Patent Publication Number: US-2021161744-A1

Title: Method and apparatus for extracorporeal support of premature fetus

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 16/848,085, filed on Apr. 14, 2020, which is a continuation of U.S. patent application Ser. No. 15/736,825, filed on Dec. 15, 2017, which is a National Stage Application filed under 35 U.S.C. 371 of International PCT/US2016/038045, filed on Jun. 17, 2016, which claims the benefit of U.S. Provisional Application No. 62/181,861, filed Jun. 19, 2015, and U.S. Provisional Application No. 62/260,251, filed Nov. 26, 2015, the disclosures of which are incorporated herein by reference in their entireties. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates generally to neonatal care. More specifically, the present disclosure describes devices, systems, and methods related to the maintenance of homeostasis in an extreme premature fetus outside of the womb. According to one aspect, the present disclosure relates to improving outcomes of premature fetuses born prior to 28 weeks gestation. 
     BACKGROUND 
     Extreme prematurity is the leading cause of infant morbidity and mortality in the United States, with over one third of all infant deaths and one half of cerebral palsy diagnoses attributed to prematurity. Respiratory failure represents the most common and challenging problem associated with extreme prematurity, as gas exchange in critically preterm neonates is impaired by structural and functional immaturity of the lungs. Advances in neonatal intensive care have achieved improved survival and pushed the limits of viability of preterm neonates to 22 to 24 weeks gestation, which marks the transition from the canalicular to the saccular phase of lung development. Although survival has become possible, there is still a high rate of chronic lung disease and other complications of organ immaturity, particularly in fetuses born prior to 28 weeks gestation. The development of a system that could support normal fetal growth and organ maturation for even a few weeks could significantly reduce the morbidity and mortality of extreme prematurity, and improve quality of life in survivors. 
     Premature birth may occur due to any one of a multitude of reasons. For example, premature birth may occur spontaneously due to preterm rupture of the membranes (PROM), structural uterine features such as shortened cervix, secondary to traumatic or infectious stimuli, or due to multiple gestation. Preterm labor and delivery is also frequently encountered in the context of fetoscopy or fetal surgery, where instrumentation of the uterus often stimulates uncontrolled labor despite maximal tocolytic therapy. 
     The 2010 CDC National Vital Statistics Report notes birth rates at a gestational age of less than 28 weeks in the United States over the past decade have remained stable at approximately 0.7%, or 30,000 births annually. Similarly, birth rates at gestational ages 28-32 weeks over the past decade in the United States have been stable at 1.2%, or 50,000 births annually. Patients with pulmonary hypoplasia secondary to congenital diaphragmatic hernia, oligohydramnios, or abdominal wall defects are also significant. The National Birth Defects Prevention Network reports an annual incidence of congenital diaphragmatic hernia between 0.9 to 5.8 per 10,000 live births in the United States, or approximately 375-2,500 births annually. The incidence of other causes of pulmonary hypoplasia is not well documented. 
     Respiratory failure remains the major challenge to survival in the critically premature infant. The development of an extrauterine system to support ongoing fetal growth and development would represent a changing paradigm in the management of such patients. The development of an “artificial placenta” has been the subject of investigation for over 50 years with little success. Previous attempts to achieve adequate oxygenation of the fetus in animal models have employed traditional extracorporeal membrane oxygenation (ECMO) with pump support, and have been limited by circulatory overload and cardiac failure in treated animals. The known systems have suffered from unacceptable complications, including: 1) progressive circulatory failure due to after-load or pre-load imbalance imposed on the fetal heart by oxygenator resistance or by circuits incorporating various pumps; and 2) contamination and fetal sepsis. 
     Accordingly, despite previous attempts to address the long-felt need for a system to support fetal growth and development for preterm fetuses, a solution has remained elusive. 
     SUMMARY 
     The present disclosure provides an extracorporeal system to support a mammal, such as a premature fetus. According to one aspect of the disclosure, the system includes a fluid reservoir having one or more flexible walls. The fluid reservoir is configured to enclose a fetus within a fluid environment and may have an expandable volume and a sealable opening. The system may include a fluid supply line configured to supply a volume of fluid into the fluid reservoir. The system may further include a fluid discharge line configured to discharge fluid from the fluid reservoir. The system may include a pumpless pediatric oxygenator configured to exchange oxygen and carbon dioxide in the blood of the fetus while the fetus is maintained within the fluid reservoir. 
     According to another aspect of the disclosure, a method of treatment for a premature fetus is provided. The method includes the steps of providing a fluid reservoir having one or more flexible walls, filling the fluid reservoir with fluid, placing the premature fetus within the fluid reservoir, connecting the premature fetus to a pumpless oxygenator that is configured to exchange oxygen and carbon dioxide with the blood of the premature fetus, or any combination thereof. The method may further include the steps of enclosing the premature fetus within the fluid reservoir, maintaining the premature fetus within the fluid reservoir for a period of time during which the premature fetus can grow and/or develop, while the premature fetus is within the fluid reservoir modifying the fluid reservoir to expand the volume of fluid reservoir, while the premature fetus is within the fluid reservoir infusing fluid into the fluid reservoir, and while the premature fetus is within the fluid reservoir discharging fluid from the fluid reservoir. 
     According to another aspect of the disclosure, an extracorporeal system configured to support a mammal, such as a premature fetus, is provided. The system includes a fluid reservoir configured to maintain the premature fetus in a sealed, liquid environment, a pumpless pediatric oxygenator configured to exchange oxygen and carbon dioxide in the blood of the premature fetus while the premature fetus is maintained within the fluid reservoir, a mechanism configured to manipulate the fluid reservoir, or any combination thereof. The mechanism is configured to rotate, translate, or both rotate and translate the fluid reservoir while the fetus is maintained in the fluid reservoir so that the position of the fetus is varied while the fetus is maintained in the fluid reservoir. According to one embodiment, the mechanism includes a pair of supports spaced apart from one another and each connected with the fluid reservoir. The mechanism may include a drive mechanism configured to displace the first support relative to the second support, thereby altering the orientation of the fluid reservoir. Additionally or alternatively, the mechanism may include a drive mechanism configured to rotate the fluid reservoir, for example about an axis. 
     According to another aspect of the disclosure, an extracorporeal system configured to support a mammal, such as a premature fetus, is provided. The system includes a fluid reservoir configured to enclose a premature fetus within a fluid liquid environment. The fluid reservoir includes an expandable volume, a sealable opening, or both. The system includes a fluid supply line configured to supply a volume of fluid into the fluid reservoir, and a fluid discharge line configured to discharge fluid from the fluid reservoir. The system includes an oxygenation circuit configured to exchange oxygen and carbon dioxide in the blood of the premature fetus while the premature fetus is maintained within the fluid reservoir. The oxygenation circuit includes a first fluid path from the fetus to an oxygenator and second fluid path from the oxygenator back to the fetus. The oxygenation circuit may include a by-pass line for re-circulating a portion of blood through the oxygenator. A pump may be provided along the by-pass line for pumping the portion of blood through the by-pass line. The pump may increase the flow rate of the fluid through the by-pass line relative to the flow rate of the fluid through the first and/or second fluid path. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The foregoing summary and the following detailed description of the preferred embodiments of the present invention will be best understood when read in conjunction with the appended drawings, in which: 
         FIG. 1  is an isometric view of an extracorporeal support system in a first configuration, according to one embodiment; 
         FIG. 2  is an isometric view of the extracorporeal support system illustrated in  FIG. 1 , in a second configuration; 
         FIG. 3  is an isometric view of a portion of the extracorporeal support system illustrated in  FIG. 1 ; 
         FIG. 4  is an isometric view of a portion of the extracorporeal support system illustrated in  FIG. 1 ; 
         FIG. 5  is another isometric view of the portion of the extracorporeal support system illustrated in  FIG. 4 , shown from alternate viewing angle; 
         FIG. 6  is an isometric view of an amniotic fluid circuit of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 7  is a top plan view of a fetal chamber of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment, the fetal chamber in a closed configuration; 
         FIG. 8  is an isometric view of the fetal chamber shown in  FIG. 7 , in an open configuration; 
         FIG. 9  is an alternate isometric view of the fetal chamber shown in  FIG. 7 , including an attached restriction ring; 
         FIG. 10  is a partially exploded isometric view of the fetal chamber illustrated in  FIG. 9 ; 
         FIG. 11  is a cross-sectional view of the fetal chamber illustrated in  FIG. 9 , along line  11 - 11 ; 
         FIG. 12  is a diagrammatic view of an amniotic fluid circuit of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 13  is a diagrammatic view of an amniotic fluid circuit of the extracorporeal support system illustrated in  FIG. 1 , according to another embodiment; 
         FIG. 14  is a diagrammatic view of an oxygenation circuit of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 15  is a diagrammatic view illustrating the interconnection between a central controller and a plurality of sensors and controls of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 16  is a diagrammatic view of an amniotic circuit and an oxygenation circuit of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 17  is a diagrammatic view of an oxygenation circuit of the extracorporeal support system illustrated in  FIG. 1 , according to another embodiment; 
