Artificial uterus -research background to improve survival and outcome of extremely low birth weight newborns

An estimated 15 million babies a year, are born preterm, before 37 completed weeks of gestation; one million die from complications and have signifi cant contributor to childhood morbidity, both related to this condition; unfortunately, this data are bound to increase. Preterm birth is the most common cause of death among infants worldwide, is defi ned, by the World Health Organization (WHO) as delivery before 37 weeks of pregnancy are completed and is the second leading cause of death globally for children under fi ve years, after pneumonia [1].


Introduction
An estimated 15 million babies a year, are born preterm, before 37 completed weeks of gestation; one million die from complications and have signifi cant contributor to childhood morbidity, both related to this condition; unfortunately, this data are bound to increase. Preterm birth is the most common cause of death among infants worldwide, is defi ned, by the World Health Organization (WHO) as delivery before 37 weeks of pregnancy are completed and is the second leading cause of death globally for children under fi ve years, after pneumonia [1].
There are three sub-categories of preterm babies, based on gestational age: extremely preterm (less than 28 weeks) (Figure of the premature and extremely premature newborn, including new approaches to the old nemesis of bronchopulmonary dysplasia [2], which still affects up to 50% of infants born before 28 weeks' gestation; moreover prematurity has profound consequences for the course of cardiovascular, metabolic, neurological, and pulmonary diseases throughout life [3]. The studies of an artifi cial medical technology will be focused to emulate the conditions inside the maternal uterus, which is able to incubate preterm borned human fetuses, and prevent the serious morbidity that occurs in extremely premature babies, by recreating an artifi cial womb. The last years have seen signifi cant advances in making an artifi cial uterus that could have facilitated the survival and growth of prematurely born animal fetuses starting around 23-24 weeks of gestation; also according to ethical considerations [4,5], this gestational age is the current goal of "fetal viability" , the point at which a fetus has a chance of survival outside the womb, although morbidity and mortality for premature babies born before approximately 28 weeks of gestation remain high. Elizabeth Chloe Romanis, a lawyer at the University of Manchester, who has explored the bioethics of artifi cial wombs, warned that the technology would raise questions, including about which babies it should be tested on, as well as the long-term implications of being gestated in an artifi cial womb ( the law would approach foetuses and babies differently ), adding that there are also questions about how such a gestation might be viewed by society, particularly if it becomes an alternative to a "natural" pregnancy. It is clear that the legal and ethical issues emerging from the technology must be talked about now, in advance of the artifi cial womb becoming a reality [4,5]. The artifi cial uterus, as a medical assistive device, which should be ready for human trials within the next fi ve years, according to current scientists's target in the Netherlands, is an innovative project in that, instead of being an emergency life support, it treats the preterm infant as an unborn fetus [6]. This incredible plan, science fi ction for someone, is aimed at building an environment similar to the uterus's physiology, surrounding the extremely premature baby in artifi cial amniotic fl uid allowing the immature organs to develop as if they remained inside the mother's body. If successful, this technology could signifi cantly improve health outcomes for infants and perhaps ultimately be committed to supporting the health of pregnant people who have major complications from previous medical conditions or associated with pregnancy itself. This technology could then also be integrated by further ultrasound evaluations, with future customized protocols based on the new vascular resistences, already known and applied for decades [7,8], that could help clinicians in controlling infants inside the artifi cial womb, both in growth and in hemodynamics, in the various districts that are usually monitored, during the stay of the fetus, who requiring intensive surveillance, in the mother's uterus.

Study of the foetus in uterus by Leonardo da Vinci
From "Anatomy notebooks" , created thanks to autopsy studies, in Milano from 1509 to 1512, Leonardo da Vinci began to examine (since 1507, with the collaboration of Marcantonio della Torre ) "the fetus in uterus" giving a fundamental innovative contribution, unchanched for over two centuries : in particular, in 18 sheet (Figure 2), the correct position of the fetus in uterus, uterine artery and vascular system of cervixvagina, was draw with incredible precision, for the fi rst time in the history of medicine and the fetal physiology ( the fetus immersed in the amniotic fl uid that does not breath because he would drown ), are touched upon the notes . For the fi rst time, uterus had only one cavity, contrary to its seven chambers as Guido da Vigevano illustrated and contrary to Hippocrates theory that predicted its two cavities; instead, the placenta was from a cow [9,10,11]. Furthermore, Leonardo hypothesized that umbilical cord carried the urine of the fetus out of the uterus, and carried into the fetus the maternal blood.

