 So we're going to talk about the challenges that the researchers face in evaluating the mechanically sort of MCAS and pro-artificial heart. Obviously, as soon as you find out, don't put them in the human being, you've got to test them out. And the challenges that they have downstairs, I call it downstairs because it's in the dungeon, left. I have no disclosure. I have nothing to disclose on it. Besides, I prompt a few by the core and I am a little biased about that. And there were no humans harmed in the experiment with this. So mainly we're going to talk about bovine. You can know what bovine is, but we're also going to talk about why bovine, before we talk about bovine themselves for the MCAS and the pro-artificial hearts. In the labs, we have animal labs. All kind of testing is being done on all kind of animals, including the mice, the hamsters, pigs, ships, and bovine. Ideally speaking, swine would be the most resembling the human anatomy for testing the MCAS and the pro-artificial hearts. Overall size and precision of the organs are most resembling human beings. CES cavities is just about human size. Horizontal makes human-like incisions, operations. Anatomically, they are pretty much where they are in human beings. So it makes it very easy for them to work. As you can see, the planes are very similar. The heart are very, very similar, except maybe the ascending area is a little bit bigger, a little bit longer in the pig heart than the human. But other than that, it's just a fantastic match. Why are we not using pigs for the MCAS and the mechanical pro-artificial heart? Because they are very energetic. They don't listen to you when they're on the pig. They don't behave very aggressive. They don't like anything sticking out of their body. They will attack the catheters and eat up chew up the control cables. They grow very fast, if you didn't know. And that could be a problem for mechanical circularity support devices, because normally they are designed for human being. And they're flowing maybe five, 10 liters at the most. But if you have very big animal model, it may require much higher flows, they will make a very good subject matter if you have to implant something like a valve or something like that, and nothing coming out of it. And they probably make a very good test model. Seeps are very identical to human anatomy as well. They are very docile. They are smart. The problem is they're very shocked, very easily. The tissues are very fragile. Dr. Cohn used to say that you can literally shouted a ship and shock it to death. They break a leg and they'll have a heart attack just because they broke a leg. So we come to cows. Cows is human test models for vets. The vets, what's good for bovine, they're very docile, easy to handle. They have endetical blood rheology. The blood, RBCs, WBCs, and places are pretty much very similar to the human being. So you know, if that device is going to create a problem with the RBCs, we'll know it for a cent. The robust immune system, just like the human being, is this breed, parenter breed, has limited growth. So for the span of the device testing, they grow, but they don't grow too much. Too much to handle. The problem with the biggest problem, however, is with bovine is the fully developed coagulation systems. So that's a major drawback. And it just pauses the challenge for anti-goagulation management. Normally, people use committing for anti-goagulations. It's not suitable for bovine because the committing is metabolized in stomach. Anti-platelets don't work on cow's platelets. So we mostly use heparin. And INR is pretty much a standard test for that. The other problem is bovines are multi-gastrate, as we know. On its own, it's not a problem. But the rumination, and they have four stomachs, that requires very huge percentage of the cardiac output. And any ischemia, any infarct in the stomach will be detrimental for the cow because the cows don't know that their stomachs don't work. They just keep eating and eating and they don't ruminate if the stomach is infarcted or dead. They just literally keep eating and you think that it's fine for a few days until they just die. There's no turning back once you have infarctation in the cow stomach. So other problem is we know the cows are big, the big chest. Stenotomy has not been used commonly for, especially for vets, on the Thoracotomy river sections and you put a bed in it and that's weird because the cow normally sits on the chest. So if you have an open chest and the wires and everything else, you may have problem. But as far as the total artificial heart goes, stenotomy is probably the best in the Thoracotomy. It does not work very well with the anatomical structures and the way you have to make anastomosis to the vessels. So they tried here to do the stenotomy for the total artificial heart and so far it has