Utilizing biodegradable porous silicon membranes as a novel design for lung-on-a-chip microfluidic devices to investigate extracellular matrix interactions.
利用可生物降解的多孔硅膜作为片上肺微流体装置的新颖设计来研究细胞外基质相互作用。
基本信息
- 批准号:10606544
- 负责人:
- 金额:$ 9.75万
- 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:2021-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAlveolarAnatomyAnimal ModelAnimalsApoptosisArchitectureAtomic Force MicroscopyBasic ScienceBiochemicalBiocompatible MaterialsBiodegradationBiological ModelsBiomanufacturingBiomedical EngineeringCell Culture TechniquesCell secretionCellsCharacteristicsCoculture TechniquesCollagenComplexCuesDataDevelopmentDevicesDiseaseDisease ProgressionElastinEndothelial CellsEpithelial CellsExtracellular MatrixExtracellular Matrix ProteinsExtravasationFlow CytometryFunctional disorderFutureGoalsGrowth FactorHumanHuman CharacteristicsHypoxiaImmuneImmunofluorescence MicroscopyIn VitroInflammatoryIsodicentric ChromosomeKnowledgeLeadLipopolysaccharidesLungLung diseasesMacrophageMediatorMembraneMicrofluidic MicrochipsMicrofluidicsModelingOrganOutcomePathogenesisPathway interactionsPeptide HydrolasesPharmacologic SubstancePhysiologyPorosityPreventionProductionPropertyPublic HealthPulmonary HypertensionReproducibilityResearchReverse Transcriptase Polymerase Chain ReactionRoleSafetyScanning Electron MicroscopySiliconStructureSurfaceTechniquesTherapeuticThinnessTranslatingXenobioticsbiomaterial compatibilitybody systemcandidate identificationcell typecigarette smokecytokinedesigndrug candidateextracellularfabricationfibrotic lung diseaseflexibilityhuman diseasehuman modelimmunoregulationin vitro Modelin vivoinnovationinsightlive cell imagingmaterials sciencenanomaterialsnovelorgan on a chippathogenic microbepre-clinicalprospectivesuccessthree dimensional structuretoxicanttranslational impacttranslational therapeutics
项目摘要
Project Summary
Identifying the cellular pathways that promote disease or which prospective therapies are effective relies upon
appropriate mammalian models. Therefore, there is an urgent need for advanced human model systems that
can accurately reproduce human anatomy and physiology to help predict human disease progression and as-
sess potential treatment options. The long-term goal is to utilize a novel in vitro lung-on-a-chip (LOAC) microflu-
idic device to predict how xenobiotics lead to inflammatory, fibrotic and immunomodulatory pulmonary diseases
in humans. The overall objective is to create the first fully organic LOAC that is structurally supported by a cell-
derived extracellular matrix (ECM) and includes innate immune cells to simulate organ-level functionality. The
rationale for the proposed research is to employ the unique properties of porous silicon (PSi) not previously
explored to revolutionize the field of material science in the fabrication of microfluidic platforms that incorporates
dynamic ECM changes. Guided by strong preliminary data, the overall objective will be accomplished by pursing
the following three specific aims: 1) Identify the optimal parameters and cellular mechanisms to dissolve ultrathin
porous silicon during long-term culture; 2) Determine the extent to which co-cultured cells within the LOAC se-
crete and create their own ECM; and 3) Develop a multicellular alveolar structure to activate immune cells leading
to extravasation and ECM remodeling using an in vitro model of pulmonary hypertension. Under the first aim,
the working hypothesis based on preliminary data is that human macrophages (MACs) are essential to modify
and dissolve PSi. Dissolution rates of PSi will be quantified through scanning electron microscopy (SEM) and
surface analysis will be completed by atomic force microscopy (AFM) to reproducibly create flexible, structurally
intact membranes. Under the second aim, the working hypothesis is that endothelial cells (ECs) will express and
secrete cell-derived ECM proteins. Secretion of de novo synthesized ECM components will be quantified through
RT-PCR, confocal immunofluorescence (IF) microscopy and AFM. The third aim based on preliminary data in-
dicate epithelial cells (EPCs), ECs and MACs can be successfully co-cultured and are viable during long-term
culture on PSi membranes. The working hypothesis is in the presence of hypoxic conditions, MACs will become
activated and release soluble mediators leading to apoptosis of ECs and increased ECM remodeling that will be
quantified through confocal IF microscopy and live cell imaging. The proposed research is innovative, in our
opinion, because it represents a substantive departure from the status quo by utilizing the unique characteristics
of PSi, which is a biocompatible and biodegradable material. In addition, utilizing PSi provides the capability to
create a cell specific ECM that will release biochemical cues including growth factors and extracellular protein-
ases. The proposed research is significant because it is expected to have broad translational importance in the
prevention and treatment of a wide range of pulmonary diseases. Finally, therapeutic advancements in the de-
velopment of PSi nanomaterials and factors that lead to degradation in vivo are expected.
