Miniaturization of the Artificial Placenta for Clinical Application

项目摘要/摘要 早产与高死亡率和长期发病率有关。超过10年(由 R01HD073475)我们开发了一种体外气体交换系统，专门为维护 胎儿循环，允许在没有空气呼吸的情况下生长和发育，并在人工 胎盘(AP)。本研究主要完成了以下几个方面的工作：1)广泛评价了气体交换； 长期AP实验中的血流动力学和胎儿循环；2)表征肺损伤和发展 与胎龄匹配的胎羔羊和机械通气(MV)早产羔羊的比较 控制并确定最佳的呼吸道维持策略；3)评估脑氧合和脑血流灌注 在AP支持期间，使用死后MRI将AP大脑与器官对照进行比较，以评估出血， 脑白质损伤、发育；4)精炼一氧化氮(NO)/阿加曲班/NO扫流策略 消除全身抗凝；5)在过渡到空气之前显示出肺的发育和循环 以及6)对脑、肺、心、脾、肾进行功能和组织学研究， 在AP支持期间和肠道。在所有这些工作的基础上，我们现在有了一个可重现的模型来优化 装置设计，解决人工胎盘的长期效果，并将AP微型化用于临床 申请。基于这项工作，我们有了一个可重现的模型来优化设备设计，并扩展 插管和装置到极端早产儿的大小。这项研究的目标是 将导管和回路微型化，并在一个小动物模型中对该系统进行评估，该模型的大小为 非常早熟的人类。 因此，这项建议的具体目标是： 具体目标1：通过将导管和回路微型化为临床应用做准备，并开发 AP系统的伺服调节。 具体目标2：评估早产儿的充分支持和多器官结构和功能 模特。

PROJECT SUMMARY/ABSTRACT Prematurity is associated with high mortality and long-term morbidity. Over 10 years (supported by R01HD073475) we have developed an extracorporeal gas exchange system designed specifically to maintain fetal circulation, allow growth and development without air breathing, and simulate fetal physiology in an Artificial Placenta (AP). This research has accomplished the following: 1) extensively evaluated gas exchange, hemodynamics, and fetal circulation in long-term AP experiments; 2) characterized lung injury and development compared to gestational age-matched fetal lambs and mechanically ventilated (MV) prematurely delivered lamb controls and identified the best airway maintenance strategy; 3) assessed cerebral oxygenation and perfusion during AP support and compared AP brains to organ controls using postmortem MRI to assess for hemorrhage, white matter injury, and development; 4) refined the nitric oxide (NO) / argatroban / NO sweep flow strategy to eliminate systemic anticoagulation; 5) demonstrated lung development and circulation before transitioning to air breathing and recovery; and 6) performed functional and histologic studies of brain, lung, heart, spleen, kidney, and intestine during AP support. Based on all of this work, we now have a reproducible model to optimize device design, address long-term effects of the artificial placenta, and miniaturize the AP for clinical application. Based on this work, we have a reproducible model to optimize device design, and scale the cannulation and device to the size of extreme premature human infants. The goal of this research is to miniaturize the cannulas and circuit, and evaluate that system in a small animal model which is the size of extremely premature humans. As such, the specific aims of this proposal are: Specific Aim 1: To prepare for clinical application by miniaturizing the cannulas and circuit and develop servoregulation of the AP system. Specific Aim 2: To evaluate adequate support and multiorgan structure and function in a premature minisheep model.