Speaker: George B. Mychaliska
Good morning, everyone. It's my pleasure to introduce our visiting speaker today. Dr. George Mieliske is the Robert Bartlett Professor of Pediatric Surgery at the University of Michigan Medical School. I'll tell you a little bit about him. He received his medical degree in Master's in Science from the University of California, San Francisco and Berkeley, before also going on to train in General Surgery Residency at UCSF. I completed a pediatric surgery fellowship at the Children's Hospital of Michigan before then joining the surgical faculty of the University of Michigan, where his focus has been rooted in prenatal diagnosis, fetal surgery, ECMO, and congenital diaphragmatic hernia. His research is based in the extracurricular life support laboratory where he has developed novel forms of extracurricular support, some of which we will hear about this morning. Also, Dr. Mieliske has also been a dedicated educator and mentor when I had just entered medical school and barely knew that pediatric surgery was a field of medicine. His creativity and patience and mentorship and guidance really sparked the inspiration for my career today. So I can't thank him enough personally for his generosity with me. So please join me in welcoming our visiting professor, Dr. Mieliske. Thank you so much, Marin, for those kind words. It's really an honor to be here. And I've given similar talks before and I want to pitch the beginning of the talk to the trainees here and on Zoom and junior faculty and talk about my journey of purpose, actually a lot of serendipity and persistence in developing an artificial placenta. So I'm going to start there and then we'll get into the science. It's not advancing. Oh, there we go. I have no financial disclosures. Much of this work was funded by the NIH. So I went to medical school at Berkeley and UCSF and I had just completed my master's thesis on the historical, sociological, and ethical aspects of the placebo effect. And I was 100% focused on becoming a primary care physician, working in public health, international health. And then literally the first day I walked into the operating room. I had an epiphany and it was very clear to me that my purpose was to become a surgeon and to have impact. Along the way, I've been extremely fortunate to have amazing mentorship and I want to spend a few minutes talking about my mentors. So first, I had the privilege of having my carousel in the father of fetal surgery who inspired me to go into pediatric surgery but also into the emerging field of fetal surgery and fetal therapy. Then later in my career, when I moved to Michigan and still to this day, Dr. Bartlett, the father of ECMO, has been an amazing mentor and supporter and Ron Hershel, who for many years was my boss and colleague and friend, really gave me the support and the space to do this work. So initially, I was completely fascinated by the idea of fetal therapy. And this was in the 80s, Dr. Harrison and some other folks, were asking the question, is treatment too late for babies that have congenital anomalies? And so he harness the intrauterine environment to treat anomalies before birth. And I'm going to show this slide. He also really inspired me to think about one disease, which will have some interesting impact on the artificial placenta. And that's congenital diaphragmatic churnia. So I've spent almost 30 years now doing basic science work, translational and clinical work, a couple of things I want to bring to your attention that will circle back to in my talk on the artificial placenta. So for example, exit to ECMO, which was pioneered here at Boston Children's with Dr. Buck Miller and Jennings, we did that for a number of years. It has some interesting parallels to the artificial placenta. It does a smooth transition from the womb to ECMO improve outcome. The other area that's very interesting is per floor carbon-induced lung growth. And this was worked pioneered by Dr. J. Wilson here, really trying to understand the principle of mechanotransduction. And postnatally or even prenatally, can you apply mechanical forces, whether it's with a balloon or with fluid, to accelerate lung growth? So those of you who know Mike Harrison, he had a very modest office at UCSF and he had one singular quote in his office and it was from Winston Churchill. Success is the ability to go from one failure to another with no loss of enthusiasm. And truthfully, as a trainee in his lab, I sort of felt like this was false modesty because I thought he was a giant in the field and basically developed an entire field that today is just expanding every day. But this was a really interesting perspective to have and something that I have certainly experienced. Dr. Bartlett, he's got a lot of quotes. But when I came to Michigan, I had previously been for a few years at Washview trying my best to do some basic science and CDH and it was actually Ron Herschel, who said you should work in Dr. Bartlett's lab. And honestly, I knew nothing about ECMO, about working in a translational lab. And so it took me actually a couple years to sort out what I was going to do. And Dr. Bartlett one day said, pick a problem, you can spend the rest of your life solving. And so here I still am trying to solve the same problem and we'll