         FIG. 18  is a diagrammatic view of the transfer of a fetus from in-utero to the extracorporeal support system illustrated in  FIG. 1 ; 
         FIG. 19  is an isometric view of a fetal chamber of the extracorporeal support system illustrated in  FIG. 1 , according to another embodiment, the fetal chamber in an open configuration; 
         FIG. 20  is an isometric view of the fetal chamber illustrated in  FIG. 19 , in a closed configuration; 
         FIG. 21  is a cross-sectional view of a gas blender of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 22  is a diagrammatic view of a portion of an oxygenation circuit of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 23  is an isometric view of a fetal chamber of the extracorporeal support system illustrated in  FIG. 1 , according to another embodiment, the fetal chamber in a closed configuration; 
         FIG. 24  is an isometric view of the fetal chamber of the extracorporeal support system illustrated in  FIG. 23 , in an open configuration; 
         FIG. 25  is an isometric view of a fetal chamber and a mechanism configured to manipulate the fetal chamber of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 26  is an isometric view of a fetal chamber and a heating element configured to change the temperature within the fetal chamber of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 27  is an isometric view of a fetal chamber of the of the extracorporeal support system illustrated in  FIG. 1 , according to another embodiment; 
         FIG. 28  is an isometric view of a portion of the fetal chamber illustrated in  FIG. 27 ; 
         FIG. 29  is an isometric view of the fetal chamber illustrated in  FIG. 27 , and a mechanism configured to manipulate the fetal chamber, both the fetal chamber and the mechanism in a closed configuration; 
         FIG. 30  is an isometric view of the fetal chamber and mechanism illustrated in  FIG. 29 , both the fetal chamber and the mechanism in an open configuration; 
         FIG. 31  is an isometric view of a fetal chamber of the of the extracorporeal support system illustrated in  FIG. 1 , according to another embodiment, the fetal chamber in a closed configuration; 
         FIG. 32  is an isometric view of the fetal chamber illustrated in  FIG. 31 , the fetal chamber in a closed configuration; 
         FIG. 33  is an isometric view of a portion of the fetal chamber illustrated in  FIG. 31 ; 
         FIG. 34  is an isometric view of the fetal chamber illustrated in  FIG. 31 , according to another embodiment; 
         FIG. 35  is another isometric view of the fetal chamber illustrated in  FIG. 34 ; 
         FIG. 36  is an isometric view of the fetal chamber illustrated in  FIG. 31 , according to another embodiment; 
         FIG. 37  is another isometric view of the fetal chamber illustrated in  FIG. 36 ; 
         FIG. 38  is an isometric view of a portion of the extracorporeal support system illustrated in  FIG. 1 , according to one embodiment; 
         FIG. 39  is an isometric view of an extracorporeal support system in a first configuration, according to another embodiment, the extracorporeal support system in a closed configuration; 
         FIG. 40  is a side elevation view of the extracorporeal support system illustrated in  FIG. 39 ; 
         FIG. 41  is an isometric view of the extracorporeal support system illustrated in  FIG. 39 , in an open configuration; 
         FIG. 42  is a diagrammatic view of a fetal chamber of the extracorporeal support system, according to one embodiment; 
         FIG. 43  is a first graph illustrating experimental results; 
         FIG. 44  is a second graph illustrating experimental results; 
         FIG. 45  is a third graph illustrating experimental results; 
         FIG. 46  is a fourth graph illustrating experimental results; 
         FIG. 47  is a fifth graph illustrating experimental results; 
         FIG. 48  is a sixth graph illustrating experimental results; 
         FIG. 49  is a seventh graph illustrating experimental results; 
         FIG. 50  is first table illustrating experimental results; 
         FIG. 51  is an eighth graph illustrating experimental results; 
         FIG. 52  is a ninth graph illustrating experimental results; 
         FIG. 53  is a tenth graph illustrating experimental results; 
         FIG. 54  is a eleventh graph illustrating experimental results; 
         FIG. 55  is a second table illustrating experimental results; 
         FIG. 56  is a third table illustrating experimental results; 
         FIG. 57  is a twelfth graph illustrating experimental results; 
         FIG. 58  is a thirteenth graph illustrating experimental results; 
         FIG. 59  is a fourteenth graph illustrating experimental results; 
         FIG. 60  is a fourth table illustrating experimental results; 
         FIG. 61  is a fifteenth graph illustrating experimental results; 
         FIG. 62  is a sixteenth graph illustrating experimental results; 
         FIG. 63  is a seventeenth graph illustrating experimental results; 
         FIG. 64  is a fifth illustrating experimental results; 
     
    
    
     DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS 
     Aspects of the disclosure will now be described in detail with reference to the drawings, wherein like reference numbers refer to like elements throughout, unless specified otherwise. Referring to  FIGS. 1 to 5  an extracorporeal support system  10  may be configured to treat premature fetuses (referred to herein as “fetuses”). The system  10  includes a fetal chamber  100  configured to house a fetus  5 , an amniotic fluid circuit  200  configured to provide a flow of amniotic fluid to the fetal chamber  100 , and an oxygenation circuit  400  configured to remove carbon dioxide from the fetus&#39;s blood and supply oxygen to the fetus&#39;s blood. The system  10  is configured to maintain the fetus  5  in the fetal chamber  100  immersed in amniotic fluid that is part of the amniotic fluid circuit  200 . The system  10  is further configured such that the oxygenation circuit  400  provides adequate gas exchange for the fetus  5  to sustain life. In this way, the system  10  provides an environment similar to an intrauterine environment to facilitate continued growth and development of the fetus  5 . The system  10  may include a cart  50  that facilitates monitoring, caring for, and transporting the fetus  5  within a medical facility. According to one embodiment, a central controller  700 , such as a microprocessor may be provided to receive signals from various elements of the system  10  and control operation of various subassemblies of the system  10 . The details of each of the subsystems will be described in greater detail below. 
     The fetal chamber  100  includes an enclosed fluid chamber configured to house the fetus  5  in a sterile liquid environment. The fetal chamber  100  is configured to provide a fluid environment that allows fetal breathing and swallowing to support normal lung and gastrointestinal development, as well as providing fluid and electrolyte balance. 
     According to one aspect of the disclosure, the fetal chamber  100  is configured to generally conform to the shape of the fetus  5 , and to minimize areas of stagnation that could promote bacterial growth that could lead to infection. As shown in the illustrated embodiment the fetal chamber  100  may be configured to generally conform to the shape of a human fetus  5 . According to another embodiment, for example as shown in  FIG. 31 , the fetal chamber  100  may be configured to generally conform to the shape of a non-human fetus, such as a lamb fetus. 
     Referring to  FIGS. 7 to 11 , according to one aspect of the disclosure, the fetal chamber  100  includes rigid walls to provide a rigid chamber. According to another aspect of the disclosure, as shown in the illustrated embodiments, the fetal chamber  100  includes one or more flexible walls  120 . As shown in the illustrated embodiment, the fetal chamber  100  may include a sac or bag formed of flexible material, such as a plastic film, for example a flexible polyethylene film. The film may incorporate an antimicrobial element to control the growth and spread of microbes in the fetal chamber  100 . The antimicrobial element may be organic or inorganic. According to one aspect of the disclosure the antimicrobial element includes an inorganic element such as silver. According to one example, the one or more flexible walls  120  of the fetal chamber  100  are made of a material including metallocene polyethylene film, for example about 80 micrometer thick and containing 2% silver cation as an antimicrobial element. 
     Referring to  FIGS. 7 to 11 , the fetal chamber  100  may include a generally rigid frame  110  that supports one or more flexible walls  120 . The rigid frame  110  may be formed of a variety of materials, including, but not limited to plastic or metal. The flexible walls  120  are fixedly connected with the rigid frame  110 , for example by welding or an adhesive. The flexible walls  120  allow a volume defined by the fetal chamber  100  to expand and contract. According to one aspect of the disclosure, the fetal chamber  100  is configured to expand as the fetus  5  enclosed within the fetal chamber  100  grows, allowing the volume of the chamber to be increased without opening or changing the fetal chamber  100  of the system  10 . According to one aspect of the disclosure the fetal chamber  100  may include a single flexible wall  120 . According to another aspect of the disclosure, the fetal chamber  100  may include a plurality of flexible walls  120 , for example upper and lower flexible walls  120  fixedly connected with the rigid frame  110 . 
     As shown in the illustrated embodiment, the fetal chamber  100  includes a sealable opening configured to allow the fetus  5  to be placed into the fetal chamber  100  in an open configuration (as shown in  FIG. 8 ) and then sealed once the fetus  5  is inside the fetal chamber  100  in a closed configuration (as shown in  FIG. 7 ). According to one aspect of the disclosure, the fetal chamber  100  may have a clamshell design in which the fetal chamber  100  includes an upper half  102  and a lower half  104  connected by at least one hinge  106  so that the upper half  102  is pivotable relative to the lower half  104 . As shown in the illustrated embodiment, the fetal chamber  100  may include a seal  116 , such as an elastomeric material (for example resilient plastic, urethane or rubber) extends around at least a portion, for example an entirety, of the periphery of the upper half  102 , the lower half  104 , or both. The fetal chamber  100  may further include a lip  118  on either the upper half, the lower half, or both, the seal configured to cooperate with the seal  116  on the opposite (upper or lower) half of the fetal chamber  100  to form a fluid-tight seal when the fetal chamber  100  is in the closed configuration. The fetal chamber  100  preferably includes a mechanism  114  configured to retain the fetal chamber  100  in the closed configuration. For instance, the fetal chamber  100  may include one or more latches configured to releasably lock the upper half  102  of the fetal chamber  100  to the lower half  104  of the fetal chamber  100  to maintain the fetal chamber  100  in the closed, fluid-tight configuration. 
