Artificial Wombs Could Help Save Extremely Premature Babies

Welcome to the latest issue of the AstroFeather Tech Review!

The US Food and Drug Administration (FDA) met in late September to discuss potential clinical trials for artificial womb technology (AWT). Since then, public interest in the topic has grown, and in this issue we'll take a deep dive into a leading AWT research model and some of its competitors.

In this issue, you'll also find some helpful updates on medical AI technology (including FDA approvals and product launches) and recent implementations of AI and technology in hospital systems, including Kaiser Permanente, Mayo Clinic, and Ochsner Health.

Thanks - Adides Williams, Founder @ AstroFeather AI

In this issue's recap (15 – 20 min read time):

Update #1: Artificial wombs could help save extremely premature babies.

Update #2: Medical Tech: Product Launches, Trials, and FDA Approvals.

Update #3: Healthcare Industry News: AI and tech implementations in the hospital setting.

Update #1. Artificial wombs could help save extremely premature infants.

The latest: A US Food and Drug Administration (FDA) advisory committee recently held a two-day meeting to discuss the ethics, safety, and potential clinical trials of artificial womb technology (AWT), including the EXTEND (EXTra-uterine Environment for Neonatal Development) artificial womb system, which may one day be used to improve the survival rates of extremely premature babies.

Extremely premature babies are born at less than 28 weeks of pregnancy (often weighing less than two pounds) and face significant health risks due to the underdevelopment of vital organs. For example, because the lungs and brain do not finish developing until late in pregnancy, extremely premature babies are at risk for lifelong health problems, including breathing difficulties, developmental delays, and cerebral palsy. Notably, when extremely premature babies are born, their lungs have not developed enough to breathe air, and the simple act of breathing a gas (such as oxygen from a ventilator) damages lung development and can lead to chronic lung diseases (such as bronchopulmonary dysplasia).

To help extremely premature babies adjust outside the womb while their lungs continue to grow, researchers at the Children’s Hospital of Philadelphia developed the EXTEND system, a novel artificial womb technology that mimics the maternal uterus, is designed to nurture extremely premature babies born at 23 to 25 weeks of pregnancy, and has been tested on more than 300 premature lambs, according to Alan Flake, co-inventor of EXTEND.

How it works (Part 1) – Artificial Womb Basics

Artificial wombs represent a technological advance that is, for some, equal parts exciting, fascinating, and worrisome! To complicate matters, there is still an ongoing debate about how to refer to a human (or animal) developing in an artificial womb, although for this section I'll use the terminology "fetal neonate" (or “fetonate” as previously suggested in the literature).

The artificial womb systems that have been most successful (in the last decade or so) work by allowing the fetal neonate to continue to develop (outside of the maternal womb) in a temperature-controlled, fluid-filled, sterile environment. There, they can continue to “breathe” artificial amniotic fluid (as if they were still in the womb), with their hearts pumping blood through the umbilical cord into an external oxygenator. Thus, the artificial womb generally consists of three main components:

1. Umbilical cord interface (umbilical access): After C-section delivery, surgeons create the umbilical cord interface by inserting cannulas (flexible tubes) into the umbilical vessels of the fetal neonate, which are then connected to an oxygenator that provides oxygen. While in the artificial womb, the umbilical cord interface is the fetal neonate's lifeline, replacing the function of the original umbilical cord, including facilitating the transfer of oxygenated blood (and nutrients).

2. Pumpless oxygenator circuit: Once connected to a pumpless oxygenator, the fetal neonate's heart pumps blood through the device, where carbon dioxide is removed from the bloodstream and oxygen is added in its place. As the oxygenated blood exits the oxygenator, it re-enters the fetal neonate through the umbilical cord interface. Together, the umbilical cord interface and the pumpless oxygenator are sometimes referred to as an "artificial placenta" because the combined device system removes waste products from the fetal neonate's circulation while adding oxygen to its blood like a natural placenta.

3. Artificial amniotic sac (fluid incubation): Once blood circulation has been established through the umbilical cord interface + pumpless oxygenator system, the fetal neonate is placed in a durable container that encloses it (protecting it from the outside world) and is filled with sterile, nutrient-rich artificial amniotic fluid formulated to mimic the composition of natural uterine fluid. At this stage, the fetal neonate can continue to "breathe" "amniotic fluid" until the lungs have matured to the point where they are ready to be exposed to the outside world.

