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Anisotropy energy

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Anisotropic energy is energy that is directionally specific. The word anisotropy means "directionally dependent", hence the definition. The most common form of anisotropic energy is magnetocrystalline anisotropy, which is commonly studied in ferromagnets.[1] In ferromagnets, there are islands or domains of atoms that are all coordinated in a certain direction; this spontaneous positioning is often called the "easy" direction, indicating that this is the lowest energy state for these atoms. In order to study magnetocrystalline anisotropy, energy (usually in the form of an electric current) is applied to the domain, which causes the crystals to deflect from the "easy" to "hard" positions. The energy required to do this is defined as the anisotropic energy. The easy and hard alignments and their relative energies are due to the interaction between spin magnetic moment of each atom and the crystal lattice of the compound being studied.

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  • Heart 2.0 (Beta): Engineering and the Human Heart

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>> We made a little facetious joke heart 2.0 Beta, right? Because, you know, I met Google and I used to have female data for a long time, until I got regular team now. And so I just--I wanted to kind of refer to this idea that were trying to do heart--grow heart in a new way. And, so first what I'm going to do is I'm going to give you a rationale for what is Cardiac Tissue Engineering, why do we even want to grow heart in the lab at all. And then give you some background on the heart itself and then the--because the idea is that in order to grow heart really well in the lab, we need to know more about the native heart, okay. So we'll start with the rationale, for why we want to grow heart in the lab in the first place then you know, kind of go back and we visit the heart itself. And then I'll give you some selected and biased strategies for Cardiac Engineering because all really be going through my stuff. So it's a very biased selected strategy for Cardiac Tissue Engineering, but please feel free to stop me as we go along, makes it much more fun for me and hopefully more informative for you. All right. So it's always nice to start with some art work. This is the Fountain of Youth. This sort of our inspiration for the field of tissue engineering, I mean, you see all the people kind of coming in on the left, you know, hunched over and not doing so well, getting into this beautiful pool and then getting out on the other side, rejuvenated. And the--the kind of inspiration for--to the field of Tissue Engineering is kind of to search for this for pre-revealed fountain of youth by being able to grow spare parts for the human body, to help us extend their lives. And, so, you know, maybe I ideas that, you know, at some point if we actually, you know, are successful that we will be able to kind of have a one stop shop for organs--yes, so to transplants made to order, so to speak. So hearts and bones and cartilage and all kind of things as they wear out we can replace them. This is the idea. So the motivation for the heart in particular is that, you know, heart diseases such--is such a big issue, I mean, we all know these days heart disease kills more people than all cancer combined. And if the world globalizes then the population ages, the toll is only going to continue to grow. And if you combine that with the hearts limited ability to regenerate, and the lack of organ donors, we really have a strong rationale for being able to--for needing to find any solutions. In addition, we have a very limited ability to test new drugs. Imagine if every time you need to test any drug, you need to have a clinical trial, and so that there's a limited number of people with [INDISTINCT] as well. And so if you combine all those things with it just a basic desire, to study cardiac development, we got a really strong rational for wanting to be able to grow pieces of human heart without, you know, or get pieces of human heart that don't involve using a whole human being, that makes sense? And so its got some popular preps and recently Wired did--it had cover story, much [INDISTINCT] what my work is on Tissue Engineering and then of course it's, you know, its been in the popular--news press. As well on--I don't know if anyone recognizes Grey's Anatomy, a show that I watch where they actually Tissue engineered some cartilage. So this is, you know, this is--this is a topic that's getting more and more in the public mind. So how did--how do we actually--how we actually grow tissue? Perhaps, does anyone in the audience have any experience in working the Bio Lab or having grown bell pepper, if you had? No? Okay. So let me--let me tell you a little bit about what it's like to grow tissue. So basically we have--you take cells out of their native environment, and we put them into what we call Petri dishes. And if we keep them sterile, keep them moist and, you know, give them food, we can grow them in incubators [INDISTINCT] quite well. We grow them, you know, in--on the bottom of the dish. And you can look at them under the microscope and there their growing. And this has been--this is kind of a traditional mode cell culture for a long time maybe almost a 100 years. The problem is, is that in order to get these cell that we grow in the dish for more complex tissues, it's much more of a challenge because, you know, the Petri dishes aren't very much like the human body. And so the cells are kind of home sick to their native environment state. The Petri dish doesn't feel like what would feel like--so for heart cells, example, the Petri dish doesn't feel like what it would feel for that cell in for the heart. And so the cell doesn't respond the way it would, and it certainly can't build the people tissue. And, so we need to do better to copy their natural environment in order to get them to not just survive, but to thrive. And so this is the rationale behind the Tissue Engineering Paradigm which doesn't use Petri dishes at all, but in fact uses bio material scaffolds, a three dimensional Petri dishes. So the big difference is really bad instead of growing cells on the bottom of the dish, we're growing cell in a 3D environment--three-dimensional. And, so in order to be able to do that, we have these the biodegradable scaffolds on which we add cells, and give them a lot of, you know, schmuck that they need, which basically means growth factors, sugars, protein, the things that these cells need to really grow. And the mix those into what we call cell culture medium this is like the food, it kind of mimic--there's some serum in there kind of mimic the--what the nutrients that would be provided by the blood. And so [INDISTINCT] as we culture cells in this kind of environment that will do much better at--in growing 3D tissues. And so what our lab does that's really--that really--we got a hand up? Yeah. >> Yeah. So it sounds, like, your forming the shape with the scaffold? >> Yeah. We're forming the shape with the scaffolds. >> Where as with the baby somehow the heart just matched [INDISTINCT] assemble with a great shape, can you explain if how