Studying Nanotoxicity Using Bioprinted Human Liver Tissues
使用生物打印的人类肝组织研究纳米毒性
基本信息
- 批准号:10654014
- 负责人:
- 金额:$ 21.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-Dimensional3D PrintAdherent CultureAffectAnimal ModelAnimalsArchitectureAreaBiomimeticsBovine Serum AlbuminCRISPR libraryCRISPR screenCRISPR/Cas technologyCancer ModelCell CommunicationCell LineCell SurvivalCell modelCellsCitratesComplexCopperDependenceDisease modelDrug Delivery SystemsEncapsulatedEndothelial CellsEnvironmentEvaluationExhibitsExtracellular MatrixGene ExpressionGeneticGenetic ScreeningGeometryHealthHepaticHepatic lobuleHepatocyteHepatotoxicityHomeostasisHumanImageIn VitroIndustrializationInfluentialsIonsKidneyKupffer CellsLiverMalignant NeoplasmsMethodsMicrofluidic MicrochipsMicrofluidicsModelingMorphologyNanotechnologyOpticsOrganOxidation-ReductionParticle SizePathologyPathway interactionsPatternPerfusionPeripheralPharmacotherapyPhysiologicalPolyethylene GlycolsPopulationPrintingProcessProliferatingPropertyResolutionSpeedSpleenStructureSupporting CellSystemTechniquesTestingTissue ModelTissuesToxic effectToxicity TestsToxicologyTransfectionWorkacute toxicitybioprintingcell typecostcytotoxicityfabricationgenome-widegenotoxicityimmunoregulationimmunotoxicityimprovedin vivoinduced pluripotent stem cellinnovationiron oxidemanganese oxidemetal oxidemimeticsnanomaterialsnanoparticlenanotoxicitynovelnovel strategiespredictive modelingresponsescaffoldscreeningspecies differencestellate cellstem cellsthree dimensional cell culturethree-dimensional modelinguptake
项目摘要
Summary
The use of NPs (NPs) for industrial processes and biomedical applications such as imaging, sensing,
drug delivery and treatment is one of areas where nanotechnology is expected to have an influential impact.
However, the toxicity of nanomaterials is a significant health concern. Currently NP toxicity studies are mainly
performed on organ level accumulation in animal models and on traditional 2D culture of human hepatocytes.
But animal models are often costly, have a low throughput, and are limited in terms of reliably predicting
hepatotoxicity of NPs on human due to species difference. Traditional 2D cultures using human liver cells are
still insufficient to reliably predict the toxicity of NPs. While a few toxicology studies using human-based 3D
models have been recently developed, the majority of these 3D human liver models are homogeneous by mixing
a single matrix material with a single type of hepatic cells, therefore not representing the physiological conditions.
The objective of this proposal is to develop high throughput 3D human multicellular liver models which
will offer improved hepatocellular functions and generate more reliable prediction of hepatotoxicity of various
NPs. In Specific Aim 1, a rapid 3D bioprinting method will be used to develop multicellular liver models by
encapsulating human primary hepatocytes or hiPSC-derived hepatic progenitor cells and other non-parenchymal
cells into native extracellular matrix components with a defined liver-specific structure. The cell viability,
proliferation, morphology, and gene expression of different cell populations will be characterized. The hepatic
function of the multicellular liver models will also be evaluated. In Specific Aim 2, the NP-induced toxicity
dependencies and mechanisms using CRISPR-Cas9 and the bioprinted 3D multicellular liver models will be
investigated. Several commonly used NPs, including Fe3O4, Mn3O4, MnO2, CuO, CuS, and Ag of 20 nm particle
size with relevant coatings including citrate, polyethylene glycol, and bovine serum albumin will be studied.
The proposed work integrates several innovative aspects for studying NP toxicity under physiologically-
relevant conditions, including a) a novel 3D bioprinting system with a superior speed, resolution and ability to
print muti-materials and cells, b) innovative 3D liver models with biomimetic arrangement of multiple cell types
in desired geometry and several native extracellular matrix materials to recapitulate the native microenvironment,
and c) a novel approach using CRISPR-Cas9 screening to analyze NPs in 3D bioprinted liver tissue models. An
interdisciplinary team is assembled including a pioneer in 3D printing, bioprinting, nanomaterials and
nanotoxicity, and a leading expert in liver pathology.
概括
使用NP(NP)用于工业过程和生物医学应用,例如成像,传感,
药物输送和治疗是预计纳米技术会产生影响力的领域之一。
但是,纳米材料的毒性是一个重大的健康问题。目前NP毒性研究主要是
在动物模型和人类肝细胞的传统2D培养物中进行器官水平的积累。
但是动物模型通常是昂贵的,吞吐量较低,并且在可靠预测方面受到限制
由于物种差异,NPS对人类的肝毒性。使用人肝细胞的传统2D培养物是
仍然不足以可靠地预测NP的毒性。而一些使用基于人类的3D的毒理学研究
最近开发了模型,这些3D人肝模型中的大多数是通过混合而均匀的
具有单一类型的肝细胞的单个基质材料,因此不能代表生理条件。
该提案的目的是开发高吞吐量3D人类多细胞肝模型
将提供改进的肝细胞功能,并产生对各种肝毒性的更可靠的预测
NPS。在特定目标1中,将使用快速的3D生物打印方法来开发多细胞肝模型
封装人类原发性肝细胞或hipsc衍生的肝祖细胞和其他非副作用
细胞进入具有定义的肝特异性结构的天然细胞外基质成分。细胞活力,
将表征不同细胞群体的增殖,形态和基因表达。肝
还将评估多细胞肝模型的功能。在特定的目标2中,NP诱导的毒性
使用CRISPR-CAS9和生物打印3D多细胞肝模型的依赖性和机制将是
调查。几种常用的NP,包括Fe3O4,MN3O4,MNO2,CuO,CUS和20 nm粒子的Ag
将研究包括柠檬酸盐,聚乙二醇和牛血清白蛋白在内的相关涂料的尺寸。
拟议的工作整合了几个创新方面,用于研究在生理学下的NP毒性
相关条件,包括a)具有较高速度,分辨率和能力的新型3D生物打印系统
打印杂种材料和细胞,b)具有多种细胞类型的仿生布置的创新3D肝模型
在所需的几何形状和几种天然的细胞外基质材料中,以概括天然微环境,
c)一种使用CRISPR-CAS9筛选的新方法来分析3D生物打印肝组织模型中的NP。一个
跨学科团队组成了,包括3D打印,生物打印,纳米材料和
纳米毒性,肝病病理学领域的领先专家。
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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{{ truncateString('SHAOCHEN CHEN', 18)}}的其他基金
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- 资助金额:
$ 21.48万 - 项目类别:
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使用生物打印的人类肝组织研究纳米毒性
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- 批准号:
10414977 - 财政年份:2020
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10740924 - 财政年份:2020
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