get to that shortly. So in my career, I've always been a drawn to high risk, high reward areas, but I've looked at it a little bit differently. So in clinical care, I think the principles are first do no harm in innovation, but you need to be very precise, particularly as a surgeon. And you need to take calculated risks. In a research, and this took me a while to wrap my arms around, it became really important in my view to take big risks to embrace failure, always learning from experience and never giving up. And so for me, I've really thought about especially in the last number of years, like how do you grow? Like I'm still growing and trying to learn. And for me, I've recited, and I try and impart this on my trainees that you have to embrace a certain amount of discomfort. And there needs to be some sacrifice to persevere. This is, I have, I could have many slides, but this just gives you an idea of what resilience looks like. I mean, just constantly writing grant applications, this is early in my career, I'll read one of them for you. One would expect that the investigators could clearly articulate how their proposal would allow them to move from their current level of lack of success to the level required to accomplish their specific aims. So just brutal. And, but what's also so interesting when I look back at some of these critiques, oftentimes they were right. And so it was again painful, but an opportunity to learn, to make something better, to look at it from a different perspective. And of course, you know, I think it's really important, though, I don't want this sound too grim, to have the support of family and friends. This is my favorite little quote, this is from my daughter, this many years ago. I think she was seven years old, and I was working nights, weekends, early mornings on my first R01, and she wrote, Dear Dad, good luck on your grant. I hope you get it. And if you don't, you didn't a plus job to me. So sweet. That one worked out. So I have commissioned her for additional drawings. I don't always work, but okay, last few thoughts. I'll take both in the clinical realm, but certainly in the work that I'm going to present to you, because it's going to span many years. I really want to acknowledge the incredible amount of teamwork that's involved. And believe it or not, this is Dr. Bartlett here. Of course, all of this work would not be possible without the tremendous infrastructure and mentorship that he's provided. But this is just a tiny snapshot of all the undergraduates, medical students, postdoc fellows. And just keep in mind the animal studies that I'm going to present. I will get to them in just a minute. The critical care physicians, respiratory therapists, perfusionists, taking care of these animals at 2am were undergraduate students that were sophomores, juniors who were trained in the lab. Like at 2 in the morning, that was it. So it's kind of, it's a remarkable testament, perhaps, to the science, but also to the people who put in a huge effort. And of course, this is really my pride and joy that postdoc fellows who really did all the work. I mean, just sensational. And some you will recognize Dr. Fallon, your junior fellow right now, Brian Gray, Joe Church, she just joined us at Michigan. They not only did extraordinary work, but to me, it was like the greatest pleasure to mentor many of these trainees who are now doing amazing things. So when I was in the lab, very interested in fetal therapy, I really flipped it around and thought about harnessing the intrauterine environment to treat prematurity. And the main question that I've been working on is, can we recreate fetal physiology to support extremely premature infants? It seems like a very logical thing to do. So interestingly, this idea has been around for over 60 years. When the Beatles grace the cover of Life Magazine in 1964, there was an obscure article about an artificial womb. And if you look at the schematic, this is really one aversion of the artificial placenta. So the idea has been around for some time. The progress has been episodic. And in my view, it's been due to limitations both in technology and our understanding of fetal physiology. By the way, as an aside, any Beatles fans here, I've just gone back to them. Just amazing, right? Penny Lane, Strawberry Fields Forever, Right Frog, Classics. Okay, good for the OR playlist. So historically, after the 60s, there was growth of neonatal and pediatric ECMO led by the father of ECMO, Dr. Bartlett. And there was early success for term and near term infants. And pretty much that was the space for extra corporeal support and only episodic progress in the artificial placenta. So interestingly, during my time at Michigan, this was what, 2017, we published an article looking at the ELSO registry. People had been and still are pushing the boundaries of ECLS in more premature infants. And so I'm sure you know the kind of standard criteria, 34 weeks estimated gestational age, two kilograms. And those criteria are not completely random, but we're based on prior studies looking at both size, rates of intraventricular hemorrhage. But for many years, people had been pushing the boundaries. And so we compared 29 to 33 week infants to 34-week infants. And the results, I think, are kind of interesting. Statistically, as