3D Acellular Vascular Beds: Characterization and Re-endothelialization
3D 无细胞血管床:表征和再内皮化
基本信息
- 批准号:8096092
- 负责人:
- 金额:$ 18.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlternative TherapiesAnastomosis - actionAngiogenic FactorArchitectureBasal laminaBiological ModelsBiological PreservationBlood VesselsBlood capillariesCaliberCell Culture TechniquesCell SurvivalCellsCellularityClinicalComplexDefectDimensionsEndothelial CellsEngineeringEthylene GlycolsExcisionExtracellular MatrixFibrinFractalsFutureGene ExpressionGoalsHistocompatibility TestingHistologyHumanImmuneImmune responseImmunohistochemistryImplantLiquid substanceMesenchymal Stem CellsMethodsMicrofilamentsModelingMorphologyNecrosisNerveNerve TissueNutrientOrganPatientsPenetrationPerfusionPeripheral NervesPhenotypePhysiologicalProceduresProcessProliferatingPropertyProstaglandins IProteinsProtocols documentationPulsatile FlowRattusResearchResearch PersonnelShapesSourceStressStructure of parenchyma of lungSurgical AnastomosisSystemTechniquesTechnologyThickTissue EngineeringTissuesTranslatingTransplantationVascular SystemVascularizationWaiting ListsWestern BlottingWorkbasecapillarycapillary bedcookingcrosslinkethylene glycolexperiencefluid flowimmunogenicimmunogenicityimplantationin vivopreconditioningregenerativeregenerative therapyscaffoldshear stresstissue regenerationtwo-dimensionalvascular bed
项目摘要
DESCRIPTION (provided by applicant): The goal of the proposed research is to develop a three-dimensional (3D) vascular bed from natural tissues, which can ultimately be used in scaffolds for tissue engineering applications requiring immediate vascularization or which can be used as stand-alone grafts for necrotic tissues in the body. To create the vascular construct, a decellularization procedure, which the PI has previously developed to accurately preserve the intricate micro-architecture of peripheral nerve, will be used to remove the immunogenic cellular components from highly vascularized lung tissue and to simultaneously preserve the microvessel extracellular matrix. This acellular vascular bed will be subsequently re-endothelialized with human mesenchymal stem cells (hMSCs) that have been trans differentiated into an endothelial cell phenotype, based on previous work of the Co-I. Decellularized tissues offer excellent clinical opportunities; in fact, many examples of current regenerative therapies utilize natural, acellular tissues (e.g., SIS products from Cook Biotech, AlloDerm from LifeCell, and Avance from AxoGen; note: the Avance nerve graft is based on the PI's decellularization processes for nerve). In addition, MSCs offer great potential for clinical translational because they are immune-privileged or they can be isolated from the patient and expanded ex vivo. In Specific Aim 1, highly vascularized lung tissue will be decellularized using the PI's previous decellularization protocol and subsequently characterized for matrix preservation, cellular removal, and in vivo immune response. Particular focus will be on preserving the 3D vascular interconnected network of large vessels and capillaries. The decellularization method has been effective in maintaining basal laminae of 5-10 microns diameter in nerve, supporting the hypothesis that this method can maintain capillary networks composed of the same matrix proteins. In Specific Aim 2, the decellularized vascular bed will be re-endothelialized by injecting transdifferentiated human MSCs into the vascular axis of the tissue. Human MSCs will be transdifferentiated in a poly(ethylene glycol) (PEG) crosslinked fibrin matrix (PEGylated fibrin) towards endothelial lineages, as performed previously by the Co-I. The ability of these cells to expand and form lumen inside the 3D acellular vascular construct will be evaluated. Once seeded, these transdifferentiated hMSCs will be subjected to pulsatile flow, to precondition the cells for physiological stresses that are found in the native vascular system. The vascular constructs developed in this proposal could be used to promote vascularization and regeneration of tissues in critically-sized defects (>100 microns) in a multitude of tissue types, as well as be used as a model system to investigate the properties of transdifferentiated hMSCs.
