Biofabrication of Multicompartment Human Liver Tissues for Chemical Screening

用于化学筛选的多室人肝组织的生物制造

基本信息

  • 批准号:
    10317252
  • 负责人:
  • 金额:
    $ 23.47万
  • 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:
    2021-08-01 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT / PROJECT SUMMARY Title: Biofabrication of Multicompartment Human Liver Tissues for Chemical Screening Drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug attrition, black box warnings on drugs, and withdrawals of drugs from the marketplace. Unfortunately, animal models do not always suffice to evaluate human DILI due to significant species-specific differences in drug metabolism pathways; therefore, in vitro models of the human liver are being increasingly utilized to evaluate compound (drugs/chemicals) metabolism and toxicity. However, current in vitro models of the human liver are unable to determine the effects of compounds on the three major compartments of the liver, namely hepatic, vascular, and biliary, and how toxicity to one compartment may affect the other compartments. Similarly, while there has been some progress in developing implantable liver tissue surrogates as cell-based therapies for patients suffering from end-stage liver failure, such tissues do not contain the above-mentioned liver compartments with physiological interconnections. Our studies have shown that primary human hepatocytes (PHH) and liver endothelial cells (LEC) display high levels of in vivo-like functions for 4+ weeks in vitro when organized into 3-dimensional (3D) extracellular matrix (ECM) microgels that are generated using a high-throughput droplet microfluidics platform (so-called microtissues). This microtissue technology is uniquely suited to control the microenvironment of liver cells and could potentially protect cells from the shear stress induced via 3D bioprinting. Furthermore, we have shown that cholangiocytes display sprouting behavior in decellularized liver ECM (dECM) but not in collagen-I or Matrigel alone and such sprouting behavior can be directed via 3D bioprinting. In this high-risk/high-reward R21 proposal, we will leverage these platforms and findings to test the novel hypothesis that a 3D-printed biomaterial scaffold containing hepatic microtissues and liver dECM can be used to generate liver-like functional and integrated compartments (vascular, hepatic, and biliary). In aim 1, we will fabricate and characterize 3D- printed structures containing hepatic microtissues and LEC-lined vascular channels, while in aim 2, we will incorporate cholangiocytes into the biofabricated structures and investigate the ability to control and detect bile flow. If successful, our efforts will yield a first-of-its-kind scalable 3D-printed human liver tissue containing integrated hepatic, vascular, and biliary compartments that displays stable levels of diverse liver functions for several weeks in vitro. Ultimately, our 3D-printed human liver tissue can be used for investigating the effects of compounds on all three compartments of the liver and their interactions, as well as for implanting into animal models as potential cell-based therapy for chronic liver disease and acute liver failure.
摘要/项目摘要 用于化学筛选的多室人肝组织的生物制造 药物性肝损伤(DILI)是临床前和临床药物损耗的主要原因,黑盒警告 毒品,以及从市场上撤回毒品。不幸的是,动物模型并不总是满足于 由于药物代谢途径在物种上的显著差异,评估人类DILI;因此,在 人体肝脏的体外模型越来越多地被用于评估化合物(药物/化学品) 新陈代谢和毒性。然而,目前的人体肝脏体外模型还不能确定其影响。 肝脏的三个主要部分,即肝脏、血管和胆管上的化合物,以及如何 对一个车厢的毒性可能会影响其他车厢。同样,尽管取得了一些进展, 为终末期患者开发可移植肝组织替代品作为基于细胞的治疗 肝功能衰竭时,此类组织不含上述肝间室具有生理性 互联互通。我们的研究表明,原代人肝细胞(PHH)和肝内皮细胞 (LEC)在体外4周以上表现出高水平的体内类似功能,当组织成三维(3D)时 使用高通量液滴微流体平台生成的细胞外基质(ECM)微凝胶 (所谓的微组织)。这种微组织技术特别适合控制肝脏的微环境。 并潜在地保护细胞免受3D生物打印所产生的剪应力。此外,我们还拥有 结果表明,胆管细胞在脱细胞肝细胞外基质(DECM)中表现出萌发行为,而在I型胶原中则不表现出萌发行为。 或者只有Matrigel,这样的发芽行为可以通过3D生物打印来指导。在这种高风险/高回报的情况下 R21提案,我们将利用这些平台和发现来测试3D打印的新假设 含有肝脏微组织和肝细胞外基质的生物材料支架可用于生成类肝样功能 和完整的间隔(血管、肝脏和胆管)。在目标1中,我们将制造和表征3D- 包含肝脏微组织和LEC衬里的血管通道的印刷结构,而在目标2中,我们将 将胆管细胞结合到生物加厚结构中,并研究控制和检测胆汁的能力 流。如果成功,我们的努力将产生首个可缩放的3D打印人体肝脏组织,其中包含 综合的肝脏、血管和胆管间隔,显示出稳定的不同肝功能水平 在体外培养数周。最终,我们的3D打印的人体肝脏组织可以用于研究 肝脏所有三个隔室上的化合物及其相互作用,以及植入动物体内 作为慢性肝病和急性肝衰竭潜在的基于细胞的治疗模型。

