Development of an Artificial Placenta for Support of Premature Infants

描述(由申请者提供)：治疗早产儿仍然是一个悬而未决的问题，也是公共卫生的首要任务。每年有近50万人早产，死于早产相关问题的婴儿比死于其他任何单一原因的婴儿都多。虽然这些婴儿中的许多人通过常规治疗恢复，但极低胎龄儿(Elgans，定义为28周估计胎龄)的死亡率和发病率极高，只有不到50%的新生儿无残疾存活。这些并发症中的许多都是由于我们试图给未成熟的肺通风和逆转胎儿循环而引起的。尽管在使用表面活性物质和较小侵入性的机械通气策略治疗早产儿方面已经取得了进展，但有效的治疗方案仍然是一个尚未解决的问题。早产儿产后治疗的一个重大范式转变将是通过特殊设计的体外气体交换系统来模拟宫内环境，该系统可以维持胎儿循环，并允许在没有空气呼吸的情况下生长和发育；我们将这项技术称为人工胎盘(AP)。我们的长期目标是临床 AP在提高伊尔干人存活率和降低发病率方面的应用。我们已经建立了对应于人类早产不同阶段的胎羊模型。我们最初在妊娠130天(相当于人类妊娠29周；肺发育的囊状期)恢复空气呼吸的胎羊身上开发了AP。最新的初步数据表明，在110天的绵羊模型(相当于22周的妊娠人类胎儿；肺发育的管状期)上提供为期一周的完全体外支持是可行的，且血流动力学稳定，气体交换良好，肺泡化正常发展，脑灌流稳定，胎儿循环维持，所有这些都不需要机械通气。这项研究计划的目标是评估和改进这一宫内模拟系统，以支持从极早产到肺发育的管状阶段的胎儿羔羊，以及可行的宫外新生儿生理。为实现这一目标，本研究的具体目标是：1.在118日龄羔羊模型中，评价不同条件下的胎儿循环、血流动力学和肺发育。2.评价无肝素AP时脑部和全身出血及栓塞情况，评价脑血流灌注、功能、发育及脑白质损伤情况。3.使用人造胎盘维持模拟的宫内环境，直到肺发育和循环能够支持空气呼吸，包括解决长期支持的潜在问题(感染、营养、胃肠功能和代谢问题)。

DESCRIPTION (provided by applicant): Treatment of prematurity remains an unsolved problem and a top public health priority. There are nearly 500,000 premature births each year and more infants die of preterm-related problems than from any other single cause. Although many of these babies recover with conventional management, the mortality and morbidity of extremely low gestational age newborns (ELGANs, defined as <28 weeks estimated gestational age) is extremely high, with less than 50% surviving without disability. Many of these complications are caused, in part, by our attempts to ventilate the immature lungs and reverse fetal circulation. Although incremental progress has been made in treating premature infants with surfactant and less invasive ventilation strategies, effective treatment options remain an unsolved problem. A major paradigm shift in the post-natal treatment of prematurity would be to simulate the intrauterine environment with a specially designed extracorporeal gas exchange system which maintains fetal circulation and allows growth and development without air breathing; we call this technology the Artificial Placenta (AP). Our long term goal is the clinical application of the AP to improve survival and reduce morbidity in ELGANs. We have developed fetal lamb models which correspond to various stages of prematurity in humans. We initially developed the AP in fetal lambs of 130 day gestation (corresponding to 29 weeks human gestation; saccular stage of lung development) with recovery to air breathing. More recent preliminary data demonstrate the feasibility of providing complete extracorporeal support for one week in a 110 day sheep model (equivalent to a 22 week gestation human fetus; canalicular stage of lung development) with hemodynamic stability, excellent gas exchange, normally developing alveolarization, stable cerebral perfusion and maintenance of fetal circulation, all without mechanical ventilation. The goal of this research proposal is to evaluate and refine this system of intrauterine simulation to support fetal lambs from extreme prematurity, at the canalicular stage of lung development, to viable extra-uterine neonatal physiology. To accomplish this goal, the specific aims of this proposal are: 1. to evaluate fetal circulation, hemodynamics, and lung development under variable conditions of airway management and controlled fetal/newborn circulation in the 118 day lamb model. 2. To evaluate brain and systemic bleeding and embolism during AP without heparin and assess cerebral perfusion, function, development, and white matter injury. 3. To maintain the simulated intrauterine environment using the artificial placenta until lung development and circulation can support air breathing, including addressing potential problems with long-term support (infection, nutrition, gastrointestinal function, and metabolic issues).