that does that and why [INDISTINCT] >> So did anybody get the questions? So how do we copy development or do we copy--is that paradigm for us to copy development in the lab and the tissue [INDISTINCT] The answer is "yes," and I'm kind of handle that question a little bit later because we do show some embryos later in the talk. So if we don't answer your question by then, I'd be really happy to talk further. So yeah, we definitely look to development--embryonic development, specifically, for inspiration, for some of the Biomaterials that we chose, for the growth factor that we chose to deliver, and also when I was going to--was getting here for the biophysical cues that we chose to deliver. So Biophysical cues meaning motion, you know, the mechanical stretch or electrical signals or flow of fluids. And so, these are sheer stresses, mechanical stresses, and electrical signals. These--this is kind of the revolutionary thing that's kind of more recent developments in Tissue Engineering is looking just beyond kind of drugs and chemical, and looking to some of the--these other cues as well. And always looking to nature for inspiration, so nature being either developments, wound healing, or homeostasis. And in fact, I'll have examples from each of those of three types of the--of the--of systems. So the idea's the Bio-mimetic paradigm, so copying nature, because the better--the better that we do at copying nature better the cells will do in the lab. And so in the cardiac context, we can--two of the main types of signals that we--that we choose to copy are either the electrical signals that are involved in getting a heart beat or the blood flow through capillary bed because cardiac cells are really greedy. There's a very dense blood supply in cardiac tissue and, so we copy that in the lab by outfitting biomaterials on which we grow the tissues with--we pierce some with blazers so that there's hole to which we can flow the cell culture media, so their food kind of--it much more on in contact with the cell. And a lot of my work has been on this, actually, been on the--on the [INDISTINCT] using electrodes to make mini pacemakers to be able electrically pace the cells in the lab, and get them to beat. And we find that both of these biophysical cues are actually quite powerful in getting the cells to create better tissues. Okay. So this is kind of the--oh, yes, question? >> What is the--which part of better tissues? >> Okay. So this is the great question. Where to find better tissues? And this is a real challenge for, especially for someone like myself who's an engineer, coming into a biological context in which we have very different senses of how to measure things. And not only that very different senses of--what opposes a statistical difference and the measurement--I think that's it. And so, hopefully, well--as I give you examples of some of the tissues that we've grown and show you which one are better than others. Hopefully, you'll get a sense of how we do that, but it kind of a bit of an [INDISTINCT] process. So we see that the tissues maybe beating a little bit more, and so then we'll decide to make a measurement that's associated with that. Another question? >> Is the ultimate objective to replace scar tissue from a heart attack with [INDISTINCT] >> Yeah. So everyone heard the question? Is says if the goal of tissue engineering to replace scar tissue, and I would actually say the answer is, it depends on who you [INDISTINCT] So be--it's be--there is a goal of Cardiac Tissue Engineering to kind of make a bandage for the heart, but you can put on the heart after heart attack to help the heart heal. But the idea is also to avoid scar tissue ever having formed in the first place. And so, in that sense, the answer would be no. We're not trying to replace scar [INDISTINCT] we're trying to prevent it from ever having formed, but there are people who are particularly studying inflammation responses in scar tissues specifically, but this not our personal goad in the lab--well, my personal goal. Other colleagues of ours are focusing on that. Is there another question? Okay. So hopefully, you have a general sense of what Tissue Engineering is. And the idea that we're trying copy nature in the lab. And so now, I'm just going to jump into a little bit of cardiac physiology to give you a sense of what are the types of things that we look to in a heart context for inspiration. So the heart, right? This should--this should look familiar to everybody, right? At some point, maybe in the past, some bio class in high school. The heart is a pump in the most simplest term, it's a--it takes blood in. There's the blue blood, is the deoxygenated blood, pumps it out to the lungs where it gets oxygenated, comes back from the lungs and gets pumped out to the rest of the body oxygenated. So basically, what the heart does is distributes oxygenated blood throughout the body. And then actually--so it needs to be quite strong because, you know, if we look at this schematic of where all of the blood goes in the body, it's really quite remarkable that it's just one piece of tissue about the size of a human fist that accomplishes all of this, okay? And so, this schematic is a sense of, you know, just where in the body that the blood goes and, you know, we've got arteries on this side, the capillary beds and then veins on the other side. I hope this just gives you an appreciation for the shear strength of this muscle, okay? And in order to be able to perform this task, even all of the changing, you know, demands of the body. There needs to be--you would imagine there's a control system involved and indeed there is. So, I just want to give you a sense--you know, this is a standard control system thing, you know, diagram where there's, you know, a control logic, there's sensors, there's effectors, there's a control variable. All of these things exist in the body. The heart senses what local demands are, adjusts accordingly and et cetera, okay? And so, the main feedback loops to be able to accomplish this in the body are not surprisingly between the brain and the heart and also the vascular bed. And so, there's a feedback loop that involves sensory nerves as well as autonomic innervation from the central nervous system that together accomplish control over the heart rate and vascular tone. So just to say, there are many challenges to the cardiovascular system, okay? Just sitting down right now, not a huge demand on the heart, right? Let's be honest. But if you were to stand up really quickly, your heart rate would really have to change in order to ensure that you wouldn't faint, right? Or if you eat a big meal, your heart rate's going to change. Okay. Running for the bus, if you have a fever, your heart rate's going to change, but maybe on the order of minutes to hours as opposed to seconds, needing to respond. So there are different--there are different time scales that which the heart needs to respond. In addition to--just, you know, needing to respond. So, there are other things--if you were training for a marathon like I was, there are much more long-term changes that the heart needs to accomplish. And so, as you might imagine, there are different types of biological processes that are behind all of these--all of these control systems. And just