you might imagine, the survival was different. It was 48% versus 58%. The ICH rate was not statistically different. The infarcts was a little bit higher. You can see still about 20%. So you know, it's possible to start pushing down extra corporeal support and premature infants with the knowledge that there will be some increase risks. And the survival, though, of 48% is still better than zero. So interesting to consider. And I think that's coming back into clinical work. In the last two decades, there has been accelerated progress. I'll talk mostly about development of the artificial placenta approach at Michigan. But I'll also discuss really remarkable work on the extent system from Dr. Flake at CHOP over the last 15 years. And there's also been more interest in the AV-ECLS approach, a system called EVE, which is very similar to the extent system. So looking at the clinical problem briefly is really elegans, which are defined as infants born at less than 28 weeks estimated just at the same time. And we know that the mortality and morbidity is particularly high. And I think the most important clinical point and problem to solve is that the severe complications, which are very predictable in premature infants, chronic lung disease, neurodevelopmental problems, IVH, and ECROP-Sepsis. We've seen all of that in 23, 24, 25-weeks. That is due to a combination of both organ immaturity, but also the unintended, Iatrogenic consequences of conventional postnatal therapy. So 23-weeks, 24-weeks, their lungs are not developed to a point where they can tolerate gas. It just makes sense. But obviously we do the best we can. This is a really cool slide. I borrowed from Barbara Warner, neonatologist at WashU. I just thought it was a cool slide. There have been a lot of advances in neonatal care over the decades, but still the survival and neurodevelopmental outcomes are a problem. So these graphs show data from the NICHD. You can see that over time, the survival increases, and predictably it increases with just astational age. But there's still significant morbidity. And the only thing I would say that's interesting that I've been reading about lately is there are some outliers. So for example, in Japan, in Iowa, there are cohort studies, not big NICHD data, showing pretty remarkable survival and long-term outcomes in extremely premature infants. So I think I'm not a neonatologist. I don't know if there's any in the room, but I think there's something to learn from the medical management of some groups. So again, I'm going to be focusing this talk clinically on the elegans. And I'll start out just by talking about the two different approaches before I talk about the evolution of our work. So these are schematics actually from Dr. Flake, nice pictures showing the artificial placenta approach, which is infusion through the umbilical vein drainage through the jugular, or the artificial womb or extend or what I refer to as AV ECLS approach, which is purely transambulical with infusion through the umbilical vein and drainage through the umbilical arteries. And it's a pumpless system that's driven by the fetal heart. So these are just a few other pictures. And you may have seen this lamb in a bag. Again, this is the chop groove. And I'll talk about the different approaches to airway management, but this is a simulated womb. And you can see that the cannulas are attached outside to the umbilical vessels. So when comparing these two different approaches, I'll circle back to this at the end of my talk, talking about the target population and cannulation. But for the AV ECLS transambulical approach, in my mind, it's limited to the most premature infants. And the reason is because you have you have to transition during delivery. And initially it was an exit procedure, but now it's a Caesarian delivery. So for this approach to work, it needs to be seamless from the maternal womb to the device. In the VVE ECLS or artificial placenta approach, it can be applied to all elegans. And currently the way we're thinking about it is applying this technology after postnatal risk stratification and failing ventilation. The drainage cannulas, as I've noted, are different. The umbilical artery versus the jugular vein. The infusion is the same umbilical vein. The circuit pump. Again, different, a pumpless system. It's the fetal heart driving the system versus the mechanical pump. And airway management is different. In the AV ECLS approach, it's a bio bag or will be in a human, a pod system with a submerged infant versus our approach, which is intubated with fluid filled lungs. And I will get to that. I think there's advantages and disadvantages to both approaches. The key principles, however, are very similar. So the first principle is maintaining fetal circulation. This is done in maintaining a low oxygen environment, which is normal for fetus. The absence of mechanical, sorry, the absence of mechanical ventilation, fluid filled lungs in one manner or another. And there can be different cannulation and perfusion approaches. So I could spend 20 minutes on this slide. This was at least, yeah, it was probably a decade of evolution. So I personally love the biomimetic approach. Like, let's recreate what nature does. And so that's the way we started back in the