     A first orifice at a first end  108  of the fetal chamber  100  forms an inlet  142  configured to receive amniotic fluid into the fetal chamber  100 . A second orifice at a second end  109  of the fetal chamber  100  forms an outlet  144  configured to discharge amniotic fluid from the fetal chamber  100 . In the embodiment shown in  FIG. 7 , the fetal chamber  100  is elongated to accommodate a human fetus  5 . As shown in the illustrated embodiment, a length of the fetal chamber  100 , measured for example from the inlet  142  to the outlet  144 , may be greater than a width of the fetal chamber  100 , measured in a direction perpendicular to the length. The first end  108  and the second end  109  may taper inwardly to minimize locations within the fetal chamber  100  where amniotic fluid may stagnate. As shown in the illustrated embodiment, the fetal chamber  100  is an ovate or elliptical shape having a major axis along the length of the fetal chamber  100  and the minor axis along the width of the fetal chamber  100 . 
     According to one aspect of the disclosure, the fetal chamber  100  is configured to receive the fetus  5  such that a head of the fetus  5  is adjacent the inlet  142 . Positioning the fetus  5  within the fetal chamber  100  such that the head of the fetus  5  is adjacent the inlet  142  may allow more efficient removal of waste generated by the fetus  5  from the fetal chamber  100 . 
     The fetal chamber  100  may include a plurality of sensors configured to monitor conditions within the fetal chamber  100 . For instance, the fetal chamber  100  may include one or more temperature sensor configured to detect fluid temperature within the fetal chamber  100 . In the present embodiment, the fetal chamber  120  includes at least one, for example a pair of, thermocouples  130  configured to monitor fluid temperature within the fetal chamber  100 . Additionally, one or more fluid pressure sensors  140  may be positioned within the fetal chamber  100 . For example, as shown in the illustrated embodiment, a fluid pressure sensor  140  may be positioned within the fetal chamber  100  adjacent the outlet  144 , the fluid pressure sensor configured to monitor fluid pressure within the fetal chamber  100 . Alternatively, the fluid pressure sensor  140  may be mounted within the outlet  144  such that the fluid pressure sensor is configured to monitor fluid pressure of fluid discharging from the fetal chamber  100 . 
     The fetal chamber  100  may also include one or more sealed openings configured to provide access an interior of the fetal chamber  100 . According to one aspect of the disclosure, the one or more sealed openings may include an upper port  122 , formed in the upper half  102  of the fetal chamber  100  for example, and a lower port  124 , formed in the lower half  104  of the fetal chamber  100 . As shown in the illustrated embodiment, at least one of the upper port  122  and the lower port  124  are sealed by a valve that provides one way flow. For example the valve may be configured to permit access into the fetal chamber  100  while impeding fluid flow out of the fetal chamber  100 . The valves may be any of a variety of valves configured to control flow of fluid. According to one example, the valves may be duck bill valves. The upper port  122  and the lower port  124  are each configured to allow insertion of a suction device into the fetal chamber  100 , for example to evacuate air bubbles, stool contamination, and other contaminates from the fetal chamber  100 . 
     The fetal chamber  100  may further include an orifice  135  configured to provide access for conduits or other portions of the oxygenation circuit  400  described further below. The fetal chamber may include a seal configured to seal the orifice  135  when the fetal chamber is in the closed configuration. 
     The fetal chamber  100  may be formed with a predetermined fixed volume that is sufficiently large to accommodate the fetus  5  after it has grown for several weeks or months. In this way, the fetal chamber  100  is configured to maintain the fetus  5  within the fetal chamber  100  during the entire period of development without the fetus  5  growing too large for the fetal chamber  100 . Alternatively, the fetal chamber  100  may include a variable volume chamber so that the fetal chamber volume can be sized to the minimum volume necessary to support the fetus  5  when the fetus  5  is initially enclosed within the fetal chamber  100 . As the fetus  5  grows, the fetal chamber  100  is configured to be expanded without opening the fetal chamber  100 . 
     The system  10  may include one or more mechanisms configured to vary the volume of the fetal chamber  100 . According to one aspect of the disclosure, the system  10  includes one or more restriction rings  150  configured to constrain the flexible walls  120  of the fetal chamber  100 , thereby reducing the volume of the fetal chamber  100 . The restriction ring  150  may be configured to releasably attach to the frame  110  of the fetal chamber  100  so that the restriction ring  150  can be attached and detached from the fetal chamber  100 . 
     As shown in the illustrated embodiment, the restriction ring  150  may be shaped generally similarly to the shape of the flexible wall  120 . The restriction ring may include an inner protrusion  152  extending around at least a portion of an interior edge of the restriction ring  150 . When attached to the frame  110 , the inner protrusion  152  of the restriction ring  150  is spaced inwardly from an outer edge of the flexible wall  120 . The inner protrusion  152  of the restriction ring  150  applies inward pressure against the flexible wall  120  thereby restricting outward displacement of the flexible wall  120 . As a result, the restriction ring  150  restricts the internal volume of the fetal chamber  100 . 
     The restriction ring  150  may include a plurality of latches or clips  154 , for example formed around a periphery of the restriction ring  150  configured to releasably connect the restriction ring  150  to the chamber frame  110 . As shown in the illustrated embodiment, the clips  154  are configured to snap over tabs  155  formed on the chamber frame  110  to retain the restriction rings  150  against the outward force of fluid pressure within the fetal chamber  100  pushing the flexible wall  120  outwardly. According to one embodiment, the system  10  is devoid of a restriction ring  150 . According to another embodiment, the system  10  includes a single restriction ring  150 . According to another embodiment, the system  10  may include a plurality of restriction rings  150 , for example a first restriction ring  150  configured to be attached to the upper half  102  of the fetal chamber  100  to restrict the upper flexible wall  120  and a second restriction ring  150  is configured to be attached to the lower half  104  of the fetal chamber  100  to restrict the lower flexible wall  120 . As the fetus  5  grows, the restriction ring(s)  150  can be detached from the fetal chamber  100  to allow the flexible walls  120  to expand outwardly, thereby increasing the internal volume of the fetal chamber  100 . Additionally, the system  10  may include a plurality of different sized restriction rings  150 , with each ring allowing the flexible walls  120  to expand to a different extent. In this way, as the fetus  5  grows, the volume of the fetal chamber  100  can be increased incrementally over time. 
     Referring to  FIGS. 4 to 6 , the amniotic circuit  200  of the system  10  is configured to provide a fluid, for example a sterile fluid, to the fetal chamber  100  and is further configured to discharge the fluid from the fetal chamber  100 . According to one aspect of the disclosure, the amniotic circuit  200  is configured to control flow of the fluid entering the fetal chamber  100  and being discharged from the fetal chamber  100  to maintain fluid pressure in the fetal chamber  100  within a pre-determined range. The amniotic circuit  200  may be a closed circuit in which the fluid discharges from the fetal chamber  100 , is processed by filtration and sterilization prior to being recycled back into the fetal chamber  100 . However, as shown in the illustrated embodiment, the amniotic circuit  200  may be an open circuit in which the fluid flows from a supply tank  210  which houses a reservoir of fresh amniotic fluid into the fetal chamber  100  and the fluid exits the fetal chamber  100  and is discharged into a waste tank  220 . The amniotic circuit  200  also may include one or more elements configured to process the fluid prior to injecting the fluid into the fetal chamber  100  as discussed further below. 
     It should be understood that the terms “fluid” and “amniotic fluid” is used to refer to the fluid that is used to fill the fetal chamber  100 . The composition of the fluid may vary depending on a variety of factors. For instance, the amniotic fluid may include primarily water, such as distilled water, and may be mixed with a variety of elements, such as electrolytes (for example, but not limited to, sodium chloride, sodium bicarbonate, potassium chloride, calcium chloride, or any combination thereof) dissolved in solution to mimic the ionic concentration of naturally occurring amniotic fluid for a fetus in utero. Additionally, glucose, amino acids, lipids, essential vitamins, minerals, trace elements, or any combination thereof may be added to the amniotic fluid. Accordingly, the term amniotic fluid in this specification does not refer to a solution having a particular composition, but instead refers to the fluid used to fill the fetal chamber  100 . 
     The amniotic circuit  200  includes the supply tank  210  configured to store a reservoir of unused amniotic fluid. The supply tank  210  may include a portable tank  210   a  configured to be transported on the cart  50 , a larger tank  210   b  configured to remain in a particular area and having a substantially larger volume configured to provide a supply of amniotic fluid for a longer period of time than the portable tank  210   a , or both. The amniotic circuit  200  includes the waste tank  220  configured to collect amniotic fluid discharged from the fetal chamber  100 . The waste tank  220  may include a portable tank  220   a  configured to be transported on the cart  50 , a larger tank  220   b  configured to remain in a particular area and having a substantially larger volume configured to receive used amniotic fluid over a longer period of time than the portable tank  220   a . For instance, the larger tanks  210   b  and  220   b  may have volumes that are at least one order of magnitude larger than the portable tanks  210   a  and  220   a.    
