has placed increasing levels of demand for cardiac bypass grafting (CABG), which is now the
most common cardiac surgery in the world. Despite CABG interventions with autologous tissues are viewed as
one of the most effective treatment options, their failure of rate remains as high as 42.8%, with only 50% to
60% maintaining patency after 10 years. Vascular engineering research has sought to develop tissue
engineered vascular grafts (TEVG) in the form of acellular or cellularized constructs as an alternative solution.
Despite decades of research advancements, very few TEVGs have reached clinical studies, and there are no
clinically approved TEVGs currently in use. Here we seek to advance our understanding of how TEVGs are
infiltrated by the host’s cells when stimulated by three different isoforms of the protein Transforming Growth
Factor Beta, and the impact this treatment can have on cellular remodeling of the TEVGs.
Aim 1: Investigate native vascular tissue stromal cell migration onto and proliferation within a TEVG
that is compliance matched and TGFβ isoform loaded in a 3D culture system. We will test the hypothesis
that compliance matched TEVGs containing TGFβ2 loaded microparticles can modulate the rates of explanted
native vascular tissue cellular migration and proliferation onto an adjoined TEVG at significantly higher levels
than delivery of two alternative TGFβ isoforms utilizing a 3D culture system. Native rat arterial tissues will be
canulated and placed into the 3D culture system adjoined to a compliance matched TEVGs. The acellular
TEVGs will initially be manufactured to carry PLGA microparticles (MPs) loaded with TGFβ isoforms (TGFβ-1,
-2, -3, respectively) to provide a controlled release of TGFβ from the intimal layer of the TEVGs. We will
assess early and late term cellular migration and proliferation onto the TEVG scaffolds as a function of culture
time and TGFβ isoform release across a selection of release rates and dosages. We will quantify these results
using multiphoton intravital imaging of the specialized 3D biaxial TEVG culture system.
Aim 2: Assess the cellular remodeling of the compliance matched TGFβ isoform loaded TEVGs
through intravital 2-photon imaging. To investigate the subsequent ECM remodeling of the compliance
matched TEVGs carrying TGFβ isoform loaded MPs in 3D culture, we will utilize intravital imaging of explanted
native rat abdominal aortas adjoined to TEVGs in culture as before. In this supplemental aim, we will utilize the
2-photon imaging system to quantify ECM remodeling via collagen/elastin content though second harmonic
generation (SHG, collagens) and 2-photon excited fluorescence (2PEF, elastin) signals. We will assess
scaffold matrix remodeling by relative SHG and 2PEF levels as a function of culture time and the respective
TGFβ isoform delivered.
Aim 3: Investigate the impact of progressive biaxial biomechanical stimulation of the TGFβ isoform
loaded TEVGs by assessing cellular migration, proliferation, and remodeling of the TEVGs by
infiltrating stromal cells. We will utilize another feature of our custom-built bioreactors (biaxial biomechanical
loading) to impose controlled pulsatile pressures and axial stretches upon the TEVGs to determine if this
biomechanical stimulation synergizes with the TGFβ isoform delivery to enhance cellular activity. As before,
the native rat aorta tissues will be adjoined to the TEVGs, this time exposed to a selection of progressive
biaxial biomechanical conditioning scenarios. Cellular migration, proliferation, and remodeling of the TEVGs
will be assessed with our intravital 2-photon intravital imaging system as before, and TEVG remodeling will be
determined by the relative SHG and SPEF signal generation at various locations throughout the scaffolds as
before. We will assess these measures as a function of culture time and levels of biaxial biomechanical loading
in combination with TGFβ isoform delivery to determine how each uniquely impacts cellular remodeling
outcomes.