worked very well. The heart anatomy itself is very similar to human being. As you can see all the inlets and outlets, the atrius and the pulmonary artery and aorta are pretty much where the human beings are. So it makes very easy or semi-easy to anastomose, the right atrium and the left atrium and also the pulmonary artery and the aorta. The other big problem is they have very small aorta. They branch out as soon as the aorta comes out, they already have a heart, they branch out in the big bronchocephalic trunk and the descending. So you barely have enough room to cannulate and cross-clamp and have enough aorta to connect to the graft of the total artificial heart. As you can see here, the common bicephalic trunk is very, very big and you can barely see the arch of the aorta and the left subclavian. So basically you have maybe three centimeters or four centimeters at the most to work with and you barely have enough aorta after that. The most common breed that they're used in the US is Corriente, they're a very small hearty breed. They're a breed bred for the sport and roping. Six months about, they weigh about 80 to 100 kilo. They're a strong, slow-growing breed. Like I said, the weight gain in 30 to 90 days is much less than the other breed which is hand-handled because the vagant artificial hearts are designed for human, normally you don't have any more than five to 10 liters per minute capacity of the device. So the other problem with the research in any animals is the actual disease to cause an actual disease into the heart, like for total artificial heart or for vets, you need a ventricle that is disease. The ventricle is not robust. It's very hard to create that in calves. It has regenerate very, very fast. You can give them a ischemia, you can give them a coronary heart attack and they'll recover very fast. You can do damage to the heart itself and then you wait for a few days and they will recover themselves and they'll go back to what they were. The problem was emphasized in the trials of Heartmaid II. Heartmaid II is all the tests, subjects, all the models, all the tests that were done in the research lab on cows were worked very, very well. They were worked as intended. And the first trial in human was done in Europe and they put 12 Heartmaid IIs, 11 of them developed thrombus and in the pump and the diet. So, needless to say, it was almost shelved. It was almost about, they were about to next the project. Well, going back, Heartmaid I had evolved to have a really rough surface inside of a silicone and Steve can tell you about that more. Silicone with rough surface and it would grow a pseudointimal or neoepidermis layer on it. That required very little anti-coagulation in human being. So, obviously the Heartmaid II was also evolved to have rough surfaces in it. Well, there was there, rough surfaces all of them. All 11 that died had thrombus at the bearing on the pump. None of the test subject had no issues with the thrombus at the bearing. There was no indication of any kind of bearing problems. What was the problem? The problem was the heart was very healthy. So, even with the machine, the heart was actually creating every sisterly was very robust, very high flow through the machine. And that kept continuous washing of any possible plot or it didn't even allow to develop the plot. So, the ball bearings were smoothed out and the material was changed. And after that, there were more tests were run. And as we know, Heartmaid II is probably, not probably the most implemented at the time, still is. As far as the bypass stuff goes on the calf, bi-caval Venus, Venus, we used to do double arterial, bi-caval arterial because of the issues with the clamp and remaining aorta. But recently they have figured out a way and they're working on doing just one aorta cannula. So, last few cows we've done, we've done with the one aorta cannula. And we stay warm-ish because they like to come off at 838, 39 degrees centigrade before we go to ICU. Blood pressure 70, 80, 85 flow more than 55 per kilo. So, how do they do in post-op management for, these are for bi-cavalers now, to artificial heart. What do they look for? They look for obviously the aortic pressure, the right atrial pressure, left atrial pressure, pulmonary artery pressure, CVP. And also they look at the systemic and pulmonary vascular resistance that's continuous all the time for first few days. The other parameters are for the unit itself, is right and left flow because this machine, this device has only one moving part, only one motor. You want to know that motor speed and impeller position, the impeller also the position of the impeller, axle position of the impeller can move left or right and that will change the flow dynamics on both side left and right, depending upon where the impeller is and it's automatically controlled. So, you want to