How it works (Part 2) – The EXTEND System

The EXTrauterine Environment for Neonatal Development (EXTEND) is a novel artificial womb technology that combines multiple medical devices to create an environment that closely mimics the conditions of the maternal womb. EXTEND consists of a pumpless oxygenator, an umbilical cord interface, and a “biobag” (a sealable plastic bag filled with heated, continuously circulated artificial amniotic fluid to support development). Notably, the system has primarily been tested on lambs:

1. Cesarean section delivery of lambs: Adult female sheep (ewes) are anesthetized and during surgery an incision is made in the lower part of the abdomen (midline laparotomy) to access the uterus, followed by another incision in the uterus itself (hysterotomy) to expose the umbilical cord of the fetal lamb.

2. Umbilical cord interface (umbilical access): The surrounding umbilical tissue is then cut away to expose the umbilical vessels. Specially designed cannulas are then inserted into two umbilical arteries and one umbilical vein and secured in place with sutures. The technique maintains approximately 5-10 cm of natural umbilical cord between the tips of the cannula and the abdominal wall. The fetal lamb cannulas are then connected to an external oxygenator circuit.

3. Pumpless oxygenator circuit: The EXTEND model uses a pumpless arterio-venous (AV) circuit powered by the fetal heart and includes a hollow-fiber membrane oxygenator that works by circulating blood outside the body through a series of membranes to add oxygen and remove carbon dioxide. The oxygenator's inflow and outflow tubes are coated with heparin (to prevent clot formation), the system is primed with heparinized maternal blood, and sweep gas (a blended mixture of medical air, nitrogen, and oxygen) is supplied to the oxygenator.

4. Artificial amniotic sac (fluid incubation): After the umbilical cord is connected to the external oxygenator, the fetal lambs are placed in a biobag, which is then sealed and filled with sterile artificial amniotic fluid that is maintained at a pH, temperature, and electrolyte concentration (of sodium, potassium, bicarbonates, and chloride) similar to natural amniotic fluid. Notably, the EXTEND system ensures that the biobag has a continuous flow of fresh artificial amniotic fluid (through continuous exchange) to maintain a sterile fluid environment.

5. Nutrition and medication: Fetal lambs receive nutritional supplements consisting of dextrose and amino acids (with supplemental lipids, iron, and electrolytes). They are also infused with heparin and transfused with maternal blood as needed (to maintain fetal hemoglobin levels).

Aside: If you'd like to see the the EXTEND system in action, then I recommend the following videos:

• Insider Tech's coverage [YouTube video here]

• Great overview from the EXTEND team [YouTube video here]

Results

By several measures, including research results, venture capital funding, and early feedback from the FDA, the EXTEND system represents a significant improvement in artificial womb technology (AWT). While several labs around the world are working to develop AWTs, according to an article in Nature, researchers have stated that the EXTEND system is "probably the closest to human trials," a sentiment likely shared by the FDA, given the agency's willingness to include the EXTEND system in its two-day discussion of potential clinical trials of AWTs:

Research studies: Since the landmark first publication of the EXTEND system, it has been extensively reviewed and studied. In general, fetal lambs, whose lungs had developed to the equivalent of an extremely premature human infant at approximately 23 weeks, grew in the EXTEND artificial womb system for 20-28 days and appeared to be comfortable, exhibiting normal sleep/wake cycles and intermittent breathing and swallowing! After this roughly 4-week period, the lambs were euthanized to study their organ development and were found to have lung and brain growth similar to normal lambs:

• Lung development and growth: The lungs of fetal lambs on the EXTEND system progressed normally from an early stage of lung development (canalicular phase) to a more advanced stage (saccular phase), just like control lambs of the same age. This lung progression did not require corticosteroids (known to help fetal lung maturation) or tracheal occlusion (a surgical technique that blocks the trachea - "windpipe" - leading to an accumulation of fluid in the lungs, which in turn causes the lungs to stretch and mature). After removal from the system, they were able to breathe almost as well as control lambs delivered by C-section (at 141 days of gestation).