as a quick overview, this is a--this is a zoomed-in picture of the cardiac ganglions. These are nerves in the heart that perform some of these short-term changes. Longer term changes, on the order of minutes to days are often accomplished by hormones and then when you're really talking long term changes, the heart actually--the muscle itself remodels. So, you can actually strengthen the muscle itself, okay? Or it can weaken in response to injury. But we're really going to focus on--in this talk on kind of the--on the cardiac control on the seconds, kind of, the order of seconds. So, this is--I just wanted to show you--I mean, this is a schematic of the, kind of, scary looking biological math of a cardiac control system. So, you've got neurons that come from the central nervous system that go to the heart. You also have nerves that go from the heart back to the nervous system, okay? So, it's a real control loop. But what you really--what I really do want--so, the simplified version is, there's kind of two things that are going on. You're either in, kind of two modes, you're either in the rest or digest mode which is maybe after lunch now, right? So probably most people are in, kind of like, the upper pocket of rest and digest. Hopefully, I'll do a good job of keeping you awake and the--this is called the parasympathetic rest or digest kind of autonomic nervous system. When the autonomic nervous system parasympathetic pathway's in control, this is how you feel. You feel like going to sleep. And if the sympathetic nervous system is kind of taking over, this is called--this is like the fight or flight responses. So, pupils dilate, heart starts to beat a lot faster, you're--there's probably a tiger or maybe the beep of a smartphone or something like this that is making you have a little bit of a panic. Okay. And the idea is that these two nervous systems are kind of imbalanced, they're not--it's not as if one is always on and the other is not, but there's a very careful modulation of the strength of these two nervous systems that work in balance to have very precise control over the heart rate. And what's interesting is that although the heart rate is set by both the rest or digest or the fight or flight pathways of the autonomic nervous system, they have very different dynamics, okay? So, vagal stimulation, which is the parasympathetic pathway so the pathway that slows down the heart, actually works much faster in getting the heart to change its heart rate. If you--if you were to really stimulate the vagus nerve, you'd get the heart to stop immediately. So, the heart is much better at responding to signals that tell it to slow down and to speed up. So the sympathetic pathway, the fight or flight, is a much different type of time scale, okay? But very, very exquisite control of the heart rate. You have questions? >> Yeah, why does this feel like the opposite? >> That's a really interesting question. Why does it feel like the opposite? I don't know. This is something that's always counterintuitive--it was very counterintuitive for me to learn in the bio lab with the rabbits. Why is it so much easier to stop the heart than to get it to start? Do you keep in mind though that this is on the--this is still on the order of seconds? Okay. So, we're looking at sympathetic stimulation. This is in the order of seconds. So, what you might feel as something fast is actually probably only going to be one or two and you could see if they've changed within that window. But the vagal stimulation--the parasympathetic pathway is really, like, on the order of maybe milliseconds. So, maybe for the human brain to process it, it sort of feels the same to us. And so, we always think of gas and brakes. This is just the human mind--the way that we think. But it's often counterintuitive for people to learn that in fact, the heart can slow down faster than it can speed up. So, if there's nothing that you remember after this talk, do remember that because that's kind of a mindwarp. Okay. So, I'm telling you that the heart rate can change. I'm telling you that there's this control system for doing so but does anyone know what the pacemaker is in the heart? Like what these things are actually--which part of the heart tells it to beat? No? Yeah, pardon? >> The sinus. >> The sinus. Yes, so, yes. Which sinus specifically? We have--we actually have two pacemakers in our heart. One is the sinoatrial node which is what our audience member referred to. So, I actually don't have a laser pointer but it's this yellow dot right there, the SA node, sinoatrial node. This is the main pacemaker of the heart. This is what receives the input from those--from those neurons, okay? The secondary pacemaker of the heart is this green up here--the atrioventricular node. So, this is the node that's between the atria of the heart which receive blood and the ventricles which pump it out to the rest of the body, okay? You might be wondering why are there two main pacemakers? There's actually a third pacemaker which is like a tertiary pacemaker, which are the Purkinje fibers. So these--the fibers that actually--you can't see them so--oh, here we can--so, the fibers that connect the entire ventricle to each other. You know, like why do we have three pacemakers if either heart only beats once? But, you know, if--has anyone ever listened to a heart beat in a stethoscope? There's, like, the "Lub dub", right? "Lub dub, lub dub" right? And the "lub" is the--are the atria beating and the "dub" are the ventricles because there--it's kind of a two step beat, okay? And so, there's actually a built in delay between when the atria contract and when the ventricles contract. So, this is a really exquisite control system here. So, this is the most text-heavy slide that we'll see. Basically, I just want to tell you--so we have these three pacemakers within the heart and they're ruled by what's called overdrive suppression, okay? So, the SA node, which is the main pacemaker of the heart has the fastest beating rate, okay? 60 paces--60 beats per second, okay? >> Per minute. >> Per minute--per minute--per second, oh goodness. That would be like a hummingbird or something. Thank you, thank you audience. There's such a wide range of heart rates actually. I think the blue whale has the slowest and the hummingbird has the fastest and that's in--I cut and paste this one line in every paper that I write but I don't--I certainly don't hold it up here. So this--so heart rates are actually--there's quite a range in the animal kingdom--neither here nor there. But the sinoatrial node has the fastest heart rate, okay? So that the main pacemaker, the kind of upper management, has the fastest heart rate and the secondary pacemaker, kind of middle management, is the--is the atrioventricular node--the AV node. So, the SA node is always telling the AV node to beat faster than it would normally beat, okay? So in this way, the SA node--even though it's not the only pacemaker in the heart, is the pacemaker of the heart. Does that make sense? Because it's always bossing around the lower levels, okay? And so, when we have cardiac pathologies, a lot of times it's because that order's been messed up. Because maybe one pacemaker, usually the SA node, is a little bit out of whack and then everything else