     Referring to  FIGS. 4 to 8 and 12 , fluid flows from the supply tank  210  to the fetal chamber  100  through a supply line  300 . The supply line forms a fluid-tight connection with the inlet  142  of the fetal chamber. A discharge line  320  forms a fluid-tight seal with the outlet  144  of the fetal chamber  100  and thereby provides a fluid path for fluid discharging from the fetal chamber  100 . The system  10  may include a heater  270  configured to provide heat to the amniotic fluid and thereby maintain the amniotic fluid at a selected temperature, for example a temperature corresponding to the temperature of amniotic fluid in utero. The heater  270  may be part of the amniotic circuit  200 , for example the heater  270  may be provided in the supply tank  210  so that the reservoir of amniotic fluid is maintained at the selected temperature. As shown in the illustrated embodiment, the heater  270  is positioned inline between the supply tanks  210  and the fetal chamber  100 . 
     According to one aspect of the disclosure, the heater may  270  be an electric heater having a control configured to vary the heat output of the heater to heat the fluid to the selected temperature as the amniotic fluid flows through the heater  270 . It may be desirable to prevent direct contact between the fluid heater  270  and the supply tank  210 . Accordingly, the heater  270  may be configured to receive a disposable fluid pathway, such as a cartridge, that allows heat exchange between the heater  270  and the fluid without the heater  270  coming in contact with the fluid. In this way, the cartridge can be replaced each time the system  10  is used to prevent cross-contamination of the heater  270  from the fluid used for one fetus  5  with the fluid used for a subsequent fetus  5 . 
     The amniotic circuit  200  may also include one or more filters  250  configured to filter the amniotic fluid prior to entering the fetal chamber  100 . As shown in the illustrated embodiment, a plurality of the filters  250 , for example three micropore filters, may be included, arranged in parallel, and positioned in-line between the supply tank  210  and the fetal chamber  100 , for example between the heater  270  and the fetal chamber  100 . Other numbers, arrangements, and positions of the filters  250  are also considered part of the present disclosure. 
     According to one aspect of the disclosure, the system  10  may include a fluid control system  228  configured to control flow of the fluid to and from the fetal chamber  100 . The fluid control system  228  may be designed to provide a constant flow of fluid to the fetal chamber  100  while maintaining a generally constant fluid pressure within the fetal chamber  100 . In particular, the fluid pressure is maintained within a predetermined range depending on various characteristics, such as the type and/or size of the fetus  5  in the fetal chamber  100 . 
     In the present instance, the supply tank(s)  210  are maintained under pressure by a pressurized gas. For instance, the large tank may be connected with a source of pressurized air such as a central medical air supply commonly used in medical facilities. Additionally, a local supply of pressurized gas may be provided. For instance, a portable tank  230  of pressurized gas may be provided to pressurize the fluid in portable tank  210  to drive the amniotic fluid toward the fetal chamber  100 . It may be desirable to provide a pressure regulator  232 , such as an electronic pressure regulator to regulate the gar pressure of the gas pressure being supplied to the supply tanks  210   a  and  210   b . In the present instance, a first pressure regulator  232   a  is provided inline between the portable gas tank  230  and the portable supply tank  210   a  and a second pressure regulator  232   b  is provided inline between the central air supply and the large tank  210   b.    
     According to one aspect of the disclosure, the system  10  may include a fluid controller configured to control flow of pressurized fluid to the fetal chamber  100 . As shown in the illustrated embodiment, the amniotic circuit  200  may include a control valve  242  inline between the supply tank(s)  210  and the fetal chamber  100 . Additionally a fluid flow meter  244  may be provided inline upstream from the fetal chamber  100  to sense the flow rate of the amniotic fluid to the fetal chamber  100 . The fluid flow meter  244  may be configured to provide signals to the central controller  700 , which in turn controls the control valve  242  to regulate flow of the amniotic fluid to the fetal chamber  100  in response to signals from the fluid flow meter  244 . 
     The system  10  may include a manifold  280  configured to control whether the amniotic fluid is supplied from the portable tank  210   a  or the large tank  210   b . According to one aspect of the disclosure the manifold  280  may include a control valve configured to control flow of the fluid from the supply tank(s)  210 . The control valve may be manual or it may be electronically controlled. In a first position, the valve disconnects fluid flow from the portable tank  210   a  and connects fluid flow from the large tank  210   b . In a second position, the valve disconnects fluid flow from the large tank  210   b  and connects fluid flow from the portable tank  210   a . In a third position, the valve disconnects both the portable tank  210   a  and the large tank  210   b  to prevent flow of the amniotic fluid from either tank so that the amniotic circuit  200  can be purged. 
     In the foregoing description, the amniotic fluid is driven toward the fetal chamber  100  using pressurized gas to create a pressure differential that urges the amniotic fluid toward the fetal chamber  100 . It should be understood however, that alternate elements can be used to drive the amniotic fluid toward the fetal chamber  100 . For instance, a pump may be provided that pumps the amniotic fluid from the tank(s)  210  to the fetal chamber  100 . The pump may be a pump that does not directly contact the fluid, such as a peristaltic pump. Additionally, the pump may be controlled by the central controller  700  to automatically control the pressure and flow rate of the fluid flowing into the fetal chamber  100 . 
     As shown in  FIG. 12 , the amniotic circuit  200  may also include one or more valves in-line with the supply line  300  to prevent back flow of the fluid from the fetal chamber  100  back toward the supply tanks  210   a  and  210   b . For instance, the amniotic circuit  200  may include one or more check valves  246  to prevent the back flow of fluid from the fetal chamber toward the supply tanks. 
     The discharge of the fluid from the fetal chamber  100  may be controlled by flow of the fluid entering the fetal chamber  100  from the supply tank  210  so that discharge of the fluid is dependent on fluid pressure in the fetal chamber  100  and flow rate of the fluid into the fetal chamber  100 . According to another embodiment, discharge of the fluid from the fetal chamber  100  is controlled independently from the infusion of the fluid into the fetal chamber  100 . For example the system  10  may include a discharge pump  240  configured to control flow of the fluid out of the fetal chamber  100 . Operation of the discharge pump  240  may be controlled by the central controller  700  based on signals received from various elements of the system  10 . 
     For example, a pressure sensor may sense fluid pressure in the fetal chamber  100  and the discharge pump  240  may operate to withdraw an amount of the fluid from the fetal chamber  100  to maintain a constant fluid pressure within a desired pressure range in the fetal chamber  100 . Additionally, the system  10  may include one or more turbidity sensors  350  (also referred to as a turbidity meter) configured to detect turbidity of the fluid in the fetal chamber  100  and/or the discharge line  320 . In response to turbidity sensed by the sensor  350 , the discharge pump  240  may adjust the flow rate of the fluid discharged from the fetal chamber  100 . For instance, an increase in turbidity in the fluid may be indicative of contaminants in the fetal chamber  100 , such as microbes or stool from the fetus  5 . To flush the contaminants from the fetal chamber  100 , the discharge pump  240  may increase the rate of fluid flow out of the fetal chamber  100 . In response, the flow rate of the fluid being supplied to the fetal chamber from the supply tank  210  is increased to maintain a constant fluid level within the fetal chamber  100 . 
     Referring now to  FIGS. 7 to 11 and 14 , the system  10  includes an oxygenation circuit  400  configured to provide gas transfer between the fetus&#39;s blood and an oxygenator  410  to provide oxygen to and remove carbon dioxide from the fetus&#39;s blood. The oxygenation circuit  400  can be connected with the fetus  5  in a venous/venous arrangement. Alternatively, the oxygenation circuit  400  may be connected with the fetus  5  in an arterial/venous arrangement. In the present instance, cannulae are placed in the great neck vessels (e.g., carotid) of the fetus  5  to connect the circulatory system of the fetus  5  to the oxygenator  410 . The placement in the great neck vessels may avoid issues of vasospasm and cannula instability in umbilical vessels. An external portion of the cannulas may be fitted with a sleeve (e.g., to permit increased tension of the stabilizing sutures). The sleeve may be made of silicone and may be, for example, about 1-10 cm in length, particularly about 3-5 cm in length. The cannulae may be sutured to the fetus  5  (for example via the fitted sleeve) to secure the cannulae to the neck of the fetus  5 . 
     The oxygenator  410  is connected with the fetus  5  via two fluid lines: a drain line  440  and an infusion line  445 . Blood flows from the fetus  5  though the drain line  440  to the oxygenator  410 . The blood then flows through the oxygenator  410  and returns to the fetus  5  via the infusion line  445 . The drain line  440  and infusion line  445  pass through the oxygenator orifice  135  in the fetal chamber  100 . According to one aspect of the disclosure the drain line  440  and the infusion line  445  pass through apertures in a mounting block  450  and the mounting block  450  is configured to be retained in the orifice  135  of the fetal chamber  100 . According to one aspect of the disclosure, the mounting block  450  is formed of a resilient material that forms a seal with the frame  110  when the upper half  102  and the lower half  104  of the fetal chamber  100  abut such that the fetal chamber  100  is in the closed configuration. In this way, the mounting block  450  provides a fluid-tight seal to impede leakage of the amniotic fluid from the fetal chamber  100 . 