项目摘要
心血管疾病是全球死亡的主要原因,目前占32%。
在COVID-19大流行开始之前报告的所有死亡病例中。心血管疾病的增加
心脏旁路移植术(CABG)的需求日益增加,这是目前最重要的手术。
最常见的心脏手术尽管使用自体组织的CABG干预被视为
最有效的治疗方案之一,其失败率仍高达42.8%,只有50%,
10年后60%保持通畅。血管工程研究试图开发组织
工程血管移植物(TEVG)以无细胞或细胞化构建体的形式作为替代解决方案。
尽管几十年来的研究进展,很少有TEVG已经达到临床研究,
目前正在使用的临床批准的TEVG。在这里,我们寻求推进我们对TEVG如何
当被转化生长蛋白的三种不同亚型刺激时,
因子β,以及这种治疗对TEVG的细胞重塑的影响。
目的1:研究天然血管组织基质细胞在TEVG上的迁移和增殖
即顺应性匹配和TGFβ同种型加载在3D培养系统中。我们将检验这个假设
含有TGFβ2负载的微粒的顺应性匹配的TEVG可以调节肿瘤的发生率,
天然血管组织细胞迁移和增殖到相邻的TEVG上,水平显著较高
相比于利用3D培养系统递送两种替代性TGFβ同种型。将天然大鼠动脉组织
插管并置于与顺应性匹配的TEVG邻接的3D培养系统中。脱细胞
TEVG最初将被制造成携带载有TGFβ同种型(TGFβ-1,
-2,-3)以提供TGFβ从TEVG的内膜层的受控释放。我们将
评估早期和晚期细胞迁移和增殖到TEVG支架上作为培养的函数
时间和TGFβ同种型的释放,在选择的释放速率和剂量。我们将量化这些结果
使用专门的3D双轴TEVG培养系统的多光子活体成像。
目的2:评估顺应性匹配的TGFβ同种型负载的TEVG的细胞重构
通过活体双光子成像调查后续的ECM合规性重塑
在3D培养中,我们将利用携带TGFβ同种型负载MP的TEVG的活体成像,
如前所述,在培养物中,将天然大鼠腹侧肌与TEVG邻接。在本补充目标中,我们将利用
2-通过二次谐波通过胶原蛋白/弹性蛋白含量量化ECM重塑的光子成像系统
产生(SHG,胶原)和2-光子激发的荧光(2 PEF,弹性蛋白)信号。我们将评估
支架基质重塑通过相对SHG和2 PEF水平作为培养时间的函数,
输送TGFβ亚型。
目的3:研究TGFβ亚型的渐进双轴生物力学刺激的影响
通过评估TEVG的细胞迁移、增殖和重塑来加载TEVG,
浸润基质细胞。我们将利用我们定制的生物反应器的另一个功能(双轴生物力学
加载),以在TEVG上施加受控的脉动压力和轴向拉伸,
生物力学刺激与TGFβ同种型递送协同作用以增强细胞活性。同以前一样,
将天然大鼠主动脉组织与TEVG邻接,这次暴露于选择的渐进性的
双向生物力学调节场景。TEVG的细胞迁移、增殖和重塑
将像以前一样用我们的活体2光子活体成像系统进行评估,TEVG重塑将被
通过在整个支架的各个位置处的相对SHG和SPEF信号产生来确定,
以前我们将评估这些措施作为培养时间和双轴生物力学负荷水平的函数
结合TGFβ亚型递送,以确定每种亚型如何独特地影响细胞重塑
结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jonathan Pieter Vande Geest其他文献
Characterizing Bruch's membrane: State-of-the-art imaging, computational segmentation, and biologic models in retinal disease and health
布鲁赫膜的特征描述:视网膜疾病与健康状态中的先进成像、计算分割及生物学模型
- DOI:
10.1016/j.preteyeres.2025.101358 - 发表时间:
2025-05-01 - 期刊:
- 影响因子:14.700
- 作者:
Joshua Ong;Amrish Selvam;Matthew Driban;Arman Zarnegar;Susana Isabel Morgado Mendes Antunes Da Silva;Jincy Joy;Ethan A. Rossi;Jonathan Pieter Vande Geest;José-Alain Sahel;Jay Chhablani - 通讯作者:
Jay Chhablani
Jonathan Pieter Vande Geest的其他文献
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{{ truncateString('Jonathan Pieter Vande Geest', 18)}}的其他基金
Biocarpet: The Next Generation Endovascular Device for Peripheral Arterial Disease
Biocarpet:治疗外周动脉疾病的下一代血管内装置
- 批准号:
10744597 - 财政年份:2023
- 资助金额:
$ 12.51万 - 项目类别:
Preclinical Assessment of a Compliance Matched Biopolymer Vascular Graft
顺应性匹配的生物聚合物血管移植物的临床前评估
- 批准号:
10366911 - 财政年份:2021
- 资助金额:
$ 12.51万 - 项目类别:
Preclinical Assessment of a Compliance Matched Biopolymer Vascular Graft
顺应性匹配的生物聚合物血管移植物的临床前评估
- 批准号:
10540762 - 财政年份:2021
- 资助金额:
$ 12.51万 - 项目类别:
Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peripapillary Sclera in Populations at High Risk for Primary Open Angle Glaucoma
原发性开角型青光眼高危人群筛板和视乳头周围巩膜的细胞外基质组织和生物力学
- 批准号:
9293031 - 财政年份:2016
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Development of a Microstructurally Inspired and Compliance Matched Tissue Enginee
开发受微观结构启发且顺应性匹配的组织工程
- 批准号:
8444206 - 财政年份:2013
- 资助金额:
$ 12.51万 - 项目类别:
Development of a Microstructurally Inspired and Compliance Matched Tissue Enginee
开发受微观结构启发且顺应性匹配的组织工程
- 批准号:
8603278 - 财政年份:2013
- 资助金额:
$ 12.51万 - 项目类别:
Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peri
筛板和周周的细胞外基质组织和生物力学
- 批准号:
8188325 - 财政年份:2011
- 资助金额:
$ 12.51万 - 项目类别:
Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peri
筛板和周周的细胞外基质组织和生物力学
- 批准号:
8703108 - 财政年份:2011
- 资助金额:
$ 12.51万 - 项目类别:
Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peri
筛板和周周的细胞外基质组织和生物力学
- 批准号:
8304189 - 财政年份:2011
- 资助金额:
$ 12.51万 - 项目类别:
Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peri
筛板和周周的细胞外基质组织和生物力学
- 批准号:
8509699 - 财政年份:2011
- 资助金额:
$ 12.51万 - 项目类别:
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