Ectogenesis
Scientists believe that ectogenesis ( creating life ouside the body ) is not far off and many of them argue that it is an inevitable technology. In 1924, John Burdon Sanderson Haldane, a british scientist known for his works in physiology, biology and genetics, conied ectogenesis ( from the greek ecto, "outer", and genesis, "generation" ), thinking the growth of an organism outside the body through an artifi cial womb. The evolutionary scientist imagined that artifi cial womb might become popular by 2074 ( that only a small minority-fewer than 30% of newborn-would be born of woman) [12]. The ectogenesis's idea had already started in 1880, by the french obstetrician Etienne Stephane Tarnier, who built a wooden box, with a compartment for a hot-water box, to reduce the mortality of premature babies [13,14]; his design did not become much more technologically until the 1950. By the 1960, was opened the fi rst Amenican newborn intensive care unit, designed by Louis Gluck [15]; the experiments began on incubators ( which provide warmth and humidity, but none of the nutrients necessary for newborn growth ) and also attempted the creation of an artifi cial placenta, a complex specialized organ that should provide life support until a foetus develops to a stage where he is able to perform these function placenta; instead, of course, in the incubator, a premature baby must have tubes inserted into his body to deliver nutrition via needle-like catheters inserted directly into the veins; they will also be sedated, at least some of the time, to stop from pulling inserted tubes out, and to decrease or prevent any discomfort or pain.

Preterm delivery
Preterm birth is commonly defi ned as any birth before 37 weeks completed weeks of gestation; an estimated 15 million infants are born preterm, globally [1]. premature infants suffer from mortality and morbidity leads research to create new ways of approaching this patients [19].

Artifi cial uterus
The fi rst patent , for an illustration of an artifi cial uterus, was issued, in 1955 [20,21], to Greenberg who had started to study and write about its potential use in the future. Greenberg's design ( Figure 3) included a tank to place the fetus fi lled with amniotic fl uid, a machine connecting to the umbilical cord, blood pumps, an artifi cial kidney, and a water heater. Cooper William, also had his US patent [22], in 1993, for another life support system for a premature baby which remains attached to its placenta through its umbilical cord: the system includes upper and lower chambers separated by a dome-like partition.
The lower chamber contains physiological liquid in which the baby is suspended, and the upper chamber contains an oxygen-containing atmosphere and a supply of nutrients for contact with the placenta which rests on the top of the domelike partition. Already before, in 1987, Kuwabara Y, in Tokyo's Juntendo University, and his staff , was the fi rst scientist to sustain in an artifi cial womb for that long; a new extra-uterine incubation system has been developed using 14 goat fetuses.
The goat fetus is surrounded by artifi cial amniotic fl uid and is connected to an extracorporeal membrane oxygenator [23,24].
The blood is drained from the umbilical arteries and returned to the umbilical vein. They developed a technique called Extra Uterine Fetal Incubation (EUFI), which successfully supported a 17 weeks goat fetus, for three weeks; EUFI is described as a rectangular transparent plastic box, fi lled with artifi cial amniotic fl uid at body temperature, connected to devices for vital functions ; the blood was cleaned with a dialysis machine connected to the umbilical cord; next step was suggested for fetal monitoring after extracted from EUFI. In 2017, US scientists from the Center for Fetal Research of Philadelphia [25], developed an artifi cial device, also called extra-uterine life support system, closely reproduces the environment of the womb; Director Flake, and his group, that kept alive extremely premature lamb fetuses (Figure 4), with biological age equivalent to a human fetus of 24 weeks of gestation, for four weeks, creating a fl uid environment from a polyethylene bag, Biobag, which incorporated an oxygen pumpless circuit, in which blood fl ow is driven exclusively by the fetal heart with a very low resistance, closely mimic the normal fetal-placental circulation, in which lambs maintained a stable circulation of blood and gas. This study was limited for four weeks, aiming at maintaining stable conditions between 23 and 28 weeks of gestation ( barrier period for the premature infants ) and indicated a greater survival of premature lambs, thanks to a bridging system between maternal uterus and extra uterine life. The animals were able to develop brain and lungs for four weeks; during this time they were able to move, open the eyes and swallow. However there were technical diffi culties related to the connection via the umbilical cord and the creation of a suitable amniotic fl uid. The researchers' s objective will therefore be to improve the system and to adapt it to a human newborn, even, Director Flake said, "friendly to the parents" [25]. , it will require the contribution of different technologies. Their goal will be to help extremely premature babies get through the critical period of 24 to 28 weeks.

Conclusions
In the fi eld of human fetal, perinatal and postnatal surveillance, the study of an artifi cial uterus will improve the outcome and the chances for survival of extremely low birth weight foetuses born before 28 weeks of gestation; if successful, it could a breakthrough. At the moment, for decades, scientists worldwide, have clinical and instrumental control systems, in order to check the normal and risk pregnancy to check the fetal well-being; in particular, fetal and maternal ultrasound studies, helps also in managing the timing of delivery becoming sophisticated and with high diagnostic value and, probably, could be integrated into the monitoring of the preterm infant incubated in a PLS system (probably). That device could save millions of babies who die due to premature births; with  PLS solution, the supply of oxygen and nutrients, connected by an artifi cial placenta, will support fetal cardiorespiratory physiology and will avoid the negative effects of air-based ventilation. Artifi cial uterus and artifi cial placenta will be similar to biological conditions.