day. So this is actually the AV ECLS system. These were our early experiments. So you can see this is a lamb submerged in an amniotic bath. We had a low resistance oxygenator, no pump, and transombilical. And maybe this was a mistake, but like way back in the day, this was actually really fun to do, but complicated. I don't know if you could tell, but we did a thoracotomy. We were really trying to understand fetal physiology. So we had flow probes around the ductus, which I learned in the sheep like humans is very tenuous. So we put the animal through a lot of stress. And that may have impacted some of our results. But in our hands, we didn't solve the problem of umbilical vessel spasm. And so if you have spasm in this system, the whole circuit goes down. So obviously umbilical vessels after birth, they spasm, that's normal. And we just had continual problems. We couldn't provide long-term support. We moved to a pump-driven system. You can see it looks very complicated. A lot of stuff. It got better, but it still wasn't working great. So at this time, this was a couple years of failure after failure, which by the way, we'll just point out at lab meetings. I was completely depressed during this era in this work. And Dr. Bartlett, every lab meeting, he'd be like, this is great. Look at what we've learned. You know, we're going to do something different. And so, you know, it's actually kind of amazing because nothing was working. And but we did start thinking at this time. Okay. What is the clinical, what is the clinical application here? Are we really going to develop a system where we have no risk stratification apart from gestational age? And then place premature babies directly from the womb to this device, which has, I'm sure, you know, risks associated with it. And so we began as we were thinking about clinical application. We changed our cannulations strategy. So this was the beginning of our work on the VV ECLS model. Brian Gray did this work. He's a, did an amazing job. And you can see, we're still in this submerged environment. And so we showed that with infusion into the umbilical vein, drainage through the jugular. Excuse me. We could maintain hemodynamics, stability, gas exchange, and fetal circulation. And again, in our experience, we had two issues with the fluid. Again, I liked it. It's a biomemetic approach. That's how the fetus normally develops. They're swallowing fluid. There's lung fluid building up. It's reaching a certain pressure than it releases. And that's part of in utero lung development. But we had a lot of problems with infection. So infection was one consideration. The other consideration was clinical application. Do we really need to submerge a premature infant? Or can we effectively recreate the important fetal physiologic principles using a different approach? And so then we move to our current iteration, which is intubation with an endotracheal tube and per floor carbon. And I'll talk a little bit about that. So the vast majority of the work I'm going to show is based on about the 118-day fetal lamb model, term being 145 days. And the reason we landed on this gestational age was that they're developmentally similar to a 23-24-week human, primarily in terms of lung development. And we'll get to this a little bit later. But I'm not a veterinarian. And I learned that organs in different animals mature at different time points. That was like an aha moment. So the lung is in the same phase of development. But for example, believe it or not, the brain is much more mature. So it's not a perfect model, but it's the one that's been used worldwide. And I think recapitulates the physiology quite well. So first studies we did, this was done by Ben Breiner's cardiac surgeon at Northwestern now, is we really wanted to compare the artificial placenta to mechanical ventilation controls and really using state-of-the-art treatment. And you can see, I can't tell you how we got an oscillator in the sheep ICU, but that's a real oscillator. We used surfactant, we used everything we could. We had the head of our NICU doctor barks, was physically in the lab, resuscitating these premature lambs. And you can see they survive for just a few hours. Their lungs were just too immature. But in the artificial placenta here, they survive for a week. And a remarkable thing about this type of extra-corporeal support is that the hemodynamics are very stable. I don't know why that's happening, my apologies. And also gas exchange is very stable over a long period of time. And you can see the PCO2 stays in the fetal range. The PO2 stays in this fetal range around 40. Remember, the fetus has fetal hemoglobin, that's the normal PO2. So as we were moving along with our work, Brian Gray was in the lab. The next question that we really wanted to ask was, can we be, can fetal circulation be reinitiated? Because again, we're imagining that we're in a deliver, a baby risks stratify them, and then apply the artificial placenta. So, in this study, these premature lambs were intubated, mechanically ventilated, and when they failed, mechanical ventilation, they were transitioned to the artificial placenta, and fetal circulation was reinitiated with stable gas exchange, hemodynamics, and minimal lung trauma. So these are just a few cool videos. This is