Development of an Artificial Placenta for Support of Premature Infants

描述（由申请人提供）：早产儿的治疗仍然是一个未解决的问题，也是公共卫生的首要任务。每年有近50万早产儿，死于早产相关问题的婴儿比任何其他单一原因都多。尽管这些婴儿中有许多通过常规管理恢复，但极低胎龄新生儿（ELGAN，定义为<28周估计胎龄）的死亡率和发病率极高，只有不到50%的婴儿无残疾存活。这些并发症中的许多部分是由于我们试图使未成熟的肺复张和逆转胎儿循环而引起的。尽管在使用表面活性剂和微创通气策略治疗早产儿方面取得了进展，但有效的治疗方案仍然是一个未解决的问题。早产儿出生后治疗的一个主要模式转变是用一个特殊设计的体外气体交换系统模拟宫内环境，该系统保持胎儿循环，并允许在没有空气呼吸的情况下生长和发育;我们称这种技术为人工胎盘（AP）。我们的长期目标是临床 应用AP提高ELGAN的存活率并降低发病率。我们已经开发了胎儿羔羊模型，对应于人类早产的各个阶段。我们最初在妊娠130天（相当于人类妊娠29周;肺发育的囊状阶段）的胎羊中开发了AP，并恢复到空气呼吸。最近的初步数据证明了在110天绵羊模型（相当于22周妊娠人类胎儿;肺发育的小管阶段）中提供完整体外支持一周的可行性，具有血流动力学稳定性、良好的气体交换、正常发育的肺泡化、稳定的脑灌注和胎儿循环的维持，所有这些都没有机械通气。本研究提案的目标是评估和完善这种宫内模拟系统，以支持胎羊从极早产，肺发育的小管阶段，到可行的子宫外新生儿生理。为实现这一目标，本提案的具体目标是：1.在118天羔羊模型中，评价在气道管理和受控胎儿/新生儿循环的可变条件下的胎儿循环、血流动力学和肺发育。2.评价无肝素AP期间的脑和全身出血和栓塞，并评估脑灌注、功能、发育和白色损伤。3.使用人工胎盘维持模拟宫内环境，直至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、胃肠道功能和代谢问题）。

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).