     As shown in the illustrated embodiment, the oxygenator  410  may be mounted onto a platform  460  adjacent the fetal chamber  100  so that the length of the drain line  440  and the infusion line  445 , to and from the oxygenator  410  respectively, is minimized. For instance, in accordance with one aspect of the disclosure, the drain line  440  and the infusion line  445  are less than 18 inches long combined, and preferably are not greater than 12 inches long combined. By minimizing the length of the drain line  440  and the infusion line  445 , the volume of blood required to prime the oxygenation circuit  400  is minimized. It may be desirable to line the drain line  440  the infusion line  445 , or both with anti-clotting measures/compounds (for example, but not limited to, immobilized polypeptide, heparin, or both). The oxygenation circuit  400  may be primed with, for example, maternal blood, blood of the fetus  5 , or both. Priming of the oxygenation circuit  400  with hemoglobin from the fetus  5  may result in optimal oxygen exchange in the oxygenation circuit  400 . Because the fetal oxygen dissociation curve is shifted to the left compared to the adult oxygen dissociation curve, fetal arterial oxygen pressures are lower than adult arterial oxygen pressures. In a particular embodiment, the blood in the oxygenation circuit  400  includes heparin. 
     The platform  460  is configured to support the oxygenator  410 . According to one example, the platform  460  includes a boss onto which the oxygenator  410  is configured to snap to retain the oxygenator  410  in position. The platform  460  may be connected with the frame  110  of the fetal chamber  100 , for example the platform  460  may be integrally molded with the frame  110 . 
     According to one aspect of the disclosure, the oxygenation circuit  400  includes a sweep gas connected with the oxygenator  410 , the sweep gas configured to facilitate gas transfer between the oxygenator  410  and the blood of the fetus  5 . The gas transfer is affected by the composition of the sweep gas and the flow rate of the sweep gas through the oxygenator  410 . As shown in  FIG. 14 , two gases, for example an oxygen source  520  and an air source  530 , are blended together in a gas blender  540  that blends the oxygen and the air to form the sweep gas. The details of the gas blender are illustrated in  FIG. 21 . The two gases may be supplied by a high volume gas reservoir, such as wall lines connected with a central gas supply configured to provide gas to the reservoir. Alternatively, the two gases maybe supplied from smaller gas reservoirs, such as a portable oxygen tank  520  and a portable air tank  530  that are mounted on the cart  50  so that the system  10  can provide sweep gas to the oxygenator  410  while the system  10  is conveyed from one area of a medical facility to another area of the medical facility. 
     The oxygenation circuit  400  may include a first control valve  525  configured to control whether the wall source oxygen supply or the portable oxygen tank  520  is connected with the gas blender  540 . The oxygenation circuit  400  may include a second control valve  535  configured to control whether the wall source air or the portable air tank  530  is connected with the gas blender  540 . The oxygenation circuit  400  may include one or more pressure sensors  522  positioned inline with the oxygen supplies and one or more pressure sensors  532  are position inline with the air supplies so that the pressure sensors  522  and  532  sense the gas pressure of the gases being fed to the gas blender  540 . 
     The oxygenation circuit  400  may include a heater  550  positioned inline between the gas blender  540  and the oxygenator  410 , the heater  550  configure to heat the sweep gas so that the temperature of the sweep gas is maintained within a predetermined range. The oxygenation circuit  400  may include a fluid flow meter  562  configured to monitor the flow rate of the sweep gas exiting the heater  550  and a sweep gas analyzer  565  configured to analyze one or more characteristics of the gas entering the oxygenator  410 . The oxygenation circuit  400  may include an exhaust gas analyzer  570  configured to analyze one or more characteristics of the gas discharged by the oxygenator  410 . For instance, the gas analyzers  565  and  570  may be configured to measure the oxygen content of the sweep gas and the exhaust gas, respectively. 
     The oxygenation circuit  400  further includes a pair of fluid pressure sensors configured to detect the fluid pressure of the blood entering the oxygenator  410  and the fluid pressure of the blood exiting the oxygenator  410 . Specifically, a first pressure sensor  590  may be positioned in-line with the drain line  440  and a second pressure sensor  592  may be positioned in-line with the infusion line  445 . In this way, the fluid pressure drop over the oxygenator  410  can be continuously monitored. Additionally, a fluid flow meter  595  may be positioned in-line with the infusion line  445  to monitor the flow rate of the blood returning to the fetus  5  from the oxygenator  410 . 
     The oxygenation circuit  400  may include one or more ports  580 , which may be utilized to withdraw blood samples for analysis or the ports  580  may be used to inject or infuse medicine or nutrition directly into the blood. For instance, one of the ports  580  may be configured to facilitate injection of medication such as antibiotics or sedatives into the blood. Similarly, another of the ports  580  may be configured to facilitate injection of nutrition such as total parental nutrition (TPN) into the blood. 
     In accordance with one aspect of the disclosure, the fetus&#39;s heart is used to drive blood flow through the oxygenation circuit  400 , so a pump is not used to drive the blood through the oxygenation circuit  400 . In other words, according to one aspect of the disclosure, the oxygenation circuit  400  is a pumpless circuit. The use of a pumpless system avoids exposure of the fetus&#39;s heart to excess preload encountered in non-pulsatile pump-assisted circuits. The pumpless system also permits intrinsic fetal circulatory regulation of flow dynamics. The oxygenator  410  preferably has very low resistance, low priming volume, low transmembrane pressure drops, and provides efficient gas exchange. In a particular embodiment, the oxygenator  410  has a pressure drop of less than about 50 mmHg or about 40 mmHg at 1.5 l/min of blood flow. In a particular embodiment, the priming volume of the oxygenator  410  is less than about 100 ml and in particular is less than about 85 ml. In a particular embodiment, the oxygenator  410  has a blood flow range up to about 2.0 l/min, about 2.5 l/min, about 2.8 l/min, or greater. In a particular embodiment, the oxygenator  410  has a gas transfer rate of about 150 ml/min, about 160 ml/min, about 180 ml/min, or greater for 02. In a particular embodiment, the oxygenator  410  is a hollow fiber membrane oxygenator (for example, but not limited to, a polymethyl pentene hollow fiber membrane oxygenator). The oxygenator  410  may be lined with anti-clotting measures/compounds such as immobilized polypeptide and/or heparin). An exemplary oxygenator is the Quadrox-iD™ pediatric oxygenator (Maquet; Wayne, N.J.). 
     The system  10  may be configured for use with fetuses, including term and preterm fetuses. The preterm fetus may be a premature fetus (for example, less than 37 weeks estimated gestational age, particularly 28 to 32 weeks estimated gestational age), extreme premature fetuses (24 to 28 weeks estimated gestational age), or pre-viable fetuses (20 to 24 weeks estimated gestational age). The gestation periods are provided for humans, though corresponding preterm fetuses of other animals may be used. In a particular embodiment, the preterm fetus has no underlying congenital disease. In a particular embodiment, the term or preterm fetus has limited capacity for pulmonary gas exchange, for example, due to pulmonary hypoplasia or a congenital anomaly affecting lung development, such as congenital diaphragmatic hernia. In a particular embodiment, the subject is a preterm or term neonate awaiting lung transplantation, for example, due to congenital pulmonary disease (e.g., bronchoalveolar dysplasia, surfactant protein B deficiency, and the like). Such transplantation surgeries are currently rarely performed in the United States. However, the number of transplantation surgeries may be increased with the more stable method for pulmonary support provided by the instant invention. The fetus  5  may also be a candidate for ex utero intrapartum treatment (EXIT) delivery, including patients with severe airway lesions and a long expected course before definitive resection. The fetus  5  may also be a fetal surgical or fetoscopic procedure patient, particularly with preterm labor precipitating early delivery. According to one aspect of the disclosure the system  10  is configured such that the fetus  5  may be maintained in the system  10  for as long as needed (for example, for days, weeks or months, until the fetus  5  is capable of life without the system  10 ). 
     Referring to  FIGS. 8, 24, 25, 27, 29, 30, and 38 , according to one aspect of the disclosure, the system  10  may be configured to displace the fetal chamber  100  so that the fetus  5  is not continuously maintained in the same orientation, for example with respect to the ground. Specifically, the system  10  may include a chamber displacement system  600  configured to displace the fetal chamber  100 . The chamber displacement system  600  may be operable to tilt and/or rotate the fetal chamber  100  to alter the orientation of the fetus  5  and the fetal chamber  100  with respect to other portions of the system  10 , for example the cart  50 . 
     According to one embodiment, the displacement system  600  may be configured to raise, lower, or both, one or both ends  108 ,  109  of the fetal chamber  100  to tilt the fetal chamber  100  relative to a horizontal orientation, for example parallel to the ground. Specifically, each end  108 ,  109  of the fetal chamber  100  may be supported by an arm of the displacement system  600 . Each of the arms can be independently extended or retracted to raise or lower each end of the fetal chamber  100 . In this way, the fetal chamber can be tilted. 
