A Biohybrid Device for Regulating Inflammation in Sepsis
调节脓毒症炎症的生物混合装置
基本信息
- 批准号:8818081
- 负责人:
- 金额:$ 34.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcuteAnti-Inflammatory AgentsAnti-inflammatoryAttenuatedBioreactorsBlood CirculationCCL2 geneCXCL1 geneCellsCessation of lifeChronicClinical TrialsComputer SimulationDataDendritic CellsDevicesDiagnosisDiseaseEndotoxinsFeedbackFree RadicalsFunctional disorderGene-ModifiedGoalsHepG2HepatocyteHumanImmuneIn VitroIndividualInfectionInflammationInflammatoryInflammatory ResponseInjuryLeadLipidsMedical DeviceMethodologyMolecularOrganPatientsPatternProcessProductionRattusReactionRegulationResolutionSepsisSolidSolutionsStimulusStressSystemTNF geneTestingTextTherapeuticTimeTissuesTraumaTumor Necrosis Factor-alphaWorkabstractingbasebiological adaptation to stresscell injurychemokineclinical efficacycomputer based statistical methodscostcytokineexperiencein vitro Modelin vivoinhibitor/antagonistinsightnovelnovel strategiespathogenpromoterreceptorresearch studysepticstressor
项目摘要
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than 30 lines of text.
Sepsis accounts for nearly 10% of total U.S. deaths, costing nearly $17 billion. Sepsis induces an acute
inflammatory response. Properly-regulated inflammation allows for recognition and reaction to injury or
infection, but inadequate or overly-robust inflammation can lead to multiple organ dysfunction and death. We
propose that acute inflammation in sepsis may evolve too rapidly to be modulated appropriately, and suggest
that therapies should focus not on abolishing inflammation, but rather on attenuating self-sustaining
inflammation. Based on a combination of experiments and computational modeling, we propose a self-
regulating device for patient-specific, adaptive regulation of inflammation. Our device, seeded with genetically-
modified human HepG2 hepatocytes, has already been tested both in vitro and in endotoxemic and septic rats.
We propose to create a novel class of biohybrid devices for regulating inflammation in sepsis using an iterative
process of computational simulations combined with in vitro and in vivo studies (Aim 1), and to define the
impact of the circulating inflammatory milieu on the HepG2 cells in the biohybrid device (Aim 2). We will
optimize the molecular composition, timing, and duration of bioreactor-based delivery of sTNFR – driven
constitutively or in an adaptive fashion as inferred from preliminary computational modeling. These studies will
be carried out iteratively with computational modeling of the disease and the impact of the biohybrid devices on
the disease in the context of in silico clinical trials, in order to predict the likelihood of clinical efficacy of this
transformative class of medical device. Furthermore, we will define in vitro the inflammatory and stress
responses of HepG2 cells subjected to the extracorporeal inflammatory milieu they will encounter in the
context of our studies, and utilize these data to optimize in vivo bioreactor conditions and to revise in silico
clinical trials. This approach represents a novel strategy for rational reprogramming of acute inflammation in
sepsis, with potential impact on other acute inflammatory diseases.
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超过30行文字。
脓毒症占美国总死亡人数的近10%,耗资近170亿美元。脓毒症引起急性
炎症反应。适当调节的炎症允许对损伤的识别和反应,
感染,但不充分或过度强烈的炎症可导致多器官功能障碍和死亡。我们
提出脓毒症中的急性炎症可能发展得太快而无法适当调节,并建议
治疗的重点不应该是消除炎症,而应该是减少自我维持的炎症,
炎症基于实验和计算建模的结合,我们提出了一个自-
调节装置,用于患者特异性的、适应性的炎症调节。我们的装置,植入了基因-
修饰的人HepG 2肝细胞已经在体外和内毒素血症和脓毒症大鼠中进行了测试。
我们建议创建一种新型的生物混合装置,用于调节脓毒症中的炎症,
结合体外和体内研究的计算模拟过程(目标1),并定义
循环炎症环境对生物混合装置中HepG 2细胞的影响(目的2)。我们将
优化sTNFR驱动的基于生物反应器的递送的分子组成、时机和持续时间,
组成性地或以从初步计算建模推断的自适应方式。这些研究将
迭代地进行疾病的计算建模和生物混合装置对疾病的影响。
在计算机临床试验的背景下,为了预测这种药物临床疗效的可能性,
医疗器械的变革类。此外,我们将在体外定义炎症和应激
HepG 2细胞在体外炎症环境中的反应,它们将在体外炎症环境中遇到。
我们的研究背景,并利用这些数据来优化体内生物反应器条件,并在计算机上修改
临床试验这种方法代表了一种合理重编程急性炎症的新策略,
败血症,对其他急性炎症性疾病有潜在影响。
项目成果
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Incorporating hepatic cell function into lung ex vivo lung perfusion for transplant preservation
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- 批准号:
10666953 - 财政年份:2023
- 资助金额:
$ 34.65万 - 项目类别:
Innovative In Vivo-like Model for Vascular Tissue Engineering
血管组织工程的创新类体内模型
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8325034 - 财政年份:2011
- 资助金额:
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Innovative In Vivo-like Model for Vascular Tissue Engineering
血管组织工程的创新类体内模型
- 批准号:
8490420 - 财政年份:2011
- 资助金额:
$ 34.65万 - 项目类别:
Innovative In Vivo-like Model for Vascular Tissue Engineering
血管组织工程的创新类体内模型
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8135937 - 财政年份:2011
- 资助金额:
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$ 34.65万 - 项目类别:
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7021496 - 财政年份:2005
- 资助金额:
$ 34.65万 - 项目类别:
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