A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing
用于药物筛选和疗效测试的肌腱炎症和纤维化的微生理系统
基本信息
- 批准号:10674534
- 负责人:
- 金额:$ 72.19万
- 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:2020-08-15 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccelerationAcuteAdhesionsAntibodiesBiologicalBiological AssayBiological MarkersBiological ModelsBlood TestsBlood VesselsBlood flowCell Cycle RegulationCellsChronicCicatrixCirculationClinicalClinical TrialsCollagenComplexConfocal MicroscopyConnective and Soft TissueDetectionDevicesDiseaseDisease modelDoseDrug ScreeningEndothelial CellsEndotheliumEngineeringEnzyme-Linked Immunosorbent AssayEvaluationExtracellular MatrixExtravasationFDA approvedFRAP1 geneFibroblastsFibrosisFlexorGamma-H2AXGene set enrichment analysisGoalsHealthHumanHydrogelsImageImmunologyImpairmentIn SituInfiltrationInflammationInflammation MediatorsInflammatoryIntervention TrialLabelLibrariesLinkMacrophageMeasurementMeasuresMechanicsMediatingMembraneMicrofabricationMicrofluidic MicrochipsMicrofluidicsMicroscopicMicroscopyMolecularMusMusculoskeletalMyofibroblastNanoporousOperative Surgical ProceduresOpticsOutcomePI3K/AKTParacrine CommunicationPathologyPatientsPeriodicityPermeabilityPharmaceutical PreparationsPhasePhenotypePorosityProceduresProcessProtein SecretionPublishingReplacement ArthroplastyRoleSDZ RADSafetySamplingSensitivity and SpecificitySerumSideSignal TransductionSiliconSirolimusSpinal FusionSystemTendinopathyTendon InjuriesTendon structureTestingTherapeuticTimeTissue EngineeringTissuesTransforming Growth Factor betaTranslatingVascular Endothelial Cellbiological developmentbiomarker selectioncell motilityclinically relevantdesigndrug candidatedrug discoverydrug efficacydruggable targetefficacy evaluationefficacy testingexperiencehealinghigh throughput screeninghuman tissueimprovedinduced pluripotent stem cellinduced pluripotent stem cell technologyinhibitorinjuredinnovationintercellular communicationjoint functionmTOR Inhibitormanufacturemetermicrophysiology systemmicroscopic imagingmouse modelnanonanofabricationnext generation sequencingorgan on a chipphotonicspreclinical trialprimary outcomeprogramsregenerative therapyrepairedsecondary outcomesenescencesensorsensor technologyvirtual clinical trial
项目摘要
Acute and chronic tendon injuries are among the most common musculoskeletal health problems. Typically, an
injured tendon experiences fibrotic scarring that leaves the tissue mechanically compromised and prone to
debilitating adhesions that impair joint function. In a fibrotic tendon scar, the cell-cell and paracrine signaling
between inflammatory cells, such as macrophages, and tendon fibroblasts activate the latter into
fibroproliferative myofibroblasts, ultimately differentiating into a senescent phenotype. Our previous studies
using next-generation sequencing and gene set enrichment analysis mechanistically linked fibrosis and
senescence in injured mouse tendons with TGF-beta activated mTOR signaling. To further elucidate this
pathology, the goal of this proposal is to engineer a microfluidic human tendon-on-chip (hToC) system and use
it to more accurately model the biological aspects of the inflammation and fibrosis in injured tendons. In the
UG3 phase of this proposal, the chip will be fabricated featuring a multicompartmental design and microfluidic
channels to incorporate a fibroblast-seeded collagen hydrogel and simulate vascular blood flow, respectively.
Ultrathin, highly permeable, and optically transparent porous silicon membranes (SiM) will separate the
hydrogel from circulation and provide a substrate for an endothelial barrier in between. The signaling between
the fibroblasts, hydrogel-resident- and circulating-macrophages, and endothelial cells will be enabled through
nanoporous SiM (~60 nm), while a microporous SiM (~ 8 µm) will allow extravasation of circulating
macrophages and infiltration of the hydrogel under TGF-beta stimulation. To allow for a patient-centric chip,
tendon fibroblasts will be used to create the tendon hydrogel and to reprogram donor-matching iPSCs to derive
the endothelial cells and macrophages, respectively. An additional innovation will be the integration of label-
free photonic sensors into the microfluidic device to allow on-chip sensing, which has been long appreciated as
a critical, unmet need for organ-on-chip devices. The UG3 studies will use the chip to validate the role of
mTOR in the disease model and identify biologically relevant biomarkers. In the UH3 phase, we will utilize the
chip as a pre-clinical trial platform for testing efficacy and safety of FDA-approved mTOR inhibitors as potential
disease modifying drugs, and as a drug screening platform to identify and prioritize safer and more potent
inhibitors of mTOR and senescence in tendon injury for clinical trials. To successfully complete this innovative
project, we have assembled a team of accomplished experts in tendon tissue engineering and surgery,
immunology, iPSC technology, GMP cell manufacturing, nano- and micro-fabrication, sensor technology, and
high throughput screening. The proposed studies will develop a human microphysiological system to catalyze
clinical trials and accelerate drug discovery for acute and chronic tendon injuries.