actually, I'm going to stop that for a second. This is jumping ahead to our miniaturized model. This is about a 1 kilogram mini sheep. It's a different type of sheep. We'll talk about that later, but this gives you just the general idea of the approach. This is the drainage cannula infusion, and this is an endotracheal tube filled with profloric harvain. And you can see these animals require minimal sedation. They're very comfortable. They're not moving a lot in this clip, but they do have some movements. I was trying to capture for you. This is the meniscus of profloric harvain, and frequently this meniscus moves simulating fetal breathing movement. This is a more mature lamb that's been on the artificial placenta for a couple weeks. The sweep has been turned off. There are lungs have been suctioned, and they're just breathing some supplemental oxygen. The next patient, next sheep, was on the artificial placenta for almost three weeks. You can see that the sweep is off. They're breathing room air. We've decannulated later. They do need some physical therapy. That's a separate concern, but that gives you an idea of what it looks like in the lab. The next question that we really wanted to answer is during artificial placenta support, do the organs continue along their developmental path? Because the whole point of this and one of several things that separates it from our typical application of ECMO is that during this time of support, we want these premature organs to mature, and we want them to be protected and show signs of development. I'll show you a little more data on the lungs and brain, but we looked at multiple organ systems, including the GI tract, the liver, spleen, heart, kidney. Most of our data indicated they were usually about one week, ten days, so it wasn't a super long period of time, but that the organs were protected. They weren't damaged with this type of extra-corporeal support, and they showed some signs of development going on. We did a pretty deep dive looking at lung protection and development. We did physiologic studies as well as molecular and histologic analysis. After ten days of AP support, premature lamb at 118 days, we're able to transition to mechanical ventilation, and their compliance and other respiratory markers were similar to age-match controls. Then we did a substantial amount of functional morphological and molecular data indicating that development continues, and lungs are protected from injury during AP support. We also experimented a lot with the type of fluid that is in the lungs, including mimicking amniotic fluid, and we found that intratrachial for fluorocarbon's minimized lung injury, and they promoted normal lung development compared to other types of fluid. When going back to this idea of lung management, because I think it's important, we've been thinking along the Maya principles, most advanced yet acceptable. This is actually from the matrix, but that's pretty cool. Looking at, again, the advantages and disadvantages of a submerged model versus the modified model that we use. I'll just point out that from the beginning, we were thinking back. Remember that slide on CDH that I showed, that perfloric carbons, a couple cool things about perfloric carbons. I think they're back. Recently, talk to a company who's trying to get FDA approval to use it as a lavage agent. I think we'll see it back in clinical practice. But some of our data, when we looked at lung development, when we apply the constant pressure to the perfloric carbon, it may be that that actually accelerates lung growth. Not only is that maybe has some benefit to things like CDH with hyperplastic lungs, but we may be able to accelerate the lung development by applying a certain pressure to the perfloric carbon. And also, we've been thinking about, I'm ready to do it at some time soon, that maybe the perfloric carbons will serve as a bridge with partial liquid ventilation before these animals are prepared for air breathing. And so, I'll just show this slide, this kind of random, this was a randomized controlled trial. We did in CDH patients on ECMO. So, again, this goes back to really the early scientific work of Jay Wilson showing that if you apply a pressure, even with liquid, to lungs, they don't just radiographically get bigger. They're not ballooning out, but they're actually alveolizing, so they're growing. So, it may be an approach. Our study didn't show a benefit per se compared to our controls, but there was pronounced lung growth in the CDH model. It just didn't solve the problem of pulmonary hypertension, which was always kind of the hope if the lungs grow. Maybe they'll be vascular in growth and diminution of pulmonary hypertension. So, as I showed you earlier, and you know, neurodevelopmental outcomes are poor in extremely premature infants. So, it was really important to study cerebral oxygenation and perfusion in this model. So, early studies, we used nearest monitoring, we had carotid flow probes, and we demonstrated that cerebral oxygenation and blood flow in premature lambs is maintained during AP support. And then this was something I had no idea about, but you can do, believe it or not, okay, we're getting to the elephant already. That's wrong with my slides. You can do post-mortem MRIs, and that's actually