Augmentation of Hemostasis in Pediatric Cardiopulmonary Bypass
小儿心肺转流术中的强化止血
基本信息
- 批准号:8770359
- 负责人:
- 金额:$ 25.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffinityAgeAnimalsAntibodiesBindingBiocompatible MaterialsBiodistributionBiological AssayBiophysicsBirthBleeding time procedureBloodBlood CirculationBlood Coagulation DisordersBlood Coagulation FactorBlood PlateletsBlood specimenCardiac Surgery proceduresCardiopulmonary BypassChildhoodCoagulation ProcessComplexComplicationContractsCoupledDataDevelopmentEngineeringFiberFibrinFibrinogenGelGoalsHalf-LifeHemorrhageHemostatic AgentsHemostatic functionHydrogelsIn VitroInjuryMapsMethodsMicrofluidic MicrochipsMicroscopicMissionModelingMolecularMonitorMorbidity - disease rateNatureNeonatalOutcomePatientsPediatric Surgical ProceduresPlasmaPolymersProthrombinResearchRodentRodent ModelSamplingScientistSiteSpecificitySurgical suturesTechniquesTechnologyThrombelastographyTransfusionWhole BloodWorkWound Healingbaseblood productcardiac repaircrosslinkdesignimprovedin vivoinnovationmortalitymultidisciplinaryneonatenovelparticlepoly-N-isopropylacrylamidepublic health relevanceskillstreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Bleeding after cardiopulmonary bypass (CPB) is a serious complication of cardiac surgery and is associated with substantial morbidity and mortality; neonates in particular are vulnerable to post-CPB bleeding. In these patients, transfusion post-CPB is a necessity. Transfused blood products consist primarily of platelets and fibrinogen (in the form of cryoprecipitate) prepared from adult blood. Although the transfusion of adult blood products to pediatric patients is performed routinely to control blood loss, reduction in the usage of transfused blood products has been shown to correlate with better patient outcomes. Unfortunately, few alternatives exist, highlighting the need for better methods to control bleeding. Hemostasis involves the formation of a platelet plug embedded within a fibrin mesh. However, clot formation is impaired in neonates, in part, due to deficiencies
in several coagulation factors at birth and platelet hyporeactivity. CPB further impairs these already compromised platelets. Thus, the overarching design goal of this project is to create a biomaterial that recapitulates key hemostatic functions of platelets to augment clotting in neonatal CPB patients. To achieve this objective, we utilize platelet-like particles (PLPs), recently designed in our lab, that mimic numerous features of natural platelets by interacting with fibrin with high affinity and, more importantly, specificity at the sites of injury to augment
clotting in plasma samples obtained from neonates undergoing CPB. To achieve this objective, the proposal is divided into two specific aims: 1. Characterization of platelet function and clottig in neonatal CPB plasma samples in the a) absence and b) presence of PLPs and 2. Characterization of augmentation of clotting in vivo in a rodent model of platelet hyporeactivity. In Aim 1, we will analyze neonatal platelet function in blood samples collected prior to CPB (baseline), post-CPB and post-transfusion from neonates undergoing elective cardiac surgery, through thromboelastography/platelet mapping assays and dynamic clotting assays utilizing a novel endothelialized microfluidic device developed in our labs. We will then perform identical analyses with post-CPB samples in the presences of PLPs. Because neonatal patients are known to have hyporeactive platelets, in Aim 2, we will model this condition and evaluate the efficacy of PLPs in vivo in a small animal platelet deficiency model by monitoring bleeding times. Furthermore, the biodistribution and circulation half-life of PLPs will be evaluated. The proposed research is innovative because it combines unique microgels with fibrin specific binding motifs to create PLPs that interact extensively with fibrin networks. These features result in particles that are capable of recapitulating more features of nature platelets than previously achieved by other platelet-mimicking materials. The significance of the proposed research is that this work will enable better treatment options for coagulopathy in neonatal CPB patients.
描述(由申请人提供):体外循环(CPB)后出血是心脏手术的严重并发症,与大量的发病率和死亡率相关;新生儿尤其容易发生体外循环后出血。对于这些患者,体外循环后输血是必要的。输注的血液制品主要由成人血液制备的血小板和纤维蛋白原(冷沉淀形式)组成。尽管常规向儿科患者输注成人血液制品以控制失血,但已证明减少输血血液制品的使用与更好的患者预后相关。不幸的是,几乎没有替代方案,这凸显了需要更好的方法来控制出血。止血涉及形成嵌入纤维蛋白网内的血小板塞。然而,新生儿的血栓形成受到损害,部分原因是缺乏
出生时的几种凝血因子和血小板反应性低下。体外循环进一步损害这些已经受损的血小板。因此,该项目的总体设计目标是创造一种生物材料,能够概括血小板的关键止血功能,以增强新生儿体外循环患者的凝血功能。为了实现这一目标,我们利用实验室最近设计的血小板样颗粒(PLP),它通过与纤维蛋白以高亲和力相互作用来模拟天然血小板的许多特征,更重要的是,在损伤部位具有特异性,以增强
从接受 CPB 的新生儿获得的血浆样本中的凝血。为了实现这一目标,该提案分为两个具体目标: 1. 在 a) 不存在和 b) PLP 存在的情况下,表征新生儿 CPB 血浆样本中的血小板功能和凝血;2. 表征在 a) 不存在和 b) 存在 PLP 的情况下体内凝血增强的特征血小板低反应性啮齿动物模型。在目标 1 中,我们将通过利用新型内皮化微流体进行血栓弹力图/血小板图分析和动态凝血分析,分析从接受择期心脏手术的新生儿在 CPB 之前(基线)、CPB 后和输血后收集的血液样本中的新生儿血小板功能我们实验室开发的设备。然后,我们将在 PLP 存在的情况下对 CPB 后样本进行相同的分析。由于已知新生儿患者的血小板反应性低下,因此在目标 2 中,我们将模拟这种情况,并通过监测出血时间来评估 PLP 在小动物血小板缺乏模型中的体内功效。此外,还将评估 PLP 的生物分布和循环半衰期。拟议的研究具有创新性,因为它将独特的微凝胶与纤维蛋白特异性结合基序相结合,创建了与纤维蛋白网络广泛相互作用的 PLP。这些特征使得颗粒能够比以前通过其他模拟血小板材料实现的更多天然血小板特征。本研究的意义在于,这项工作将为新生儿 CPB 患者的凝血障碍提供更好的治疗选择。
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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Thomas Harrison Barker其他文献
Thomas Harrison Barker的其他文献
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