• Brain development and growth: The brains of fetal lambs were examined while they were in the EXTEND system and after removal. While in the artificial womb system, evaluation showed that brain development was normal with no white matter injury or signs of bleeding inside the skull (intracranial hemorrhaging). Signs of brain development were also evident in the regular patterns of sleep and wakefulness as measured by a technique that records the activity of the extraocular muscles responsible for eye movement (ocular electromyography). Post-mortem analysis of lambs developed in the EXTEND system also showed normal brain structure. Other indicators of brain growth, including thickness of brain folds (gyral thickness) and skull size (biparietal diameter), were also similar to the control group.

• Heart development: In a separate study, a temporary decrease in the heart's ability to contract and pump blood (cardiac contractility) was observed in fetal lambs within the first week of exposure to the EXTEND system. Although normal heart function and strength resumed and persisted for the duration of the experiment after this adjustment period, the researchers emphasize that further study is needed. Finally, in another study, fetal lambs supported by the EXTEND system for 19-25 days showed no signs of heart damage (myocardial injury) or inflammation, and heart development and structure were normal compared to lambs of the same age that were not part of the study.

FDA approval status: The FDA has not yet approved the EXTEND technology, although the agency has designated the system as a "breakthrough therapy," according to a report in the Wall Street Journal. As noted above, the EXTEND was also one of the AWTs recently discussed by the FDA when considering potential clinical trials for the technology.

Venture capital funding status: In 2019, several members of the EXTEND research team joined the Philadelphia startup Vitara Biomedical, which has since raised $100 million (including a $75 million Series B funding round led by Spark Ventures in 2022).

Yes, but...

The EXTEND system has undoubtedly been used successfully to develop animal fetuses in the laboratory. However, now that the FDA is seriously considering the possibility of first-in-human clinical trials, there are several concerns about using the technology to help extremely premature human babies:

• C-section delivery: The EXTEND system requires C-section delivery because the physiological changes that occur in the baby during natural birth (including closure of the umbilical arteries) make it difficult to safely cannulate the umbilical vessels and transfer the baby to an artificial uterus for further development. However, there are several non-trivial risks to a pregnant woman (including infection and increased blood loss) that must be considered with elective C-sections.

• Artificial amniotic fluid: A hallmark of the EXTEND system is its closed fluid environment with continuous exchange of artificial amniotic fluid, which has many advantages, including preserving the ability of the fetal neonate to inhale and swallow "amniotic fluid" to promote lung and intestinal growth. However, there is a need to improve the simple electrolyte solution used in the EXTEND system so that its functionality and composition mimics that of natural amniotic fluid (which contains important growth promoting and nutritional factors).

• Medication risks: According to current published research on the EXTEND system, the developing fetal neonate is exposed to several medications, including those designed to prevent blood clotting (heparin) and maintain circulation (prostaglandin E1, PGE1). Close monitoring of these medications is critical because of the potential risks associated with long-term exposure, including bleeding inside the skull (intracranial hemorrhage) from anticoagulants and low blood potassium (hypokalemia) or low blood pressure (hypotension) from PGE1.

• Nutrition: In the EXTEND system, fetal neonates receive all their nutrition directly through the veins and into the bloodstream, bypassing the digestive system (an intravenous process known as total parenteral nutrition - TPN). However, there is concern that prolonged exposure to TPN may increase the risk of developing TPN-associated cholestasis (a condition in which bile (digestive fluid) doesn't flow properly from the liver, leading to various complications, including liver failure).

Behind the news

Research on artificial wombs and (closely related) artificial placentas has been ongoing since the 1960s. More recently, laboratories around the world (including the US, Spain, Canada, Japan, and Australia) have been working towards developing clinically relevant artificial wombs that could one day be used for human babies. While the EXTEND model (from the Children's Hospital of Philadelphia) and the venous-venous extracorporeal life support (VV ECLS) model (from the University of Michigan) are well known, I wanted to highlight one other noteworthy AWT:

Exo-vivo Uterine Environment (EVE): The EVE therapy model was developed in collaboration between Tohoku University (Sendai, Japan) and the University of Western Australia (Perth, Australia) and has been used to support premature fetal lambs (112 - 115 days gestation) and extremely premature fetal lambs (95 days gestation). On average, premature lambs have survived 7 days on the EVE model and extremely premature lambs have survived approximately 5 days, albeit with evidence of brain damage due to technical issues. The design of the EVE model is similar to the EXTEND model and can be roughly described as follows:

• Umbilical cord interface (umbilical access): After C-section delivery, fetal lambs are subjected to (intra-abdominal) cannulation of two umbilical arteries and one umbilical vein. The fetal lamb cannulas are then connected to an external oxygenator system.