急性和慢性肌腱损伤是最常见的肌肉骨骼健康问题之一。通常,
受伤的肌腱经历纤维化瘢痕,
使关节功能受损的粘连。在纤维化的肌腱瘢痕中,细胞-细胞和旁分泌信号
炎症细胞,如巨噬细胞和肌腱成纤维细胞之间的相互作用激活后者,
纤维增生性肌成纤维细胞,最终分化成衰老表型。我们以前的研究
使用下一代测序和基因集富集分析,
在具有TGF-β激活的mTOR信号传导的损伤的小鼠肌腱中的衰老。为了进一步阐明这一点,
病理学,该提案的目标是设计一个微流体人类肌腱芯片(hToC)系统,并使用
它可以更准确地模拟受伤肌腱中炎症和纤维化的生物学方面。在
UG 3阶段的这一建议,芯片将制造具有多室设计和微流体
通道以分别掺入成纤维细胞接种的胶原水凝胶和模拟血管血流。
超薄,高渗透性,光学透明的多孔硅膜(SiM)将分离
并在其间提供用于内皮屏障基底。之间的信令
成纤维细胞、水凝胶驻留的和循环的巨噬细胞以及内皮细胞将通过
纳米多孔SiM(~60 nm),而微孔SiM(~ 8 µm)将允许循环血液外渗。
巨噬细胞和TGF-β刺激下的水凝胶浸润。为了实现以病人为中心的芯片,
肌腱成纤维细胞将被用于创建肌腱水凝胶,并重新编程供体匹配的iPSC,
内皮细胞和巨噬细胞。另一个创新将是标签的整合-
将自由光子传感器引入微流体装置中以允许芯片上感测,这长期以来一直被认为是
这是对器官芯片设备的一个关键的、未满足的需求。UG 3研究将使用该芯片来验证
mTOR在疾病模型中的作用,并鉴定生物学相关的生物标志物。在UH 3阶段,我们将利用
芯片作为临床前试验平台,用于测试FDA批准的mTOR抑制剂的有效性和安全性,
疾病修饰药物,并作为药物筛选平台,以识别和优先考虑更安全,更有效的药物
用于临床试验的mTOR抑制剂和肌腱损伤中的衰老。为了成功地完成这一创新
项目中,我们聚集了一批在肌腱组织工程和外科方面有成就的专家,
免疫学、iPSC技术、GMP细胞制造、纳米和微米制造、传感器技术,以及
高通量筛选。拟议的研究将开发一种人类微生理系统,
临床试验和加速药物发现的急性和慢性肌腱损伤。
项目成果
期刊论文数量(1)
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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Hani A Awad其他文献
Hani A Awad的其他文献
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{{ truncateString('Hani A Awad', 18)}}的其他基金
Training in Musculoskeletal Science: Comprehensive Training in Pain Studies
肌肉骨骼科学培训:疼痛研究综合培训
- 批准号:
10853550 - 财政年份:2023
- 资助金额:
$ 72.19万 - 项目类别:
Biomechanics, Biomaterials and Multimodal Tissue Imaging Core (BBMTI Core)
生物力学、生物材料和多模态组织成像核心(BBMTI 核心)
- 批准号:
10232836 - 财政年份:2022
- 资助金额:
$ 72.19万 - 项目类别:
A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing
用于药物筛选和疗效测试的肌腱炎症和纤维化的微生理系统
- 批准号:
10515790 - 财政年份:2020
- 资助金额:
$ 72.19万 - 项目类别:
A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing: MPS Database Engagement
用于药物筛选和功效测试的肌腱炎症和纤维化的微生理系统:MPS 数据库参与
- 批准号:
10430792 - 财政年份:2020
- 资助金额:
$ 72.19万 - 项目类别:
A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing
用于药物筛选和疗效测试的肌腱炎症和纤维化的微生理系统
- 批准号:
10239102 - 财政年份:2020
- 资助金额:
$ 72.19万 - 项目类别:
A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing
用于药物筛选和疗效测试的肌腱炎症和纤维化的微生理系统
- 批准号:
10037991 - 财政年份:2020
- 资助金额:
$ 72.19万 - 项目类别:
Project 1: Elucidating the Mechanisms of S. aureus Motility in Bone and Developing Interventions
项目 1:阐明金黄色葡萄球菌在骨中的运动机制并制定干预措施
- 批准号:
10247795 - 财政年份:2017
- 资助金额:
$ 72.19万 - 项目类别:
Elucidating the Mechanisms of S. aureus Motility in Bone and Developing Interventions
阐明金黄色葡萄球菌在骨中的运动机制并制定干预措施
- 批准号:
10402966 - 财政年份:2017
- 资助金额:
$ 72.19万 - 项目类别:
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