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 大流行开始之前所有报告的死亡人数中心血管疾病的增加。
日益突出的地位使得对心脏搭桥术(CABG)的需求不断增加,该术现在已成为
尽管冠状动脉搭桥术(CABG)干预自体组织被视为世界上最常见的心脏手术。
作为最有效的治疗方案之一,其失败率仍高达 42.8%,而失败率仅为 50%
10 年后 60% 仍保持通畅 血管工程研究致力于开发组织。
非细胞或细胞化结构形式的工程血管移植物(TEVG)作为替代解决方案。
尽管研究取得了数十年的进展,但很少有 TEVG 进入临床研究,而且还没有
目前正在使用经临床批准的 TEVG,我们在此寻求加深对 TEVG 用途的理解。
当受到三种不同亚型的蛋白质转化生长刺激时,宿主细胞会渗透
因子 Beta,以及这种治疗对 TEVG 细胞重塑的影响。
目标 1:研究天然血管组织基质细胞在 TEVG 上的迁移和增殖
这是顺应性匹配的并且 TGFβ 同种型加载在 3D 培养系统中我们将检验该假设。
含有 TGFβ2 负载微粒的顺应性匹配 TEVG 可以调节外植率
天然血管组织细胞以显着更高的水平迁移和增殖到相邻的 TEVG 上
比利用 3D 培养系统输送两种替代 TGFβ 亚型的效果更好。
插管并放入与顺应性匹配的无细胞 TEVG 相邻的 3D 培养系统中。
TEVG 最初将被制造为携带装载有 TGFβ 同种型(TGFβ-1、
-2、-3)以从 TEVG 内膜层控制释放 TGFβ。
评估早期和晚期细胞在 TEVG 支架上的迁移和增殖作为培养的功能
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。
目标 2:评估顺应性匹配的 TGFβ 同种型负载 TEVG 的细胞重塑
通过活体 2 光子成像研究随后的 ECM 重塑。
在 3D 培养中匹配携带 TGFβ 同种型负载 MP 的 TEVG,我们将利用外植体的活体成像
与之前一样,将本地大鼠腹主动脉与培养物中的 TEVG 相连。
双光子成像系统通过二次谐波通过胶原蛋白/弹性蛋白含量量化 ECM 重塑
我们将评估生成(SHG、胶原蛋白)和 2 光子激发荧光(2PEF、弹性蛋白)信号。
相对 SHG 和 2PEF 水平作为培养时间和各自的函数的支架基质重塑
递送 TGFβ 同种型。
目标 3:研究渐进式双轴生物力学刺激对 TGFβ 同工型的影响
通过评估 TEVG 的细胞迁移、增殖和重塑来加载 TEVG
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)对 TEVG 施加受控脉动压力和轴向拉伸,以确定这是否
生物力学刺激与 TGFβ 同种型传递协同作用,增强细胞活性。
天然大鼠主动脉组织将与 TEVG 相邻,这次暴露于一系列渐进的
TEVG 的双轴生物力学调节场景。
将像以前一样使用我们的活体 2 光子活体成像系统进行评估,并且 TEVG 重塑将
由整个支架中不同位置处的相对 SHG 和 SPEF 信号生成确定:
之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。
与 TGFβ 同工型递送相结合,以确定每种同工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
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
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Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peripapillary Sclera in Populations at High Risk for Primary Open Angle Glaucoma
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开发受微观结构启发且顺应性匹配的组织工程
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8444206 - 财政年份:2013
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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
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8603278 - 财政年份:2013
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Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peri
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8188325 - 财政年份:2011
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Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peri
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- 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
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- 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
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$ 12.51万 - 项目类别:
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