follows, okay? The Purkinje fibers also have an intrinsic beating rate but it's much, much slower. And so really, when they say the pacemaker of the heart, we really only mean the SA node. But there are--there is intrinsic pacemaker activity in other parts of the heart as well. But who's actually doing the beating? Who is the--who is the person, who is the character in the heart that's actually getting it to beat and in fact that these billions of cardiac myocytes, these are muscle cells. And they're really, really amazing. You know, they're the most physically active cell in the human body, they're contracting all the time. Billions of beats in a life time, billions of these cells, they really--they never pause to rest. And they're just--they're just so exquisite and not only that, they're beating and synchroning your entire lifetime and they almost never mess up ever. And when they do, there's usually catastrophe associated with it. So these guys are the guys that are doing all the work. And how do they do that? Question? Yes? >> [INDISTINCT] >> Did everybody hear that question? "Are these cells are the same ones that we're born with that beat our entire life?" The answer is yes. And we've had these since birth. Yeah, it's pretty amazing. Rats when they're born, they're born with three quarters of the number of heart cells that they will have for their entire lifetime. So they replicate one half time but we were born with our--with what we got. So be nice to them, they're pretty expensive. How do they do this, how do they connect to each other so well? They--so, has anyone ever built an electrical circuit before are there some of you guys, yeah? All right. So how do you do it? You take wires and you plug wires to other wires and there are resistors, there capacitors, there are inductors, they're all these little things like little bits that you can connect to each other in a bread board, let's say and they all have different electrical impedances, right? So the thing about the heart is for it to beat so well in synchrony, they need to be really well connected to each other. And so what's amazing the heart cells is that they are very--they're very interconnected to each other not just mechanically which makes them because the heart has to beat all at once, but also electrically because every single beat is an electrical event. And so these--the electrical connections between cardiac cells are these Gap Junctions. So it's actually physically, physical little holes between each cardiac cell that allow ions which are the electrical charge in our bodies to flow between them. And so it's a very, very low resistance pathway compared to nerves. It's a very different type of electrical connection than what you would expect with that--that what you have in the brain, let's say. Okay, so very, very fast connections and very low resistance. okay and very, very dense Gap Junctions on so that the cells really beat as one giant cell together. So they're mechanically and electrically connected to each other. They're also anisotropically connected to each other. So if you don't know what the word anisotropic means, it means that it's kind of-- there are more connections along a fiber than across fibers. And so what this accomplishes is a spatial resistance so that you have these fibers as opposed to having a big rectangle. Okay. So the electrical signal really moves along a fiber because there--there's a less resistant down the fiber than across between fibers. Does that make sense? Is there a question? I heard a breathing. Okay. >> So well, so that there's a pace and time for the signal to get the--from the source to travel on the speed of light? >> Right. So did everybody hear that? You know, so just it take sometime--is this--do signals travel at the speed of light? No. No, they travel at--I actually--I don't want to put a number on it, but maybe [INDISTINCT] meters per second is how fast. and so that's why there's a delay between--some of the delays are actually built in to the system between the SA node and the Av node just allowing for that. But I don't want to put a number on it, I'm not sure but it certainly not instantaneous. And in fact, I'd like to show you a map of how fast that takes and that's why there's--that's why we have an EKG signal it's because I've actually showing the spatial movement of the electrical signal. So this actually answers your question. So how does that signal propagate through the heart? And I don't want to dwell on this for too long, but basically the signal is not--surprisingly starts the pacemaker, goes to the secondary pacemaker and then it's distributed throughout the heart. And this is a very unhealthy heart, this is exactly what it looks like and this is why unhealthy EKG's going to look the same for pretty much every individual because it really does map the electrical signals that would be on the surface of the skin. Okay. So it's--it really travels as a single wavefront. The electrical conduction in the heart--it's the action potential so the electrical signal at each point in the heart. Actually, it's a slightly different shape for reasons that we won't really get into but we have to do with the Ion channels that are in each cell. So each cell type is a little bit different so the electrical signal in each part of the heart--it's actually a little bit different. But when you add all those signals out and you also take into trunk the temporal delay in the signal, this is how you get a characteristic EKG that you probably heard you know QRST so that the QRS complex. This is only people often talk about in the--in medical drama. But basically you're adding up this electrical signal and they sum into this familiar looking EKG that you would, you know see on television. So the electric cardiogram has these five waves. And since they're so characteristic, we can be able--we can perform diagnoses on people if there--if that signal is not--if it's perturbed. Okay. So just really quickly, I wanted to go through and show you some with Arrhythmias. When we have problems in the heart, they're often tied to these conduction abnormalities. So the heart is not conducting the way it should it be. Meaning that, there's something wrong with the--with the ions--that--the movement of ions. Or maybe there's a problem with the Gap Junctions between the cells but with the heart, whenever there's something wrong mechanically, it can almost always be diagnosed electrically. This is an amazing tool that we have. So this is just an example here of a shortened PR interval meaning that the atria--the delay between the atria and the ventricle is a little bit shorter than it should be. We have what's called the closed conduction loop, this is when gap junctions are kind of messed up. And so you might have resistance that variable and so if there's a bit of a block there that's only temporarily present, you can get what's called a reentrant loop. And this is actually a very dangerous situation because if the heart is conducting signals in a loop, it will beat out of control and then as you might imagine blood is not efficiently pumped through the body. And so this is often--something happens in the atria, I think this is my next slide. When we have atrial fibrillation, this is something that caused by this