• Oxygenator circuit: The EVE model uses a pumpless arterio-venous (AV) circuit with two hollow-fiber membrane oxygenators in parallel orientation to circulate oxygenated blood. The inflow and outflow tubes are coated with heparin (to prevent clot formation), and the system is primed with heparinized maternal blood.

• Artificial amniotic sac (fluid incubation): After the umbilical cord is connected to an external oxygenator, the fetal lambs are completely immersed in sterile artificial amniotic fluid that is maintained at a pH, temperature, and electrolyte concentration similar to that of the Merino sheep. Notably, the artificial amniotic fluid in the EVE system is recirculated (reused after filtration and sterilization) and is completely replaced only every 6 hours.

• Nutrition and medication: Nutrient supplementation (including glucose, amino acids, and lipids) is administered via a catharized fetal jugular vein. Fetal lambs are also treated with heparin (to prevent blood clots) and corticosteroids to stimulate lung maturation, suppress inflammation, and prevent hypotension.

Why it matters

Artificial wombs have been the subject of literary speculation and ethical debate in the developed world for at least a century. In 1923, the English biologist J.B.S. Haldane gave a lecture at Cambridge University entitled "Daedalus, or, Science and the Future," which is considered the first extended discussion of the subject, and tells the story of two scientists who removed the ovaries of a woman who had died in a plane crash, fertilized her eggs, and successfully grew embryos in a "suitable fluid" for nine months before bringing them "out in the air" (a process Haldane called "ectogenesis").

While feminists like Dora Russell defended the idea of ectogenesis (1925), believing it could free women from the physical and social constraints of pregnancy and childbirth, others like science fiction writer Aldous Huxley offered a dystopian take on the process in Brave New World (1932), depicting a world of hatcheries and lab-grown humans specifically engineered to meet society's desires. Since then, depictions of the artificial womb have often signaled an irrevocable departure from nature, such as the "axolotl tanks" in Frank Herbert's Dune Messiah (1969), "uterine replicators" in the Vorkosigan Saga (1986 – 2018), and "the pods" in the Matrix films (1999 – 2003, 2021).

In contrast to these often grim depictions of artificial wombs, steady technological advances since the 1960s and culminating in the artificial womb systems discussed in the stories above (including the EXTEND and EVE systems) have moved artificial wombs from literary speculation to a near medical reality that could one day be used to save the lives of extremely premature babies worldwide.

Each year, an estimated 13.4 million infants worldwide are born prematurely (before 37 weeks) (indicating a global preterm birth rate of about 10% (based on roughly 134 million live births)), and roughly 900,000 will die before the age of five due to preterm birth-related complications. According to the CDC, in 2021 there were 384,000 preterm births in the US (about 10.5% of an estimated 3.66 million live births) and 65% of all infant deaths were preterm. However, while extremely preterm infants represent only 0.6% of all live births in the US, they account for 40% of all infant deaths. Finally, the estimated economic burden of preterm birth in the US (alone) is substantial at $25.2 billion to $26.2 billion.

It's clear that despite advances in neonatal intensive care practices, extreme prematurity remains a leading cause of infant death and related long-term health problems, a major driver of the economic burden associated with preterm birth, and an unsolved clinical problem. An artificial womb system that could help extremely premature babies further develop until they are truly ready to face the world would be revolutionary, resulting in more infant lives saved with a reduced risk of developing lifelong health complications.

Update #2. Medical Tech: Product Launches, Trials, and FDA Approvals.

Exo launched its Iris handheld ultrasound device, which uses AI to improve diagnostic imaging: The Iris handheld ultrasound connects to a smartphone and is designed to replace traditional cart-based ultrasound machines. It incorporates Exo's AI technology, including SweepAI, which captures high-quality scans as the probe sweeps across a patient's body. The device also includes FDA-cleared AI algorithms for calculating bladder volume, as well as AI tools for detecting hip dysplasia and assessing thyroid nodules.

Atropos Health launched its Geneva OS (Generative Operating System) and ChatRWD (Real World Data) application: Geneva OS uses natural language processing and generative AI to quickly query real-world clinical data and can help users create publication-quality observational research studies based on Atropos' 160 million deidentified patient records. The ChatRWD interface allows users to quickly search those same patient records by asking questions in plain language and receiving suggestions for refining queries.

