Development of an Artificial Placenta for Support of Premature Infants

描述（由申请人提供）：早产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，死于与早产有关的问题的婴儿比死于任何其他单一原因的婴儿都多。虽然这些婴儿中有许多通过常规治疗得以康复，但极低胎龄新生儿（ELGANs，定义为估计胎龄<28周）的死亡率和发病率极高，只有不到50%的人没有残疾。在某种程度上，许多并发症是由于我们试图给未成熟的肺部通气和逆转胎儿循环而引起的。尽管在使用表面活性剂和低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。产后治疗早产儿的一个主要模式转变是用一个专门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，并允许胎儿在没有空气呼吸的情况下生长发育；我们称这项技术为人工胎盘（AP）。我们的长期目标是临床

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).