reentrant loop. and so what the--what the doctors will often do is find those--that small piece of tissue that's creating this reentrant loop and actually just go in there and ablate it, to go on there and kill it basically this is the cure. And so I'm really thinking ahead maybe instead of thinking about how to cure the heart by killing pieces of it, maybe we can think about curing the heart by growing pieces of it or curing it. Right. So atrial fibrillation is actually quite an epidemic right now with no real cure and it's only getting worse. So right now, the only cure is either ablation or just giving patients antithrombic medications so, things to prevent them from having clots. Because the real risk of having atrial fibrillation is stroke. >> [INDISTINCT] >> All right. Question. >> Why is it getting worse? >> It's getting worse because our population is aging and actually it's a big mystery, it's the question is why atrial fibrillation such an epidemic? This is actually that people don't know. It is some sort of symptom or parasympathetic or sympathetic--an imbalance there where maybe people have too much adrenal fatigue. It's kind of a big mystery right now in that space. Not my expertise but at conferences, it comes up a lot. The ventricular fibrillation is usually the next step after this, you know it's kind of crazy--kind of crazy type fibrillation the next step after this really is just a flat line. This is--this is very dangerous. This is usually--if this is what someone's EKG looks like, it's probably not going to be an EKG for much longer. So this is what I'm going to say "Oh, we're in Vtech Oh, we're in Vfib," and then they bring out the fibrillators and the paddles and everything that's this is where the ventricles are going crazy. >> So [INDISTINCT] how does it work? >> So questions is How does--how does the defibrillation work? And the answer is mystery. Isn't that funny? So there--some people might disagree but my short answer is, unknown. Basically--but the longer short answer is that the defibrillation depolarizes the entire heart. So basically gets every single cell in the heart to electrically get excited at the same time but for mysterious reasons, that can often reset the heart to beat normally and that, that's the mystery part. So we know that defibrillation actually gets the entire heart to beat in synchrony but then for some reason it can often sort of pick for you or you leave off and be okay. Has anyone ever been had a defibrillator used on them? Wow. >> Pretty fun. >> He said great fun. Okay. Wow. >> Compared to Efib. >> Compared to Efib, I've heard this--I've heard it feels like being kicked by a big animal. I don't know is that's how you'd describe it, but this is how a patient that I met had describe it. A lot of people get defibrillators implanted. Okay. So heart attack again has a very characteristic EKG associated with it which I don't really want to get into. But I do want to say that--one thing I do want to focus on is the slide is that when we have--when someone has myocardial infarction, this is heart attack, this is when a coronary artery is secluded, so blocked off , so a piece of the heart is not getting oxygen. And then the heart, heart cells are very greedy, I mean as you might imagine it takes a lot of energy for them to beat billions of times in a lifetime, right? So they--if they don't have oxygen all the time they're kind of screwed. So they die really fast. So anytime that the heart is exposed to a lack of oxygen, those cells are compromised almost immediately. And because the heart has a very limited ability to regenerate, this is a huge problem and often leads to kind of a sterile and heart disease. So this--all of these to say that this is our motivation. So, I'm almost going to start here again and say this is a motivation of cardiac tissue engineering, is to kind of make a patch for the heart, make a patch for the piece of heart that's been compromised by myocardial infarction. Okay. And what we're going to do is we're going to again talk about this by a medic paradigm, and try and see what ca we look to in nature to inspire us to be able to grow this heart in a good way. So looking back on those things that we've gone through up until this point, how can we use that knowledge to be able to grow a piece of tissue? Okay. And so, one of you asked a little bit earlier about cardiac development. So one of the inspirations that we always look to is like, "Well, okay how do we feel the heart or how did the heart grow in the first place?" Maybe we can get some inspiration from there. And actually, what's interesting is that the heart is one of the first pieces of the embryo to manifest itself. Okay. So the--you have this tiny embryo and cells are starting to beat. Actually and even before that which is a little bit may appear they electrical gradients within the developing embryo that recruit cells to grow. Recruit cells to what's called the cardiac primitive streak within the embryo. And then the cells differentiate. And then eventually become the heart. And so, is this something that we can use as an inspiration for growing heart with in a lab? It has been for some of our studies which I'll show you. Another type of inspiration also from the embryo is Electrical Current Signaling Measured that are more pulsatile in nature. Okay. So the one that I showed you just a moment ago is more of a direct current kind of stimulation so the kind of current that your smart phone needs to charge up as opposed to what you get out of the wall which is AC or pulsatile in nature, right? So the pulsatile signals come a little bit later in the developing embryo. They come when the cells are already starting to beat. And they're starting to connect to each other. Okay. So for example these are two aggregate of cells, embryonic cells, and this was the study I can [INDISTINCT] So we really, you know, really good solid work from years ago showing that the for the interesting notes that I've shown up here are the electrical signals from one of the aggregates versus the other. And eventually, sitting next to each other, they start to beat together. Do you see that? They're kind of beating apart from each other and eventually they're beating together. So these pulsatile signals have been imply--have been implicated in how cells learn to build those gap junctions to each other. How they learn to talk to each other. Okay. So it's a little bit further a long in development. Well, we move on into homeostasis and injury. We have, yeah, those pulsatile signals that are associated with all those pacemakers, right? You have the pulsatile signals that are associated with all of those every time the heart beats. So that lift of the EKG, right? Well, what we also have in those cells are ischemic, after myocardial infarction for example. So you know everybody knows that your body is filled with salt water, right? Salt water that's pretty close to what's in the ocean. So what I often ask my students is, you know, "What conducts electricity?" People say, "Electrons." Right? And say, well, would you ever want to jump in the pool, well, why don't you want the hair dryer--No, no, no. It's not [INDISTINCT] You don't want to--you don't want to be--you don't want lightning to strike the ocean while