项目成果

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Salman R Khetani其他文献

Salman R Khetani的其他文献

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{{ truncateString('Salman R Khetani', 18)}}的其他基金

Multicellular Organotypic Mouse Model of Alcoholic Liver Disease
酒精性肝病的多细胞器官型小鼠模型
  • 批准号:
    10667672
  • 财政年份:
    2023
  • 资助金额:
    $ 23.47万
  • 项目类别:
A bio-engineered hepatic niche for ex vivo expansion of HSCs
用于 HSC 离体扩增的生物工程肝脏生态位
  • 批准号:
    10452482
  • 财政年份:
    2021
  • 资助金额:
    $ 23.47万
  • 项目类别:
A bio-engineered hepatic niche for ex vivo expansion of HSCs
用于 HSC 离体扩增的生物工程肝脏生态位
  • 批准号:
    10631071
  • 财政年份:
    2021
  • 资助金额:
    $ 23.47万
  • 项目类别:
Biofabrication of Multicompartment Human Liver Tissues for Chemical Screening
用于化学筛选的多室人肝组织的生物制造
  • 批准号:
    10457485
  • 财政年份:
    2021
  • 资助金额:
    $ 23.47万
  • 项目类别:
A Scalable 3D Human Liver Co-culture Platform for Hepatitis B Virus Infection
用于乙型肝炎病毒感染的可扩展 3D 人类肝脏共培养平台
  • 批准号:
    9814819
  • 财政年份:
    2019
  • 资助金额:
    $ 23.47万
  • 项目类别:
High-throughput exploration of chemomechanical crosstalk in the maturation of iPSC-derived human hepatocytes
iPSC 衍生的人肝细胞成熟过程中化学机械串扰的高通量探索
  • 批准号:
    10022330
  • 财政年份:
    2019
  • 资助金额:
    $ 23.47万
  • 项目类别:
Elucidating chemo-mechanical determinants of human hepatocyte and stellate cell responses in non-alcoholic fatty liver disease
阐明非酒精性脂肪肝患者肝细胞和星状细胞反应的化学机械决定因素
  • 批准号:
    10092152
  • 财政年份:
    2018
  • 资助金额:
    $ 23.47万
  • 项目类别:
Synergistic effects of ECM and heterotypic crosstalk on cellular responses in non-alcoholic fatty liver disease
ECM 和异型串扰对非酒精性脂肪肝细胞反应的协同作用
  • 批准号:
    10744973
  • 财政年份:
    2018
  • 资助金额:
    $ 23.47万
  • 项目类别:
Elucidating chemo-mechanical determinants of human hepatocyte and stellate cell responses in non-alcoholic fatty liver disease
阐明非酒精性脂肪肝患者肝细胞和星状细胞反应的化学机械决定因素
  • 批准号:
    10027053
  • 财政年份:
    2018
  • 资助金额:
    $ 23.47万
  • 项目类别:
Functionally maturing iPSC-derived human hepatocytes in 3D microgels
3D 微凝胶中功能成熟的 iPSC 衍生人肝细胞
  • 批准号:
    9226831
  • 财政年份:
    2017
  • 资助金额:
    $ 23.47万
  • 项目类别:

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开发利用自身 iPS 细胞治疗急性肝衰竭的创新疗法
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