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.