very good data on a white matter injury. So, we did that with a group at WashU, and as I mentioned before, the fetal lam model is not a good model of IVH because the terminal matrix is immature at like 70, 80 days, gestation, you can't do experiments on those lambs. But they turn out to be a very good model for white matter injury. And we didn't see white matter injury, and we saw normal cortical folding, and some other factors indicating there is some continuing lung development. Okay, the elephant in the room, and everyone doesn't believe this, but I do. I think anti-coagulation in extremely premature infants is a major problem. And this is work done by Brian Fallon, your junior fellow, just amazing. I think seminal work, not just for the artificial placenta, but for ECMO. We know that these premature infants are at high risk of intracranial hemorrhage. And the solution is local anti-coagulation. So, anti-coagulating the circuit canulas and oxygenator, but no systemic anti-coagulation. And I think this is critical not just for translation of the artificial placenta, but also for doing standard ECMO on more premature infants. It just makes sense. So, this is a busy slide here, but just want to show you this is really work that was done by Dr. Bartlett and Dr. Meierhof, now retired chemistry professor at University of Michigan. And this is a really clever biomimetic approach. It's a polymer coating. This is showing a picture of the polymer coating tubing. And the idea is that it eludes nitric oxide just like endothelial cells do, stunning the platelets as they're passing through. And we've been able to develop this coating where for several weeks it will elude nitric oxide at the same flux units as endothelial cells. So, it's really pretty cool. And then there would be a top code of our Gatraban, a direct thrombin inhibitor. And then the oxygenator can't be coated or you couldn't get gas exchange. So, what we did is just add nitric oxide to the sweet flow and coated everything else. Brian published this paper, really spectacular work, five premature labs. They survive for one week with no systemic anticoagulation. There was no bleeding or thrombosis. There was normal fetal gas exchange, hemodynamic stability, and maintenance of fetal circulation. And these truly are representative pictures of the circuit. Met hemoglobin was not too high. So, there are a lot of implications, not just for artificial placenta technology, but for standard ECMO, cardiopulmonary bypass, and indwelling catheters. So, I'm going to be moving on to the last milestones for clinical translation. Miniaturization is still a hurdle. And I think it's a hurdle for both groups. There have been some published data. Actually, the best was from the EVE group showing long-term support in a very small animal. But all of the data that I showed you and the data from the Extend system is based on that premature laminal. But those 110, 115, 118 day animals, they're two and a half, three kilograms. They're just big. And premature babies are tiny. They're less than a kilogram. So, we've been working. It's really hard to get a good model. If you go way down on gestational age in the regular sheet model, they look kind of like this. They're really difficult to work with. They're very immature in many regards. So, anyways, long story short, we've been developing this mini sheet model. So, this is about a 1 kilogram sheet. Still, it's not down to 500 grams. And there may be some limitations. I'm allowing me for two seconds to take a segue just because it's sort of interesting. As we were working on miniaturization, getting our cannula smaller, this is a few years ago, we did this interesting side project. And we were thinking, okay, can we change the cannulation entirely? Can we really simplify it? Can we use just a single lumen cannula in the jugular vein? And of course, Dr. Bartlett and Dr. Schwissenberger, that you can't see it, I can't see it. There's a paper, I think this was done on a typewriter. This is from 1980 using a very interesting type of tidal flow perfusion strategy. So, there's a single cannula in the jugular vein. And then there's a cluters on the re-infusion and drainage cannula. And I'll show you what that looks like. Let's play this. So, this shows you there's red blood going in and then the occluder's hit and then it's draining. So, it's infusing and draining. And these were done with larger cannulas, but it turns out it actually works. And we haven't really gone down that path, but we're constantly as we're coming across issues, we're experimenting with different approaches. So, getting back to miniaturization, we've worked on circuit miniaturization, cannula development, non-thrombogenic coating of miniaturized cannulas and different approaches to artificial lungs. So, we've gotten our circuit miniaturized. You can see in this schematic here, we don't know if we need it yet, but we've attached a hemofilter. And also, cannulas, the smallest cannulas that are commercially available are eight French for drainage. So, we've been working with our bioengineers. It's a really cool project, 3D printing cannulas that we can make with and we're just testing these in the animal model right now. This is an example of some of our recent experiments where able with