     Alternatively, for example as illustrated in  FIGS. 8, 25 and 38 , the chamber displacement system  600  includes a cradle  610  having first and second supports  620 ,  625  that support the first and second ends  108 ,  109  of the fetal chamber  100 . More specifically, the chamber frame  110  may include a first cradle mount  112  at the inlet  142  and a second cradle mount  112  at the outlet  144 . The cradle mounts  112  mate with the arms of the cradle  610  to permit rotation of the fetal chamber about an axis  604  that extends through the cradle mounts  112 . Additionally, the cradle  610  may be pivotable so that a first end of the cradle  610  may be pivoted upwardly relative to a second end of the cradle  610  to tilt the fetal chamber  100  relative the horizon. 
     The system  10  may be configured such that chamber displacement system  600  may be manually or automatically actuated. For instance, in a manual configuration the fetal chamber  100  is configured to be manually rotated about the axis  604 , for example a horizontal axis by an operator. Similarly, the cradle  610  may be displaced vertically by pivoting one end of the cradle  610  upwardly as shown in  FIG. 38 . Alternatively, the chamber displacement system  600  may include a drive motor configured to drive rotation of the fetal chamber  100  about the axis  604 , for example a horizontal axis. Similarly, the drive motor may drive the cradle  610  to tilt the cradle  610  vertically. 
     Referring to  FIGS. 1 to 3 , the system  10  may include a cart  50  such that the system  10  is transportable from one area in a medical facility, such as an operating room, to another area in the medical facility, such as a neonatal care center, without needing to remove the fetus  5  from the fetal chamber  100 . 
     The cart  50  may incorporate any of a plurality of elements of the system  10 . For instance, the cart  50  may include a hood  60  configured to enclose and/or cover the fetal chamber  100  to limit access to the fetal chamber  100 . The hood  60  may be pivotable or the hood  60  may be translatable, for example by lifting one or more support arms  64  to provide access to an interior of the hood  60  as necessary. 
     The hood  60  may form an enclosure with a tray  65  below the fetal chamber  100  to provide a sealed enclosure thereby isolating the fetal chamber  100  from external disturbances such as light, sound or other elements that could excite or otherwise disturb the fetus  5 , which can be detrimental to the growth of the fetus  5 . The hood  60  may include sealable access ports  62  sized to allow medical professionals to access the fetal chamber  100  without lifting the hood  60 . 
     The cart  50  may also include a plurality of therapeutic or diagnostic elements to facilitate treatment of the fetus  5  while the fetus  5  is within the fetal chamber  100 . For instance, the cart  50  may include an IV pole  80  configured to support an IV bag containing medication nutrition or other therapeutic solutions to be infused into the fetal chamber  100 , amniotic circuit  200  or oxygenation circuit  400 . 
     The tray  65  may include areas configured to organize diagnostic items, such as an ultrasound probe  70  that is connected with an ultrasound computer configured to process the ultrasound image data acquired by the ultrasound probe  70 . Similarly a bin is provided for a container of ultrasound gel  72 , the ultrasound gel configured to facilitate use of the ultrasound probe  70  to scan the fetus  5  to monitor the development of the fetus  5 . 
     The cart  50  may also include one or more access doors  58  to facilitate access to the various components of the system  10 , for example the amniotic fluid circuit  200  and the oxygenation circuit  400  when necessary while limiting access to the components of the system  10  at other times. 
     The cart  50  further includes a mount for supporting the central controller  700  for the apparatus, which in the present instance is a computer having a display  710  configured to display operating parameters and alerts and an input/output mechanism to allow the operator to input data or control aspects of the process. The input/output mechanism may include one or more input devices, including but not limited to a keyboard, mouse and track pad. 
     Referring to  FIG. 15 , the central controller  700  receives signals from various sensors and elements of the system  10  and provides control signals to various components to control the operation of the system  10 . Specifically, the central controller  700  may receive signals from sensors such as the gas pressure sensors  522 ,  532  and in response to those signals the central controller  700  may control the gas blender  540  accordingly. Similarly, the central controller  700  may receive signals from the turbidity meter  350  and control the operation of pump  240 . 
     It will be recognized by those skilled in the art that changes or modifications may be made to the embodiments described above without departing from the broad inventive concepts of the disclosure. For instance, as shown in  FIG. 13 , the fetal chamber  100  may include a fluid agitator operable to agitate and/or circulate the amniotic fluid within the fetal chamber  100  to minimize stagnate areas in the fetal chamber  100 . Additionally, as shown in  FIG. 16 , the amniotic fluid circuit  200  may incorporate a circulation loop that circulates amniotic fluid from the fetal chamber  100  to a sterilizing element, such as a UV sterilizer and then feeds the amniotic fluid back into the fetal chamber  100 . 
     Referring to  FIG. 17 , according to one aspect of the disclosure the oxygenation circuit  400  may include a recirculation path configured to provide an increased flow of blood through the oxygenator  410  to impede the formation of blood clotting in the oxygenator  410 . As shown in the illustrated embodiment, the oxygenator  410  is connected with the fetus  5  and the oxygenation line, which includes two fluid lines: the drain line  440  and the infusion line  445 . Blood flows from the fetus  5  though the drain line  440  to the oxygenator  410 , then the blood flows through the oxygenator  410  and returns to the fetus  5  via the infusion line  445 . 
     The volume of blood flowing through the oxygenation circuit  400  varies based on the size of the fetus  5 . Smaller fetuses have lower blood flow than older/larger fetuses. When the fetus  5  is small, the lower flow of blood through the oxygenation circuit  400  may increase areas of stagnation or low flow in the oxygenation circuit  400 , which can lead to clot formation. It may be possible to ameliorate clot formation by using heparin. However, it may be desirable to avoid or limit the use of heparin. 
     To increase the flow of blood through the oxygenator  410 , the oxygenation circuit  400  may include a recirculation loop  420 . The recirculation loop  420  is a circulation loop that is parallel to the drain line  440  and the infusion line  445 . The recirculation loop  420  may be connected with the oxygenator  410  in a variety of ways to allow a portion of the blood in the oxygenation circuit  400  to re-circulate rather than flowing directly to the fetus  5 . For example, the oxygenator  410  may include a pair of inlet connections and a pair of outlet connections. The recirculation loop  420  may be connected directly to an inlet of the oxygenator  410  and an outlet of the oxygenator  410 , while the drain line  440  is connected to another of the inlet connectors and the infusion line  445  is connected with another of the outlet connectors of the oxygenator  410 . Alternatively, the recirculation loop  420  may be connected with the drain line  440  so that the two lines merge to flow into the oxygenator  410 . 
     Similarly, the recirculation loop  420  may be connected with the infusion line  445  so that the flow of blood exiting the oxygenator splits, with part of the blood flow flowing to the fetus  5  via the infusion line  445  and part of the blood flow recirculating to the oxygenator  410  via the recirculation loop  420 . In either configuration, the flow of blood from the outlet of the oxygenator  410  is split so that a portion of the blood flows to the fetus  5  via the infusion line  445 , while a portion of the blood flows through the recirculation loop  420  and then flows back into the inlet of the oxygenator  410 . 
     To increase the blood flow through the oxygenator  410 , the recirculation loop  420  may include a fluid pump  430 . The fluid pump  430  may be any of a variety of pumps configured to pump fluid, including but not limited to centrifugal pumps and positive displacement pumps, such as peristaltic pumps. The fluid pump  430  provides the recirculation loop  420  within an increased flow of fluid relative to the fluid flow through the drain line  440  and the infusion line  445 . More specifically, the fluid flow through the recirculation loop  420  may be at least twice the flow rate as the flow through the drain line  440  and the infusion line  445 . For instance, the pump may provide a flow rate of 400 mL/min through the recirculation loop  420 , while the flow rate through the drain line  440  and the infusion line  445  may be approximately 100 mL/min. In this way, the flow from the recirculation loop  420  and the drain line  420  combine to provide and increased flow of blood through the oxygenator  410 . As a result, the increased fluid flow through the oxygenator  410  reduces pooling and stagnant areas within the oxygenator  410 , thereby limiting the formation of blood clots within the oxygenator circuit  400 . 
     Although the flow of blood through the oxygenator  410  is increased, the oxygenation circuit  400  is configured so that the flow rate of blood returning to the patient is not increased by the presence of the recirculation loop  420 . In other words, the flow of fluid from the fetus  5  and returning to the fetus  5  is substantially unaffected by the recirculation loop  420 . The fluid pump  430  provides a steady flow of fluid into the oxygenator  410  and diverts a substantially equal flow of fluid from the outlet of the oxygenator  410 . Therefore, the fluid flow to the infusion line  445  that returns to the fetus  5  is substantially similar to the fluid flow from the drain line  445 . In this way, the fluid pump  430  is not in line with the fluid flow from the fetus  5  to the oxygenator  410  so that the fetus&#39;s heart primarily controls the flow of blood flowing from the fetus  5  to the oxygenator  410  and returning to the fetus  5 . 
     By incorporating a recirculation loop  420  to increase the flow of fluid through the oxygenator  410 , the infusion of heparin into the fetus  5  to prevent blood clots in the oxygenation circuit  400  may be reduced or eliminated. However, for the internal surfaces of the oxygenation circuit  400  that come into contact with the fetus&#39;s blood, it may be desirable to coat such surfaces with a biologically-active compound that prevents clot formation. 
     Referring to  FIGS. 19, 20, 23, and 23-38  the system  10  may include one or more of the fetal chambers  100  in various configurations. For example,  FIGS. 19 and 20  illustrate an embodiment of the fetal chamber  100  having less of a taper at the ends  108  and  109  incorporating further connectors in the fetal chamber  100 , such as a connector  160  configured to connect to an ultraviolet sterilization unit  162 . 