you're in it, right? And too close to where the lightning strikes. But the question is does water conduct electricity? Do you think water conducts electricity? Oh, no hands are up. You think--hands going up, right. And electrons obviously conduct electricity. But what is it about salt water that makes it conduct electricity? >> Free ion. >> Right. You got free ion. And that's what we have in our body. And every single cell in your body is filled with ions because we're filled with salt water. What's interesting is that the salt water that's inside your cells is completely different concentration of ions than what's outside the cells. So everyone or anyone know how lethal injection works? >> Potassium. >> Potassium. What? >> Osmolality... >> So it alters the osmolality of the cells that is--I'm not sure. So I'm just going to--I'm going to deflect and actually--I'm not--I don't think so. I don't think it changes the osmolality of the cells. But it's definitely a different concentration of the potassium and what the cells want. Cells are really thirsty for potassium they hoard like crazy. And there's rarely any potassium in the extracellular space. And this is how every cell maintains the voltage across it. Our cell--our body is used extraordinary percentages of energy. They are just maintained by[INDISTINCT]37.53 they are very important. And so lethal injection works by growing a bunch of potassium outside the cells and they quickly stop the heart because the voltage across--the voltage of the heart cell is gone and so the heart can't beat anymore. >> [INDISTINCT] >> The results are good. Yup. So when--so basically, obvious to say, if you got a cell that's compromised, a cell that's injured, it's probably going to be in leaking ions. Okay. So when you have leaking ions, that's correct, right? So this is what where going to be looking for, for inspiration from when we're looking about--talking about injury, right? So to give you a sense here of what we're doing in Cardiac Tissue Engineering, we're looking for nature for inspiration, right? And in different circumstances, we're going to be looking at different kinds of signals. Okay. So, there's a huge amount of work that needs to be done in order to be able to really exhaustibly study all this stuff. So I'll give a short sampling of some of the work that a bias sample of studies that have been from my PhD and current work. And so, I'm giving you the example. First so our research design basically is that we take different signals. And each signal is going to imply that there's going to be a different system that we have to build. So it's actually quite a lot of work because of this. And then we have to be able to perform analytics. One of your questions earlier was how do you know if something better than something else. Okay. So all of these are very interplayed0 with each other because some analytics that you need to perform in private, you need a visual line of sight to the tissue. Sometimes this isn't possible when you're growing them and there's a lot of trade offs, engineering trade offs from where performing this research that make it fun or frustrating of depending on your perspective. So the electrical chemistry of the electrons versus ions comes into play a quite a lot. If we have short signals, we tend to ignore them. We have long signals, long signals being anything probably longer than about five milliseconds, you need to perform some work to be able to protect the cells from any corrosion or any of the chemical reactions that take place in order to be able to perform that transaction. So ideal electrons need to be biocompatible, injecting-charge efficiently and of course not corroding because then there is evil stuff in the body already exposed to the cells. Okay. So early--so our example from early development, we have a bioreactor that's what this is called a little self-cultured system that's outfitted with electrodes. This is a kind of small system, one millimeter by--except for--so the embryo bodies that were growing about one millimeter and five. So we grow a lot of them together. And what we are trying to study was whether or not this performing an electrical signal a lot like what you would find in development would help the cells form better cardiac tissue. And your question was how do you know it's better? Well, we chose to do a couple of assets after seeing analysis. One must be measured more often of reactive oxygen species which is a measurement of how well we transduce the electrical signal. And in this case, the measurement was the cells were glowing. Okay. So, this is the way that we--so there was phoretic dye associated with this the question of reactive oxygen tissue. So every time you perform a measurement there has to be some sort of dye. There has to be some sort of way to visualize it, right? And in this case we visualized it with a phoretic dye. It's kind of cool you're like in the dark of a microscope performing this like for like fluorescent, you know, taking all these pictures as we all--we felt like dark room photographers. A lot of fun and a lot of work. The other measurement that we did was the--we did another--this fluorescent dyes all come from--anyone know where they come from? Is [INDISTINCT] is associated with this one. >> Lightning bugs? >> Lightning bugs? No. Yeah. Some of them actually lightning bugs and some of them jellyfish. They are animals that create light, right? And need proteins if they're conjugated with other molecules. You can use them to make other proteins glow. So they use it for working for cardiac component. So it's a very important cardiac protein and we're able to see it because it was conjugated to--I don't know what one also came from jellyfish or lightning bugs. But it's really cool because they glow in the dark, really amazing. So it's a lot of fun to take this pictures. And well, I would love to see one day if I could copy tailor book with all of these beautiful abstract images that a scientist locked up in the dark by herself and has no one to show them too. Okay. So, an example pulsatile stimulation was embryonic stem cells. I do a lot of work on this; this is from both of my PhD work. So these pieces of tissues are about the size of mini marshmallows. So just shown over there. Lots of computer control systems to be able to perform the electrical stimulants, right? And so let me actually just show you, we did a lot of boring work with comparing kinds of electrodes. I mean, this is like years of my life here. So we compared lots and lots of kinds of different electrodes. And saw how much current went in and, you know, and picked one and then used it. And then did all kind of other things. Where we did lots of modeling and we said, "Okay, what's the electrical field going to look like? Are we growing these cells?" This is always the boring stuff, right?. Because what you really want to do, we want to see how well does it work, right? This is your question, how do you know you get a good job. All right. So let me show you a beating piece of cardiac tissue that was growing without any electrical stimulation. So you see that at the left--at the left-hand corner? Twitching a little bit. You see that? You know, like squinting. It is beating. It is beating but it's not super dramatic. They do