PUBLIC HEALTH RELEVANCE: As the organ wait list continues to exceed the number of donors each year, the need for alternative therapies to transplantation is becoming increasingly important. Yet, researchers have demonstrated that a vascular connection is necessary in order to maintain viability in tissues beyond 100-200 microns thick. To date, there is no effective manner in which to recreate this vascular connection. The goal of our proposed research is to develop three-dimensional vascular beds from natural tissues, which can ultimately be used in scaffolds for tissue engineering applications requiring immediate vascularization or which can be used as stand-alone grafts for necrotic tissues in the body. To create the vascular construct we will use a decellularization procedure, which we have previously developed to accurately preserve the intricate micro-architecture of peripheral nerve, to remove the immunogenic cellular components from highly vascularized lung tissue and to simultaneously preserve the microvessel extracellular matrix. The vascular bed will be subsequently re- endothelialized with human mesenchymal stem cells (MSCs) that have been transdifferentiated into an endothelial cell phenotype. MSCs offer great potential for clinical translational because they are immune- privileged or they can be isolated from the patient. In addition, decellularized tissues offer clinical opportunities; in fact, most examples of current scaffold-based regenerative therapies utilize natural, acellular tissues (e.g., SIS products from Cook Biotech, AlloDerm from LifeCell, and Avance from AxoGen; note: the Avance nerve graft is based on the PI's decellularization processes for nerve tissue).
描述(由申请人提供):拟议的研究的目的是从天然组织开发三维(3D)血管床,最终可用于需要立即血管化的组织工程应用的脚手架,或可以用作独立的植物植物,以作为体内的坏死组织。为了创建血管构建体,PI先前已开发出一种脱细化过程,以准确保留外围神经的复杂微体系结构,将用于从高度血管化的肺组织中去除免疫原性细胞成分并同时保留微蛋白酶外细胞外矩阵。根据CO-I的先前工作,该细胞血管床将随后用人间充质干细胞(HMSC)重新内皮,这些人间充质干细胞(HMSC)已被分化为内皮细胞表型。脱细胞组织提供了极好的临床机会;实际上,许多当前再生疗法的例子都利用天然的细胞组织(例如,来自库克生物技术的SIS产物,来自Lifecell的Alloderm和Axogen的Avance;注意:Avance神经移植是基于PI的神经脱离脱毛的过程)。此外,MSC为临床翻译提供了巨大的潜力,因为它们是免疫特性的,或者可以与患者隔离并在体内扩展。在特定的目标1中,高度血管化的肺组织将使用PI先前的脱细胞方案进行脱细胞化,然后以基质保存,细胞去除和体内免疫反应的特征。特别的重点将是保留大容器和毛细管的3D血管互连网络。脱细胞方法已有效地在神经中保持直径为5-10微米的基底层,这支持了以下假设:该方法可以维持由相同的基质蛋白组成的毛细血管网络。在特定的目标2中,通过将转分化的人MSC注入组织的血管轴,将脱细胞的血管床重新皮层。如CO-I之前,人类MSC将在聚乙二醇(PEG)(PEG)交联纤维蛋白基质(PEGYPER纤维蛋白)向内皮谱系中转差。将评估这些细胞在3D细胞血管构建体内扩展和形成管腔的能力。一旦播种,这些转分化的HMSC将受到脉冲流量的影响,以预先调节细胞的生理应激,这些生理胁迫在天然血管系统中发现。该提案中开发的血管构建体可用于促进多种组织类型中关键大小缺陷(> 100微米)中组织的血管形成和再生,并用作模型系统,以研究转分化的HMSC的性质。
公共卫生相关性:随着器官等待名单每年继续超过捐助者的数量,对移植的替代疗法的需求变得越来越重要。然而,研究人员表明,为了维持100-200微米厚的组织的生存能力,需要血管连接。迄今为止,还没有有效的方式重新创建这种血管连接。我们提出的研究的目的是开发来自天然组织的三维血管床,最终可以用于需要立即血管形成的组织工程应用的支架中,或者可以用作人体坏死组织的独立移植物。为了创建血管构建体,我们将使用脱细化程序,以前我们已经开发出该过程来准确保留外围神经的复杂微体系结构,以从高度血管化的肺组织中去除免疫原性细胞成分并同时保留微型固定外细胞外质体。随后将血管床与已转化为内皮细胞表型的人间充质干细胞(MSC)重新呈内皮。 MSC为临床翻译提供了巨大的潜力,因为它们具有免疫特权或可以与患者隔离。此外,脱细胞组织提供临床机会;实际上,当前基于脚手架的再生疗法的大多数实例都利用天然的细胞组织(例如,来自Cook Biotech的SIS产物,来自Lifecell的Alloderm和Axogen的Avance;请注意:Avance神经移植是基于PI的脱细胞脱细胞化的神经组织的脱皮过程)。
项目成果
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