     Referring to  FIGS. 23 to 26 , the fetal chamber  100  of the system  10  may include a supplemental heating element  164  within the fetal chamber  100  configured to heat the amniotic fluid within the fetal chamber  100  to help maintain the fluid temperature within a predetermined range. As illustrated in  FIG. 25 , the fetal chamber  100  may include a plurality of rollers  166  that can be driven in a first direction to tilt the cradle  610  in a first direction or driven in a reverse direction to tilt the cradle  610  in a second direction. 
     Referring to  FIGS. 27 to 30  the system  10  may include a fetal chamber  100  devoid of the rigid frame  110 . Instead, the fetal camber  100  is a generally tubular film  168  having an access opening along one side to facilitate entry of the fetus  5  into the fetal chamber  100 . The access opening includes a closure such as a slide lock mechanism to provide a fluid-tight seal. As shown, the ends  108 ,  109  of the fetal chamber  100  may be supported by hubs  170  that seal off the open ends of the tubular film  168  and that also provide access ports for the amniotic fluid inlet  142 , the amniotic fluid discharge  144 , the drain line  440 , and the infusion line  445 . The hubs  170  may further include cogs  172  configured to facilitate rotation of the fetal chamber  100  by corresponding gears. 
     Referring to  FIGS. 31 to 33 , the fetal chamber  100  of the system  10  may include a hinged frame and a flexible bag having an access opening to facilitate entry of the fetus  5  into the fetal chamber  100 . A slide lock maybe provided to seal the access opening and the edges of the bag are configured to be clamped between the upper and lower hales of the frame to provide a secondary seal. Displaceable elements, such as solenoid actuator, may be disposed in the corners of the frame. The actuators raise and lower the corners of the frame to agitate the fluid within the fetal chamber  100 , thereby minimizing stagnant areas in the fetal chamber  100 . Referring to  FIGS. 34 to 37 , the system  10  may include separate fluid chambers that can be inflated and deflated to agitate the fluid in the fetal chamber  100 . 
     Referring to  FIGS. 39 to 41 , the cart  50  of the system  10  may be configured as shown in the illustrated embodiments. According to one aspect of the disclosure, the cart  50  includes a rotatable hood  60  that encloses the fetal chamber  100 . The entire hood  60  may be configured to rotate as the fetal chamber  100  is rotated. To facilitate access into the hood  60 , access ports  62  are spaced around each side of the hood  60 . 
     Additionally, as described above the fetal chamber  100  may be configured to have a variable volume so that the volume can expand as the fetus  5  grows. One mechanism described above includes a series of restriction plates that limit the amount the fetal chamber  100  can expand. Alternatively, the fetal chamber  100  may comprise a reservoir having one or more dividers that segment the reservoir. The volume of the reservoir can be increased by manipulating or removing one or more of the dividers. In such an arrangement, the wall of the fetal chamber  100  may be generally rigid rather than having one or more flexible walls. Accordingly, it should be understood that a variety of variable volume fluid reservoirs can be used as the fetal chamber  100 . 
     The singular forms “a,” “an,” and “the” include both single and plural referents unless the context clearly dictates otherwise. As used herein, the terms “host,” “subject”, “fetus”, “infant” and “patient” refer to any animal, including mammals, for example but not limited to humans. 
     The following example is provided to illustrate various embodiments of the present disclosure. The example is illustrative and is not intended to limit the scope of the claims in any way. 
     An extracorporeal support system was provided using a pumpless circuit containing a near zero resistance oxygenator (MaquetQuadrox-ID Pediatric Oxygenator: Maquet Cardiopulmonary AG, Rastatt, Germany). The animals were maintained with both systemic antibiotics and antibiotics added to the fluid, parenteral nutrition modified to a formulation based on substrate requirements of premature lambs, sedation as required, and prostaglandin E2 (PGE2) infusions. 
     Fetal lambs were placed directly on the extracorporeal support system circuit after exposure by maternalhysterotomy and connection of the oxygenator in an antegrade orientation, with arterial inflow from a cannula placed in the right common carotid artery and venous return via a cannula in the right jugular vein inserted to the depth of the right atrium. Once full circuit flow was established, the fetal lamb was removed from the uterus and was immersed in an open incubator filled with fluid, with an electrolyte composition designed to mimic amniotic fluid. No vasopressors were utilized at any time during the runs once the lamb was stable on the circuit. 
     The early gestation fetal lambs were maintained in a fetal chamber formed of a flexible bag, referred to herein as a “Biobag”. The Biobag is a single use, completely closed system having a variable volume that can be optimized for the size of the fetus. Additionally, the configuration and number of ports, and flow and volume of fluid exchange can be optimized for a particular fetus. The Biobag was formed out of silver impregnated metallocenepolyethylene film and incorporated a parallel circuit containing a UV light chamber for additional antibacterial effect. The Biobag has an open, sealable side to facilitate insertion of the fetus at the time of cannulation and has the beneficial properties of being translucent and sonolucent for monitoring and scanning the fetus. The Biobag was contained within a mobile support platform that incorporated temperature and pressure regulation, padding, and fluid reservoirs along with fluid exchange circuitry. 
     The Biobag was constructed of metallocene polyethylene film (about 80 micrometers thick) containing 2% silver cation; the later imparts antimicrobial properties to the film. Prior to heat-welding the bag to shape, several through-wall barbed disc-ports were heat welded to the film sheet. There are four barbed ¼″ disc ports (Eldon James: PND4-E8402-QC), four threaded 1″ disc ports (Eldon James: PD38-400-E8402-QC), one barbed ⅜″ disc port (Eldon James: PND6-E8402-QC), and one barbed ⅝″ disc port (Eldon James: PND10-E8402-QC). 
     The ports were located as shown in  FIG. 42 . Port A is for inflow of amniotic fluid. Ports F and G are for an inline ultraviolet sterilization circuit (described below). Port C was used to detect fluid environment temperature and to remove trapped air from the lumen of the Biobag. Port H sits on the underside of the Biobag and allows amniotic fluid to drain out, along with meconium, urine, and other wastes. Port C has a 1-2″ length of tubing attaching a Y-connector with a temperature probe and clave for air removal. Port D is used to detect bag pressure (described below). Ports B1, B2, E1, and E2 house the Bioline-coated Maquet ECMO tubing which traverses the wall of the Biobag while maintaining sterility. Only one of each of the B-type ports and E-types ports were used for a given patient. Within the bag the ECMO tubing was connected to the vascular cannulae (implanted into the carotid artery and umbilical vein), while outside of the bag the tubing was connected to the Maquet Quadrox oxygenator. The ECMO tubing was firmly secured to the Ports B and E using compression fittings secured to the threaded 1″ port discs. Ports A, F, and G have a nylon quick-connect male fitting (http://www.mcmaster.com/#catalog/120/222/=tfgyvp) attached to the disc ports with a 1-2″ length of tubing (http://www.coleparmer.com/Product/Masterflex PharMed BPT Tubing L S 15 25/EW-06508-15). 
     A high accuracy (+/−0.1 degree C.) thermistor probe (http://www.adinstruments.com/products/nasaltemperature-probes) was positioned within the bag and exits via port C. The thermistor connects to a temperature pod (http://www.adinstruments.com/products/temperature-pods) which itself was attached to an analog to digital converted (http://www.adinstruments.com/products/powerlab) connected to a windows 7 based PC running digital data logging software (LabChart, Version 7 or 8; http://www.adinstruments.com/products/labchart). 
     Amniotic Fluid Components: The ingredients for artificial amniotic fluid (sodium chloride, sodium bicarbonate, potassium chloride and calcium chloride dissolved in distilled water) are designed to mimic the ionic concentrations (Na+ 109, Cl− 100, HCO3− 20, K+ 6.5 and Ca2+ 1.6 mmol/L) and pH (7.0) of fetal sheep amniotic fluid. Ingredients are laboratory grade chemicals purchased from commercial vendors. 
     Batches of amniotic fluid (about 340 L) were mixed and filter sterilized (0.22 micrometers; http://www.emdmillipore.com/US/en/product/Standing-Stainless-Steel-Filter-Holders-%2890-and-142-mm%29, MM NF-C743) into heat-sterilized custom polypropylene carboys using a peristaltic pump. The process took about 60 minutes. 
     Delivery to Biobag. Sterile tubing from the glass carboys was connected to a peristaltic pump. After leaving the pump, the amniotic fluid passes through two in-line 0.22 filter cartridges (http://www.emdmillipore.com/US/en/product/WEllipak-Disposable-Filter Units,MM_NF-0523), and then through a stainless-steel heat exchanger to bring the fluid up to 39.5 degrees C. before being pumped into the BioBag. An ultrasonic clamp-on tubing flow probe and meter (http://www.transonic.com/search/?Keywords=ht110&amp;display=search&amp;newSearch=true&amp;noCache=1) are used to monitor the rate of fluid deliver to the Biobag (about 50 ml/min). Amniotic fluid exits the Biobag by way of Port H located on the lower surface of the Biobag. A pressure device is incorporated into Port D to maintain pressure within the Biobag at about 8 to 10 mm Hg (normal amniotic fluid pressure in vivo). Waste amniotic fluid passes through a sterile trap prior to being sent to a floor drain. The Biobag temperature, pressure and amniotic flow were recorded on digital data logging software. 