beat even with no electrical signal. But when you give them an electrical signal, they're like Healthy. Healthy. Joy. Joy. They're so cute. I mean, I think they're so cute. But this is--so in--to answer your question, which one would you say is better, right? And so, then, you--so this is the end of process in the scientific world. How do you know is it a better job? Please take a look; I know that that's beating more. So then I never have to come up with measurement that shows it's beating more. And hopefully when I write it in my paper, there's not going to be some peer reviewer who says, "I don't really like that." And then, it turns into like a peer review kind of thing, right? So sometimes if there's a new message it turns into a peer review thing where you kind of have to convince someone that the way I'm measuring something is correct. If it's a method that's kind of accepted then you use that accepted method. Okay. So this is kind of like the scientific process. So you're asking a lot of the-- you're asking a lot of the hard question guys. Like suppose this how do you know you did a better job? Well, in this case it's so obvious but we actually have to do a lot amount of encoding just to be able to say that's better, you know in a way that's satisfied us. >> So this is beating the one that you showed--each of these was when you say electrical stimulus that's being drawn in an electrically environment and then... >> Yeah. Did everybody hear that question? Like what do I mean by electrical stimuli. I grew those tissues with electrical stimulation for a week. Okay. >> [INDISTINCT] >> And then they're beating better. And so let them grow with stimulation on. So, yeah. >> But the beating was without stimulation. >> But the beating was without stimulation? >> And the beating is also under pacing condition. So I'm even pacing this little guy and he's [INDISTINCT] it. Draw whatever conclusions you will. But... >> This one is being paced also. >> These are both being paced. This is the best this guy can do. But if you grow them with that signal, they do much better. >> Yeah. That's okay. >> And so another method measurement that we did, was, you know, began with math lab--began with a lot of this image processing which to able to do some strain analysis to be able to say how uniform is that tissue beating. And so you have to come out and some of viewers will say, "Well, I don't know if I like the way you did that strain analysis." And you feel like, "Well, I did it." "Well, the pixel of this picture was ..." You know, it's either of the two. So this is another measurement we did to be able to say they are beating better, right? It's not easy in science to say--to have this yes or no question. Well, it's easier to have a yes or no question than how much question in biology. So this is--this is a real challenge for EE type person going into [INDISTINCT] So a lot of interesting conversations there. Okay. So two more examples, one with adult stem cells. This is one of my favorite systems because it's a question, yes. >> [INDISTINCT] >> Okay. So, if I get the question right. You're asking, do we know if the--on the individual cell level, How well their connected to each other or we just microscopically measuring the tissue? The answer is we are actually just microscopically measuring the tissue with this assessment. What we also do, I mean I'm only showing you a sampling of how we draw the conclusions about whether, you know how we--how we did? But we also have to zoom in on the--not molecular level but on the cellular level. And we zoom in with transmission electron microscopy. We zoom in using some of those immunoflourescent dyes to really tease out how well are these individual cells doing. Because we do need to know that answer, we need to know not just how well the tissue is doing but how well the cells are doing. Yeah, so very good question. I left that out of here but really happy to share some of the data with you if you're interested. So talking about the cellular level actually, on the micro scale we can do some of these work too. So using some micro patterning technique with in this case, a transparent inter digitated electrode of Indium-Tin Oxide. Is anyone familiar with indium tin oxide? No. It's a semi conductor and it's transparent. And so, it's really nice because it's compatible with a lot visualization technique. And not only that because it's really small we can grow really small pieces of tissue. So, we can get some answers on the cellular level as opposed to the large tissue level. So for several reasons it's really nice to use of some of these smaller scale systems. So, again lots of modeling, lots of rainbows from modeling always looks like rainbows because were using [INDISTINCT] well, what used to be [INDISTINCT] is now consul. But then we also zoom in the cells and we say "Oh, goodness. Look. Look when we stimulate these cells electrically in culture, not only do we got more of them. Like blue dots of the nuclei because we stain them blue. So we have more when we're stimulating them. For some reason they're proliferating more. But also these green dots here are gap junctions. Okay. Gap--we stain for a gap junction protein called Connection43 which is the main cardiac protein. And we see that not only are there more cells but there better connected to each other. And so we can start to hypothesize that maybe not just an embryonic development but also in these in-vitro systems meaning systems in the lab. That maybe we're starting to copy some of the right stuff. You have a question? >> You got about ten minutes left. >> Yeah. Oh, 10 minutes left. Good. And I'm on my last example here. So thank you. So if we're going copy wound healing--so we went through examples, where we're copying early development. Where we're copying homeostasis so were copying a healthy environment but now what look can we do to maybe piggy back on the body's natural wound healing response so for regeneration, right? So if were going to copy wound healing maybe we also want to have electrical systems that can copy what that wound current is like? What it's like when the cells is injured and anions still out? So we also need at that--at that level we really need to have a direct current kind of system again. And direct current systems are really difficult to build because there long duration signals. So anything longer than, you know two or five milliseconds is long in the body, right? And so, what we have to do here is we have to actually find a way to shield the cells which are growing in that chamber up in the [INDISTINCT]. From any of the chemical reactions that have to take place in order to create--not create--generate ions from electrons in that saline solution. So there's a saline solution here, power supply comes in and that electrons coming in from the wall, right? They get chemically reacted to the silver, silver-fluoride electrodes. And any of that, you know crap? That's generated that the cell--that would kill the cells kind of stays in there. But what we have are salt bridges that allow just the ions to move from there to the cells. So we protect the cells. So this is like a lot of engineering challenges that we have to overcome just in order to be able to ask that biological question. So, there's a