Readily Available Stem Cell-Based Vascular Grafts for Emergent Surgical Care
用于紧急手术护理的现成干细胞血管移植物
基本信息
- 批准号:10841794
- 负责人:
- 金额:$ 1.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAllogenicAnastomosis - actionAnimal ModelAnimalsAnticoagulationArteriesAutologousAutologous TransplantationBiomechanicsBioreactorsBlast InjuriesBloodBlood VesselsBlood coagulationBlunt TraumaBypassCardiovascular PhysiologyCaringCellsClinicalClothingCoagulation ProcessCollaborationsCollagenContusionsCryopreservationDepositionDerivation procedureDiabetes MellitusDiameterDiseaseEctopic ExpressionElastinElderlyEmergency SituationEmergency treatmentEndothelial CellsEndotheliumEngineeringEthical IssuesExtracellular MatrixFamily suidaeFractureFunctional disorderFutureGenerationsGlycocalyxGrowthHLA AntigensHemodialysisHistologicHumanImmune responseImplantIn VitroInjuryInterventionLeadLegal patentLettersLifeLigationLimb structureLower ExtremityMechanicsMethodsModelingMonitorMorbidity - disease rateNatureNude RatsOperative Surgical ProceduresOxygenPatient CarePatientsPenetrationPerformancePeriodicityPeripheralPhase II Clinical TrialsPolyglycolic AcidPopulationPre-Clinical ModelProductionPropertyProteinsRattusReproducibilityResidual stateSaphenous VeinSmooth Muscle MyocytesSomatic CellSourceStem Cell FactorStretchingSupplementationSurfaceTensile StrengthTibial ArteriesTimeTraffic accidentsTransplantationTraumaTreatment EfficacyVariantVascular Endothelial CellVascular GraftVascular Smooth MuscleVascular remodelingWait Timeabdominal aortaadvanced diseasebrachial arterycell typeendothelial stem cellexperienceimmunogenicimmunosuppressedimplantationin vivoin vivo Modelinduced pluripotent stem cellinfection riskinjuredinjury and repairlimb lossmanufacturing scale-upmechanical propertiesmorphometrymortalitypatient populationporcine modelpre-clinicalpreclinical efficacypreventscaffoldsevere injurystem cell derived tissuesstem cellsthrombogenesisurgent carevascular injuryvascular tissue engineeringvirtual
项目摘要
Patients who have undergone vascular trauma resulting from penetrating (e.g. blast injury) or blunt (e.g. fracture
and contusion from a traffic accident) trauma often experience severe damage to their small-diameter peripheral
arteries (2-4mm, e.g. tibial or brachial arteries) and require surgical intervention to bypass or replace the injured
vessel segments. As the accessibility of saphenous veins may be low in patients of vascular trauma due to
severe injuries or loss of more than one lower extremity as a result of blast injury or severe traffic accident, and
the application of synthetic vascular grafts can be hindered by the potential risk of infection due to the contagious
nature of these types of injuries, an alternative source of vascular graft is in dire need. Acellular tissue engineered
vascular grafts (TEVGs) therefore may offer a readily available treatment for emergency care for patients of
vascular trauma. Although TEVGs of significant mechanical strength can be developed from culturing primary
human vascular smooth muscle cells (VSMCs) followed by decellularization, this platform has several obstacles
which prevent it from ultimately serving victims of vascular trauma. The finite expandability, limited accessibility,
and donor-to-donor functional variations among primary VSMCs may hinder the efficiency of TEVG production.