     UV sterilization loop: In the current design, a peristaltic pump recirculates amniotic fluid in the Biobag (about 100 ml/min) through ports G and H after passing through an in-line, ultraviolet sterilization unit (http://www.mcmaster.com/#ultraviolet-water-purifiers/=tthkg0; catalog #8967T22). The device has broad spectrum antimicrobial properties. 
     Biobag heat regulation: In the current design, the Biobag rests atop a custom-designed aluminum water-heated plate to provide effective heat transfer via conduction. The heat plate is connected to a digitally controlled, recirculating water heater. A fluid-filled mattress sits atop the heat plate for greater heat control and cushioning for the animal. The heat plate, fluid cushion, and Biobag are placed within a 32 inches by 24 inches container that is covered by an insulating, transparent polycarbonate cover. 
     Fetal cardiopulmonary monitoring: Blood pressure was continuously recorded via ports on either side (i.e. arterial and venous limbs) of the Maquet oxygenator using clinical disposable pressure transducers (http://www.icumed.com/products/critical-care/pressure-monitoring-system/transpac.aspx) connected to a bridge amplifier (http://www.adinstruments.com/products/bridge-amps) attached to the digital data logging system. Raw pressure signals are processed to calculate systolic and diastolic pressure, heart rate and the pressure difference across the oxygenator. An ultrasonic clamp-on tubing flow probe and meter (http://www.transonic.com/search/?Keywords=ht110&amp;display=search&amp;newSearch=true&amp;noCache=1) were used to monitor the rate of blood flow to the patient. 
     The Biobag was used to apply extracorporeal support to earlier gestational fetuses. At earlier gestational ages (114 to 120 days gestation), we noticed greater instability at the time of cannulation and transition to the extracorporeal support system circuit resulting in bradycardia and sometimes asystole requiring atropine and epinephrine. Once on the circuit, diminishing circuit flows and progressive edema and electrolyte imbalance were encountered within a few days of cannulation necessitating a re-assessment of the physiology. In the normal fetus, there is preferential streaming of “oxygenated” umbilical venous return across the foramen ovale to the left sided circulation due to a combination of directed streaming of blood from the ductus venosus and the anatomic orientation of the foramen ovale. 
     In our system, return of oxygenated blood was via the superior vena cava. We postulated that this resulted in less efficient right to left flow of umbilical venous return, resulting in increased right-sided venous pressure. We also speculated that the acute increase in right-sided venous pressure, combined with the normally lower systemic blood pressure in earlier gestation lambs, would result in initial instability with subsequent reduced perfusion pressure across the membrane resulting in decreased flows, and eventually inadequate oxygen delivery in younger animals. We confirmed that right-sided venous pressures were elevated (measured abdominal IVC pressures 9.6+2 mm Hg vs. 4+2 mm Hg in normal fetuses) in the carotid artery and jugular vein cannulated animals and explored two solutions. 
     Our first approach was to utilize Angiotensin II, the primary vasoactive agent during mid-gestation that is present in high concentrations in the placenta, to increase systemic blood pressure and maintain perfusion pressure across the membrane. While instability during transition was still an issue requiring epinephrine, stability and circuit flows thereafter were much improved by a continuous angiotensin II infusion which could ultimately be tapered off after approximately 1 week on extracorporeal support system as systemic pressures increased. The other approach was utilization of the umbilical vein for venous return. While we initially used the jugular vein because of concern about umbilical venous spasm, we were able to cannulate the vein using a minimal manipulation technique with topical papaverine irrigation. The cannula was advanced to a position with the tip just inside the abdominal fascia and secured using a silastic cuff attached to the abdomen. 
     Umbilical cannulation immediately eliminated the instability during the transition to the extracorporeal support system circuit. Since initiation of the umbilical venous drainage approach, cannulation instability was significantly reduced and/or eliminated; there was no need for epinephrine, and no need for gradual initiation of circuit flow. We then opened flow to the oxygenator and immediately occluded the umbilical cord. Right-sided pressures were normal, there was an improvement in flow, and more efficient right to left transfer of oxygenated blood as demonstrated by increased carotid artery oxygen saturations and improved oxygen delivery. This approach therefore utilizes umbilical venous return with occasional Angiotensin II infusion to support systemic blood pressure, if such support is needed. 
     These procedures provided stable support of three lamb fetuses at 110 to 113 days gestation for up to 21 days on extracorporeal support system. From the perspective of lung development lambs at 110 to 113 days gestation are in the mid to late cannalicular phase of lung development, which is the biological equivalent of the 23 to 24 week gestation premature fetus. All three lambs demonstrated complete hemodynamic stability and stable physiologic parameters with grossly normal growth and development. After 21 days he was transitioned to mechanical ventilatory support with stable blood gases (7.48/46.7/132/99%) on minimal ventilator settings (SIMV, FiO2 30%, PIP 15 cm H20, CPAP 5 cm H20, Rate 20). He was weaning on ventilator support when he developed marked abdominal distention, respiratory decompensation, and was euthanized. He was subsequently found to have anileal intestinal obstruction due to what appeared to be inspissated meconium. The lungs appeared well developed and mature on histologic assessment with some evidence of ventilation induced injury. 
     These results demonstrate that extreme premature fetal lambs, corresponding biologically to a 23 to 24 week gestation premature fetus, can be supported in the extracorporeal support system for up to 3 weeks without apparent physiologic derangement or organ failure. This is in stark contrast to previously published results of attempted prolonged extracorporeal support of the fetus that have been uniformly associated with progressive cardiac failure and metabolic deterioration. The lambs are remarkably stable on the extracorporeal support system, maintain fetal circulatory pathways and metabolic parameters, and demonstrate evidence of normal maturation and growth. In addition, we have demonstrated transition to postnatal life with normal long-term survival after prolonged extracorporeal support. 
     There are a number of features of the current extracorporeal support system that contribute to this success. The first is an extremely low resistance oxygenator incorporated in a pumpless circuit with low surface area and priming volumes, connected to the fetal vasculature in an arterial to venous orientation. This system is comparable to the hemodynamics of the placenta itself as evidenced by the priming volumes and flows generated in our circuit. The reported placental blood volume of the sheep is 23.1 to 48.1 ml/kg, with normal placental blood flow reported as 199+/−20 ml/min/kg. Our circuit requires a priming volume of 80 to 90 ml, or 27 ml/kg for an average 120 day 3 kg fetal lamb, and flow rates in our system ranged from 90-140 ml/min/kg over our range of gestational ages. Although the flow rates are slightly less than the normal placenta, gas exchange via the oxygenator is highly efficient and near normal fetal blood gases and oxygen saturations can be maintained well within the sweep gas parameters of the oxygenator. 
     In addition, the pumpless design of the circuit allows for some degree of “autoregulation” of circuit flow by the fetal heart and vasculature. Flow in our circuit is dependent upon the size of the cannulas and the pressure gradient across the circuit. Our lambs consistently demonstrated the ability to increase blood pressure and flow in response to induced hypoxia by increasing systemic blood pressure. A second feature of the system is the fluid environment. The fetus in the extracorporeal support system demonstrates unimpeded fluid breathing and swallowing analogous to normal fetuses. This has resulted in normal lung development and maturation by histologic and functional criteria. A third feature is our improving ability to maintain a sterile amniotic fluid environment. The development of the Biobag with its closed design and antimicrobial features was a step forward and we aim to ultimately develop an entirely antibiotic free system. Finally, the ability to eliminate heparin reduced clinical concern related to hemorrhagic events. 
     Although we have applied the system to a biologically equivalent premature fetus, the 110 day fetal lamb is considerably larger (1.5-2 kg) than an extremely low birth weight premature fetus. The size equivalent fetal lamb is approximately 80 to 93 days (350 to 750 grams) and significant modifications of circuit design may be required. Antisepsis improvement is desired as well as the avoidance of conventional pharmacologic antibiotics. We have made major strides in the design of the extracorporeal support system and have seen no infection in the Biobag animals with systemic antibiotics. 
     It should be realized that extreme premature delivery is only anticipated 50% of the time. While a delivery directly from the uterus to the extracorporeal support system is the ideal, if a fetus could be briefly supported after delivery and placed onto extracorporeal support it would markedly expand application of this technology. This would of course require not only maintenance of a sterile system, but the ability to clear contamination from the system. 
     Finally, the implications of the extracorporeal support system extend beyond clinical application, and provide a model for addressing fundamental questions regarding the role of the placenta in fetal development. Long-term physiologic maintenance of a fetus amputated from the maternal-placental axis has now been achieved, making it possible to study the relative contribution of this organ to fetal maturation. The system can also be used to bridge the transition from fetal to postnatal life, which may be applied to models of congenital lung disease to expand the window of opportunity for therapeutic interventions. The extracorporeal support system therefore represents a capability that has not been previously available for research in fetal physiology, and represents a powerful new resource for numerous translational clinical applications. 
     In light of the foregoing, it should be understood that this disclosure is not limited to the particular embodiments described herein, but is intended to include all changes and modifications that are within the scope and spirit of the disclosure as set forth in the claims.