miniaturized cannulas to get flows, approximately 100 cc per kilo per hour and we're able to maintain fetal circulation, chima dynamics, stability and fetal gas exchange. This is one animal. I will say this work has been challenging. So, going from an animal like this to an animal like this, we're learning a lot. And one thing we're learning which probably makes sense is that every little detail matters. And again, we have a 20-year-old undergraduates at 2 in the morning. Things can go wrong, but a lot of attention to detail in these little ones. This is just cool work. It's still a ways away, but our bioengineer Joe Padke is doing 3D printing, artificial lungs, very biomimetic approach that may be advantageous for the artificial placeno. I'm going to just mention that fetal hemoglobin is important and we've shown that we know this with premature infants as you transfuse blood. It's adult blood, so the percentage of fetal hemoglobin goes down. We've had to go up on our flows as the fetal hemoglobin goes down. So we're working on some other side projects. Miniaturizing is helping our priming volume is low. We give high doses of epigen. We learn this from chops. We really minimize our blood transfusions and we're working on a fetal blood bank clinically. So, in the last few minutes, I want to say a few things about a clinical translation. The approaches are different as I have alluded to. The artificial womb approach couldn't update this cool figure. It's not via exit. It's via c-section now, just to be clear. But again, it requires a seamless transition from the maternal womb to the device, because if that doesn't happen, the umbilical vessel stasem and the system goes down. So that's really critical. There are a lot of pros to that approach. There's absolutely no lung injury and there's a smooth transition. The cons are, there's very limited risk stratification apart from gestational age. And I think also there's a lot of other maternal and fetal considerations because having a c-section at for a 23-week infant requires a classical incision, has associated with more complications for that index pregnancy requires a c-section for future pregnancies. So a lot of maternal fetal considerations. In the artificial placenta approach, we're working on sort of a two-prong approach. The first would be early application after risk stratification. There may be the con, maybe mild lung injury, some baritrama from the initial resuscitation, but we also know we will not capture all the infants on day one. So it could be used as a rescue therapy later in the infants course. Again, this is actually a very cool calculator by the NICHD, but the ability to risk stratify before birth is fairly limited. Risk stratifying after birth is also complicated. So this is something that I learned you know just several years ago is that the timing of death for premature infants is really variable. And so predictably, I don't know if you can see this, for a 22-weeker, the vast majority of those that die die on day one. That's because their lungs are so immature. But if you go to a, let's go to a 24-weeker here, 25% of the deaths are on day one, but you could see that they die on very different days. So this is combining all elegans. And the question for us, and I'm going to meet with Aaron, who I don't know if you guys know, he is a master statistician. He's going to help me solve this problem. And he may, I don't say it's impossible, Aaron. Okay, please. Is can we, on the first day of life, have a model that will predict mortality? I think it's a, I don't know, it's unknown. This is unpublished, but the paper has been written, then we'll be submitting it soon. Looking at some of the neonatal, prognostic test snappy snappab that you're familiar with, we looked at those retrospectively at four hours, and we actually found that snappy two had an AUC of 0.8. So not perfect, but pretty good. We're currently in the middle of an ongoing prospective study at the University of Michigan. The problem we're running into is that survival has increased. So survival as the only metric may not be the best. And I'm thinking about doing a multi-site study to understand that better. So finishing off here, some of the key principles, our approach is utilizing the current NICU and ECMO platform with modifications. There's a lot of ethical and regulatory considerations. We don't have time to get into, but I will say this is moving to clinical translation. I participated in an FDA meeting in September of 2023, where there was a very robust discussion about artificial womb technology and clinical translation. And really, in that discussion, I thought it was a very mature discussion, it really centered around the potential risks of this unknown technology and the potential benefits. And so I think there's still a lot to learn and a lot of ethical and clinical questions about how to design a trial of safety, what are the metrics to adjudicate success in this very difficult patient population. But I think it holds a lot of promise. And I thank you for your attention. Happy to take any questions. Wow. Well, George, what an incredible body of work, which many of you are familiar with over the decades, but the way that you presented the learning lessons for people studying other things. First, and