Further, as small-diameter TEVGs require autologous endothelial cell (EC) coating prior to implantation to avoid
blood clothing, potential dysfunction of patient ECs due to either advanced age or disease, as well as the
significant time required to derive and expand the patient's autologous ECs, could prevent applicability in treating
acute vascular injury. Human induced pluripotent stem cells (hiPSCs), self-renewable cells derived from somatic
cells by the ectopic expression of stem cell factors, provide an excellent alternative to address the complications
of primary cell based TEVGs. As hiPSCs can be differentiated into virtually any somatic cell type, including
VSMCs and ECs (hiPSC-VSMCs and hiPSC-ECs), these cells provide an unlimited cell source to obtain vascular
cells to construct TEVGs of comparable quality (hiPSC-TEVGs). Further, by engineering the expression of
human leukocyte antigen (HLA) proteins, non- or low-immunogenic universal hiPSCs could be established,
making the hiPSC-TEVGs suitable for implantation into any patient. Through utilizing the hiPSC platform, TEVGs
for patients of vascular trauma can be developed on a massive scale, and of predictable and reproducible
mechanical strength. Additionally, through developing and cryopreserving allogeneic universal hiPSC-ECs,
these cells could be immediately applied to endothelialize TEVGs for small-diameter vascular intervention. Using
hiPSC-VSMCs, we have successfully developed TEVGs with mechanical strength approaching that of
saphenous veins, the common native grafts in vascular injury repair. Therefore, to achieve this future application
of hiPSC-TEVGs, it is essential to establish the approach to efficiently decellularize the hiPSC-TEVGs, provide
a luminal layer of hiPSC-ECs, and assess subsequent mechanical properties in vivo for preclinical efficacy as
detailed in this proposal.
因穿透性(如爆炸伤)或钝性(如骨折)导致血管创伤的患者
和交通事故造成的挫伤)创伤经常会对他们的小直径外周造成严重损伤
动脉(2- 4 mm,例如胫动脉或肱动脉),需要手术干预以绕过或替换受伤的
血管节段由于大隐静脉的可及性在血管创伤患者中可能较低,
由于爆炸伤或严重交通事故造成的严重伤害或一个以上下肢的丧失,以及
合成血管移植物的应用可能受到潜在的感染风险的阻碍
由于这些类型损伤的性质,迫切需要血管移植物的替代来源。脱细胞组织工程
因此,血管移植物(TEVG)可以为以下患者的紧急护理提供一种现成的治疗方法:
血管创伤尽管具有显著机械强度的TEVG可以从培养原代细胞中开发出来,
人血管平滑肌细胞(VSMC)随后去细胞化,该平台存在几个障碍
这就阻止了它最终为血管创伤的受害者服务。有限的可扩展性,有限的可访问性,
并且原代VSMC中供体与供体的功能差异可能阻碍TEVG生产的效率。
此外,由于小直径的TEVG在植入之前需要自体内皮细胞(EC)涂层,以避免
血衣,由于高龄或疾病导致的患者EC的潜在功能障碍,以及
获得和扩增患者的自体EC需要大量时间,这可能妨碍治疗的适用性。
急性血管损伤人诱导多能干细胞(hiPSC),来源于体细胞的可自我再生细胞,
细胞的异位表达的干细胞因子,提供了一个很好的替代方案,以解决并发症
基于原电池的TEVG。由于hiPSC可以分化成几乎任何体细胞类型,包括
VSMC和EC(hiPSC-VSMC和hiPSC-EC),这些细胞提供了无限的细胞来源以获得血管内皮细胞。
细胞以构建质量相当的TEVG(hiPSC-TEVG)。此外,通过工程化表达
人白细胞抗原(HLA)蛋白,可以建立非免疫原性或低免疫原性的通用hiPSC,
使hiPSC-TEVG适合植入任何患者。通过利用hiPSC平台,TEVG
可以大规模开发,并且具有可预测性和可重复性
机械强度此外,通过开发和冷冻保存同种异体通用hiPSC-EC,
这些细胞可以立即应用于内皮化TEVG,用于小直径血管介入。使用
hiPSC-VSMC,我们成功开发出机械强度接近TEVG的TEVG
隐静脉是血管损伤修复中常见的自体移植物。因此,要实现这一未来的应用
因此,必须建立有效地使hiPSC-TEVG脱细胞的方法,
hiPSC-EC的管腔层,并评估随后的体内机械特性以获得临床前疗效,
在这个提案中详细说明。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia.