项目摘要
识别促进疾病的细胞通路或有效的前瞻性治疗依赖于
合适的哺乳动物模型。因此,迫切需要先进的人体模型系统,
可以准确地再现人体解剖学和生理学,以帮助预测人类疾病的进展,
潜在的治疗选择。长期目标是利用一种新的体外肺芯片(LOAC)微流感,
预测外源性物质如何导致炎症、纤维化和免疫调节性肺部疾病的快速诊断装置
在人类身上。总体目标是创造第一个完全有机的武装冲突法,在结构上由一个细胞支撑,
衍生的细胞外基质(ECM),并且包括先天免疫细胞以模拟器官水平的功能。的
拟议研究的基本原理是利用多孔硅(PSi)的独特性质,而不是以前的
探索在微流体平台的制造中彻底改变材料科学领域,
动态ECM变化。在强有力的初步数据的指导下,将通过以下方式实现总体目标:
以下三个具体目标:1)确定最佳参数和细胞机制,以消除干扰
2)确定LOAC内共培养细胞的表达水平,
crete和创建自己的ECM;和3)发展多细胞肺泡结构,以激活免疫细胞,
外渗和ECM重塑使用肺动脉高压的体外模型。在第一个目标下,
基于初步数据的工作假设是,人类巨噬细胞(MAC)对于修饰
溶解PSi将通过扫描电子显微镜(SEM)定量PSi的溶出速率,
将通过原子力显微镜(AFM)完成表面分析,以可重复地创建柔性的、结构上
完整的膜在第二个目标下,工作假设是内皮细胞(EC)将表达并
分泌细胞来源的ECM蛋白。从头合成的ECM组分的分泌将通过
RT-PCR、共聚焦免疫荧光(IF)显微镜和AFM。第三个目标是根据初步数据-
分化上皮细胞(EPCs)、EC和MAC可以成功地共培养,并且在长期培养过程中是存活的。
在PSi膜上培养。工作假设是在缺氧条件下,MAC将成为
激活并释放可溶性介质,导致EC凋亡和ECM重塑增加,
通过共聚焦IF显微镜和活细胞成像定量。这项研究是创新的,在我们的
观点,因为它利用独特的特征,代表了对现状的实质性背离
的PSi,这是一种生物相容性和可生物降解的材料。此外,利用PSi提供了以下能力:
产生细胞特异性ECM,其将释放包括生长因子和细胞外蛋白的生化信号,
ases.拟议的研究是有意义的,因为它预计将有广泛的翻译重要性,
预防和治疗多种肺部疾病。最后,治疗的进展,在德-
预期PSi纳米材料的降解和导致体内降解的因素。
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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David James Blake其他文献
David James Blake的其他文献
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{{ truncateString('David James Blake', 18)}}的其他基金
Utilizing biodegradable porous silicon membranes as a novel design for lung-on-a-chip microfluidic devices to investigate extracellular matrix interactions.
利用可生物降解的多孔硅膜作为片上肺微流体装置的新颖设计来研究细胞外基质相互作用。
- 批准号:
10400222 - 财政年份:2021
- 资助金额:
$ 9.75万 - 项目类别:
Utilizing biodegradable porous silicon membranes as a novel design for lung-on-achip microfluidic devices to investigate extracellular matrix interactions.
利用可生物降解的多孔硅膜作为片上肺微流体装置的新颖设计来研究细胞外基质相互作用。
- 批准号:
10553441 - 财政年份:2021
- 资助金额:
$ 9.75万 - 项目类别:
Utilizing biodegradable porous silicon membranes as a novel design for lung-on-a-chip microfluidic devices to investigate extracellular matrix interactions.
利用可生物降解的多孔硅膜作为片上肺微流体装置的新颖设计来研究细胞外基质相互作用。
- 批准号:
10205273 - 财政年份:2021
- 资助金额:
$ 9.75万 - 项目类别:
A novel intervention strategy for emphysema by targeting the Nrf2 pathway
针对Nrf2通路的肺气肿新干预策略
- 批准号:
7545398 - 财政年份:2008
- 资助金额:
$ 9.75万 - 项目类别:
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