know the impeller position also, obviously you want to know how much power and how much current it needs because that will determine the resistance to flow. The other big problem I did not realize until I looked into this is the brain netiuretic peptide. BNP is produced by cardiomyocytes in the ventricle. And it is a response to cardiac stress and ischemia. This plays very important role in the cardiorenal protection. So, if you don't have the ventricle or no cardiomyocytes, no BNP, the kidneys go haywire and kidneys really don't work very well. So, they're continuously treated with LASIX. As we know, LASIX will remove more potassium. So, there's always a potassium chloride and it's large amount, 480 molecular times eight hours for 24 hours. Hypertonic sodium chloride also required because as you can see, the BNP, if you don't have BNP, the sodium reabsorption in the distal and the proximal loop is increased, meaning it will excrete more sodium and you will have hyponatremic cal. So, they also gave hypotonic sodium chloride all the time. Obviously, manatell as well. And as you know, a cal needs lots and lots of waters. You have to make sure they drink very well. You have to notice, you have to pattern. You have to see the pattern if they're drinking where they're about because they're not gonna complain. They don't complain they're in pain. They don't complain they're hungry. They don't complain they're drunk. They just eat and drink all the time. So, what are the observations that you need to make? Obviously, ruminating cal is the best cal. The calves don't ruminate, nobody gets to sleep in the ICU. Obviously, the calves awake, it's gonna eat. Urination, defecation, if they're sitting well, they're standing well, left to right chest sounds to see if there were any pulmonary issues. Like I said, no rumination is a big, big problem. You have to make sure water intake is enough. As far as lab goes, PTINR, VW Factor, because mechanical devices, plasma-free hemoglobin also, because you don't want to chew up all the herbises, ABGs, hematocrit, electrolyzed. I think they use I-STED at the lab. Why don't they use I-STED? That's such a specific one. No, please. Why don't they use I-STED? Have no tests on a cal. Yeah. Thank you. So the Bible court is designed to increase the output as the demand increases. So this particular model was, this particular test subject went from 11 liters to 14 liters with exertion and autonomous speed control and the flow control. So up to in 2019, they've done 12, 2020, as we know, we do a whole lot of those. But in 2021, we did six and 22. We already done four or five coming up. Sixth one next month, or this month, really. That was the whole operation sped up. Well, after the death or determination of the protocol, obviously, necropsy done by a pathologist, a very detailed one. Here's the picture of the Bible court machine with the heart with the aorta and the atria and the lungs attached to it. It's very close picture of it. As you can see, the primary are coming from the top. Behind it is the aorta, right atrium and the left atrium. So another picture, it's a little bit better here. You can see the aorta, PA, vina cava is also attached to the right atrium. There is where you're supposed to be in the human heart, human body. And there are, these are the bunch of patterns that they have been able to achieve, including most importantly, the most actually impressive is the last one on the corner that it can't create a pulsative flow. Remember, there is no valves in this machine. So it is so meticulously, it can so pinpointly control the speed of the rotors that it can actually create a dichotic notch if you want it in the arterial waveforms. It's that precise. So these are some slides saying, we need, how bad we need the toro artificial heart. We know that it's worth pointing out that there are other competitions or there are other machines. We have two main types, positive displacement and rori pump, positive displacement as we all know, syncardia have been used in hundreds and 102,000 or more patients. Cartmade is a pretty brand new year or two from France. They've done a few cases. They both are pulsatile. The problem with that, as we know, is too many moving parts, high failure, mechanical failure that require very high power. They're noisy and heavy driver, which in my opinion, if it keeps you alive, I probably will learn to live with it. But nonetheless, it uses a lot of power, meaning that you don't have much battery power to walk around with. As far as the rori pump goes, there's a Cleveland clinic has a one that they're working on similar to Bible core. There's little difference in the engineering there, but pretty much the same device. Dr. Cooley and Dr. DeBakey watching Dr. Frazier bringing one of those in a few years earlier. Thank you very much. Thank you. Thank you.