- DOI:10.3390/cells10040792
- 发表时间:2021-04-02
- 期刊:
- 影响因子:6
- 作者:Gao X;Gao M;Gorecka J;Langford J;Liu J;Luo J;Taniguchi R;Matsubara Y;Liu H;Guo L;Gu Y;Qyang Y;Dardik A
- 通讯作者:Dardik A
Xenogeneic-free generation of vascular smooth muscle cells from human induced pluripotent stem cells for vascular tissue engineering.
- DOI:10.1016/j.actbio.2020.10.042
- 发表时间:2021-01-01
- 期刊:
- 影响因子:9.7
- 作者:Luo J;Lin Y;Shi X;Li G;Kural MH;Anderson CW;Ellis MW;Riaz M;Tellides G;Niklason LE;Qyang Y
- 通讯作者:Qyang Y
Efficient Differentiation of Human Induced Pluripotent Stem Cells into Endothelial Cells under Xenogeneic-free Conditions for Vascular Tissue Engineering.
- DOI:10.1016/j.actbio.2020.11.007
- 发表时间:2021-01-01
- 期刊:
- 影响因子:9.7
- 作者:Luo J;Shi X;Lin Y;Yuan Y;Kural MH;Wang J;Ellis MW;Anderson CW;Zhang SM;Riaz M;Niklason LE;Qyang Y
- 通讯作者:Qyang Y
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Yibing Qyang其他文献
Yibing Qyang的其他文献
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{{ truncateString('Yibing Qyang', 18)}}的其他基金
Modulation of heart function by Muscle LIM protein-mediated mechanotransduction
肌肉 LIM 蛋白介导的机械转导调节心脏功能
- 批准号:
10645223 - 财政年份:2022
- 资助金额:
$ 1.14万 - 项目类别:
Modulation of heart function by Muscle LIM protein-mediated mechanotransduction
肌肉 LIM 蛋白介导的机械转导调节心脏功能
- 批准号:
10503955 - 财政年份:2022
- 资助金额:
$ 1.14万 - 项目类别:
Development of HLA engineered universal vascular grafts from human iPSCs
利用人类 iPSC 开发 HLA 工程通用血管移植物
- 批准号:
10457467 - 财政年份:2021
- 资助金额:
$ 1.14万 - 项目类别:
Development of HLA engineered universal vascular grafts from human iPSCs
利用人类 iPSC 开发 HLA 工程通用血管移植物
- 批准号:
10685550 - 财政年份:2021
- 资助金额:
$ 1.14万 - 项目类别:
Development of HLA engineered universal vascular grafts from human iPSCs
利用人类 iPSC 开发 HLA 工程通用血管移植物
- 批准号:
10298018 - 财政年份:2021
- 资助金额:
$ 1.14万 - 项目类别:
Readily Available Stem Cell-Based Vascular Grafts for Emergent Surgical Care
用于紧急手术护理的现成干细胞血管移植物
- 批准号:
10622873 - 财政年份:2020
- 资助金额:
$ 1.14万 - 项目类别:
Readily Available Stem Cell-Based Vascular Grafts for Emergent Surgical Care
用于紧急手术护理的现成干细胞血管移植物
- 批准号:
10414459 - 财政年份:2020
- 资助金额:
$ 1.14万 - 项目类别:
Readily Available Stem Cell-Based Vascular Grafts for Emergent Surgical Care
用于紧急手术护理的现成干细胞血管移植物
- 批准号:
10636647 - 财政年份:2020
- 资助金额:
$ 1.14万 - 项目类别:
Readily Available Stem Cell-Based Vascular Grafts for Emergent Surgical Care
用于紧急手术护理的现成干细胞血管移植物
- 批准号:
10439796 - 财政年份:2020
- 资助金额:
$ 1.14万 - 项目类别:
Readily Available Stem Cell-Based Vascular Grafts for Emergent Surgical Care
用于紧急手术护理的现成干细胞血管移植物
- 批准号:
10189694 - 财政年份:2020
- 资助金额:
$ 1.14万 - 项目类别:
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