real need for--I hope that I'm giving you a sense--there's real need for collaboration between engineers and biologist in this case. And chemical engineers as well because electro chemistry, biology, engineering, fabrications techniques. All of these things come in to play and no one person is going to know any of that stuff. So if you look at the papers that come out in tissue engineering, they're often many people from very diverse backgrounds who collaborate. That's a really kind of fun interdisciplinary fields being as one. I hope I haven't scared you. So this was a really fun project that we did with human adipose drugs stem cells. Does everyone--is everyone aware that you have tons of stem cells in your fat tissue. It's something most people don't know. But we get these cells from--people just line up to donate. They're like, "Yes, yes, you can give me lipo for science. I'll help cure cancer with lipo." Right, so, there's like, [INDISTINCT] but you know people are really excited to donate but we--there's plenty of cells. So, your adipose tissue, healthy adipose tissue has lots of stem cells in it. And these stem cells are pretty powerful. They're pretty close to what you might find in the bone marrow. So what's really nice is an--by exposing these cells to a current that's really close to what a wound current would be. So six volts per centimeter over four hours. Do you see how the cells are moving and assembling themselves and lining up? I mean this is amazing stuff. These signals really, really, talk to the cells. And so what I'm clear is how that--how that patterning that happens from the cells. And how the--that movement of the cells might correlate to what you might find in the body with wound currents. Okay. So this is an open question, this is an active area of research but it's a lot of fun to do these experiments because you're really watching the cells move and their really cute. Again, so we can assay, we can asses how much do they move? How long do they get? And so then you start doing some of this image analysis stuff to be able to answer those questions. And what we saw is that not only--well, in this case we have fewer gap junctions per cell because the cells are moving around they have to disassociate from each other to be able to move. And so--and so then more questions open up. What did that mean, if there are fewer gap junctions per cell? And so then the science continues. And we also did a really nice experiment; this is all very preliminary stuff with adipose derived stem cells from epicardial fat. So there are fat pads around the heart and there are stem cells within those fat pads. And so, what we were hypothesizing is maybe there's a role for those cells in wound healing. As limited at the cardiac wound healing process is, maybe there is something with those cells that we can do. And what was really interesting is that we saw the same movement and elongation with these human adipose derived stem cells from this epicardial fat. But this is preliminary stuff published a couple of years back. So what are we--what are we doing kind of now? How--what is--what are current developments in this field? One thing that people are doing. Well, this is actually another example from us where--this is in press right now is beginning to combine modalities. So I had said much earlier that perfusion like, blood so giving greedy cells lots of food is really important for cardiac cells as is electrical stimulation. So one thing that our group is doing and other groups are doing as well is beginning to combine some of these modalities together. Say what if we applied electrical signals and perfusion, would that be better? And what we do find and we often find with biology is that things do not sum linearly, okay? A + B sometimes equals much bigger than what that sum would be. So we're really excited about some of these results. But then again, you see there's another pretty complicated looking bioreactor that we had to build. So there's all these engineering work that goes in to asking that question. And so going forward, what would be really nice, and this is another ongoing product that have in the lab, is being able to scale up some of these systems. You guys at Google probably care a lot about scale ability. And then the tissue engineering context, it's something on people's minds but we're often building little prototypes all the time--prototypes, prototypes. But as we start answering some of these questions, then the--what's going to start to happen is that we're going to scale up, not just--to be, you know, to be able to build these things. To say, "Okay, look, we got some answers. We know how to grow a piece of tissue. Now, how do we grow 10,000 of them?" And then the answer is, "Err, like I don't know." So we have to be able to standardize these culture systems and be able to fabricate them, and be able to do in a scalable way. So, this is--this is an ongoing project that we have right now and we're excited about some patents that we filed. And then finally, let's just say we actually built that patch then you have to think about how you actually put it in the body. And so another area that's going to be opening up soon is going to be some--answering some of the questions of how do you actually put it in to a body? How do you make sure that it beats along with the heart that you detached it to? And so, what might need to happen is implantation along with the pacemaker but these are questions that are just starting to be addressed now. And then finally, finally, finally, if we have all of those questions answered, if we finally scaled everything up and have really great pieces of, heart that we can put in the body, then we've got this other really hard problem ahead of us, which I would be remiss if I didn't bring out, which is the gap between the laboratory and the world, okay? And right now, this is a huge, huge issue which I know Google is very--is very aware of. It's how to get really good ideas out of the lab and into the world. And so, I felt like I would remiss without saying but this is something that's so on every scientist's mind who's in this field. And how do we--how do we make it to that even if we've solve this problem that it actually gets to help to people, okay? And so with that, I'm going to pause again for questions and say, you know let's, you know, maybe we will get one step closer with regenerative medicine back to our Prometheus, you know, the Greek God of who's formed human being. And open it up again--well, I should just say, thank everybody and my dog and New York and wine and tea and all those things that make it possible for scientists to do their work. And finally, to say if you have more questions, I would be so delighted to answer them. And just thank you so much for your attention. This is a real honor for me.

See also

References

  1. ^ Takabatake, T.; Teshima, F.; Fujii, H.; Nishigori, S.; Suzuki, T.; Fujita, T.; Yamaguchi, Y.; Sakurai, J.; Jaccard, D. (1 May 1990). "Formation of an anisotropic energy gap in the valence-fluctuating system of CeNiSn". Physical Review B. 41 (13): 9607–9610. doi:10.1103/PhysRevB.41.9607. Retrieved 17 February 2024.
This page was last edited on 17 February 2024, at 18:10
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