then presented your life's work. I think was impactful for many of the people here who are starting their careers trying to pick their problem. I meant to say the same thing, pick the problem and take the entire career to solve. Yeah, I mean, if I can I add one quote, I want to get this right, Dr. Jackson. So you correct me, but I came here 20 years ago looking for a job before I went to Michigan. And I met with Dr. Jackson. And he said something I've thought about quite a lot, which is if you spend time on one, I was really into CDH at the time. If you spend time on one problem, over time, you'll be an expert at it. It's really true. Well, you've embodied that. And you you credited some of your success to serendipity. It would seem to me that your greatest serendipity, which you probably wasn't totally serendipitous. You probably could through that was the amazing series of mentors that you had absolutely and recognized them to this day. And they are still interesting. I want to open up this to questions. We had almost no time. There are some questions online, but what why don't we and if you have some put up put them in the Q&A, but if there's any questions in the room. George, great overview. Regarding the options that you listed to deal with the loss of Italy, but as you may know, there's emerging gene therapy technology to induce and maintain phytohemoglobin production, postnatally actually as a means of trig sickle cell disease. And I was wondering whether that's there could be a place for that to whether you have considered that as an option here. I have it and I'm not aware of that. And it's interesting. The I will say phytohemoglobin, like I'm still learning about it. It's kind of confusing. I do understand the basic physiology of it, but there is a lot of interest. So sickle cell is interesting. And when I presented this at a fetal meeting, there were a lot of people who just think it's so much better for a variety of physiologic reasons for premature infants. Forget about the artificial placenta, but many premature infants get blood transfusions obviously for a variety of reasons. And it's actually we're finding out it's not that complicated to develop. Well, I shouldn't say that. It is complicated to develop a fetal blood bank, but the basic principles are not complicated. And you can have a tolling as blood available, but I love the idea of the genetic engineering. I had exactly the same thought as he was describing it and show how small the world is. You are standing in the building below the lab where somebody else spent their career developing their technology and just in the last 12 months is going to humans and children have been cured of sickle cell with that exact approach. We can hook you up with them. They're still working with their process. Very interesting. I want to give one question online. It is okay. We'll give a little present. First. Hi, that was awesome. Really cool. I was curious what the environment, the lamb and expected baby would be in for an artificial placenta versus an artificial room. And if you thought about how the, is it a completely sterile environment versus normal environmental exposure to various antigens and how that might impact the timing of development of the immune system and like, immuno competency versus autoimmune diseases and that kind of stuff. I mean, well, first of all, great question. And let me say one other thing that I personally, I love the diversity of approaches. And personally, I think there's going to be room for both approaches. And there's advantages. There's advantages and disadvantages of both. I mean, it is interesting. The extent system to my knowledge, I know that Dr. Flake and Chop, they have a company with a lot of money. They're developing a pod system. So the baby will literally be in a pod. And you know, again, one can think of advantages and disadvantages, right? Like, I think it's, well, I think a lot of parents would have a problem with that. And you don't have direct access to the baby, the caregivers. On the other hand, so it seems very strange. On the other hand, maybe it has some advantages. Maybe you can then create that in for you to an environment, you know, with less sound, et cetera. Do you know what I mean? Modulate that the artificial placenta would be very much like the ECMO platform. So they would be on extra corporeal support in an iSLAID with an endotracheal tube and per flora carbon. So that's something we're more used to. But are there some benefits of that womb-like environment there maybe? But I think it's going to be, it would be difficult for caregivers and families not to have that direct access. You couldn't touch the baby. In the interest of time, I think we're going to have to move on. We have a big academic day plan for you and many of the people in this room. And some of the 50 on Zoom will be joining you throughout the academic day. So I'm half of the department. I want to thank our fellows who had the wisdom to pick you as our as our visiting lecturer, visiting professor. And I want to thank you for joining us and imparting your not only your scientific and clinical wisdom, but your mentorship wisdom, which is a great pleasure. Thank you.
Click "Show Transcript" to view the full transcription (42544 characters)
Comments