Anumana (a joint venture between the Mayo Clinic and Nference) has received its first FDA 510(k) clearance for its ECG-AI LEF algorithm: The algorithm analyzes electrocardiogram (ECG) scans to detect signs of low ejection fraction in patients at risk for heart failure. Low ejection fraction is a condition in which the heart's left ventricle does not pump enough blood with each contraction, and Anumana's AI tools aim to replace the traditional method of using ultrasound (echocardiogram) to diagnose the condition.

Hint Health is collaborating with OpenAI to develop an AI transcribing tool: The product, called Hint AI, will allow direct primary care (DPC) providers to record patient consultations, transcribe them, and automatically generate clinical documentation in patients' medical records, saving significant time for physicians. Hint Health also plans to incorporate AI capabilities throughout its platform, including using a HIPAA-compliant tool to query medical history, generate referrals and identify patterns in patient conditions.

Rockley Photonics aims to develop a wearable, noninvasive glucose sensor for medical applications: Rockley's glucose sensor has shown promising results in two studies. The first study involved a simulated tissue model, while the second study involved 40 participants with type 1 or type 2 diabetes over a 10-week period. The results demonstrated that Rockley's biosensor, which utilizes short wavelength infrared spectroscopy technology in its miniaturized photonic integrated circuit chips, can accurately measure glucose levels to within 5 mg/dL. This accuracy exceeds current ISO standards for glucose measurement.

Onward Medical has successfully implanted the first human with a combined system that aims to restore movement in the arms, hands, and fingers following a spinal cord injury: The system consists of the ARC-IM spinal cord stimulator and a wireless brain-computer interface (BCI). The BCI collects neurological signals, which are then translated into actions by a software program and transmitted to the ARC-IM device. This stimulates the nerves to produce the desired movement.

Update #3. Healthcare Industry News: AI and tech implementations in the hospital setting

Kaiser Permanente partners with Nabla AI: Healthcare giant Kaiser Permanente has struck a deal with AI healthcare startup Nabla to provide its doctors and clinicians with an AI assistant. The AI assistant, called Copilot, aims to reduce administrative tasks like notetaking for physicians by transcribing conversations and generating documents. In a pilot study, physicians using Copilot saved 1.5 hours of administrative time. The service will initially be rolled out to physicians at The Permanente Medical Group (TPMG) in Northern California.

Mercy partners with Microsoft: Mercy, a multi-state healthcare system, is working with Microsoft to integrate the Azure OpenAI service into Mercy's offerings. Microsoft's generative AI services will help patients understand lab results, schedule appointments, and answer healthcare-related questions. Mercy employees will have access to a chatbot (ChatGPT or GPT-4) that can provide information about the health system's policies, procedures, and HR-related inquiries. 

Mayo Clinic partners with Microsoft: Mayo Clinic is among the first to deploy Microsoft 365 Copilot, a generative AI service that combines large language models (LLMs) with Microsoft 365 data to improve productivity. By using Copilot, Mayo Clinic aims to automate tasks such as filling out forms, freeing healthcare providers from administrative tasks and allowing them to focus more on patient care. Notably, this news follows Mayo Clinic’s earlier collaboration with Google Cloud to test its medical chatbot, Med-PaLM , in a clinical setting.  

UPMC partners with Abridge: University of Pittsburgh Medical Center (UPMC) an AI-based solution called Abridge to reduce physician burnout and improve patient care. Abridge listens and takes notes during patient visits, then integrates the clinical note into the patient's electronic health record (EHR), saving providers an average of two hours per day hours of administrative work. Abridge enables providers to create real-time, structured summaries of conversations with patients, providing accurate care plans and reminders. 

Ochsner Health partners with Microsoft: Ochsner Health has launched a pilot program using AI to draft messages to patients on the MyOchsner app portal. The program is designed to improve response times and enable doctors to focus more on patient care. The feature, which uses Microsoft's Azure OpenAI service, drafts responses to routine patient requests, which are then reviewed and edited by physicians. Approximately 100 Ochsner clinicians will participate in the first phase of the pilot, testing simple messages that are not related to diagnoses or clinical judgments.

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Adides Williams, Founder @ AstroFeather (astrofeather.com)