Engineering Health Through 3D Printing

Engineering Health Through 3D Printing

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(bright upbeat music) - Glad to have everyone here. And I know you're testing the quality or degree by being able to find the room. (audience laughing) So I'm glad that all worked out. Everyone here has heard of 3D printing, otherwise you wouldn't actually be in this session.

And the attractiveness of 3D printing is being able to make things that are un-makeable by traditional methods of manufacturing, or making things that are bespoke from scanning technologies. Or maybe the democratization of fabrication. Being able to power people in different locations. But I think I would argue that 3D printing historically has been 2D printing over and over and over again.

(audience laughing) And not to throw any disparities, but it grew out of the mechanical engineering perspective and precision deposition of reagents to build up things in a three dimensional space. I'm a chemist by training, and my colleagues and I were physicists in science. We thought about things in a different way, principally because of the challenges of thinking about scale up. This is a classic way to do 3D printing with powder, you'll see a blade wiping powder, a laser hits it, centers those little particles together, it's being pushed into the table, and then you'll see this block of powder coming out and buried in that somewhere is a product.

It's kind of like cleaning a fish. But this has been the mainstay of a lot of 3D printing technologies up to this point. The challenge is, and one of the things I want you to take home from looking at this, this doesn't look scalable. But it's proved a lot of value in a lot of different industries, okay? And so 3D printing is historically slow process.

There are mushrooms that grow faster than most 3D printed parts. The layer by layer approaches give rise to mechanical properties that differ depending on the orientation of the printing process itself. That gives rise to anti search up here, the properties are different in different directions. From a design point of view, that's real challenge. And the materials that people have been able to access based on the technologies have been very limited.

Point is, 3D printing has mostly been relegated to a prototyping technology. We were curious in the very beginning, why couldn't 3D printing come from a puddle of liquid and have products rise out of that liquid in almost real time to have amazing properties? And it's the physics of this liquid actually coming in underneath the part we're really interested in. And so we set out and developed a process that does almost that, and it's a light-based process that takes a two-dimensional images and does it in a high rep rate where we can build up an object that comes up out of a puddle of liquid. And a key technological breakthrough was recognizing that a very special window underneath this puddle could be not only optically transparent, but also could be permeable to oxygen.

And why that's important is oxygen inhibits the photochemistry that the light is triggering so that we could asymmetrically get the part to bond to a platform and not a window. And so when you put all these pieces together and you lower this platform into this shallow reservoir of a light sensitive liquid, it'll get really close to the window and then we'll start projecting a two-dimensional image that is basically a cross-section of the object on the left. The part will bond to the platform and not bond to the window.

And we're basically pulling up in almost real time an object that actually has geometry that is not fabricatable by traditional manufacturing. Now this is a sped up video, but this process is now 25 to a hundred to even a thousand times faster than traditional 3D printing. That opens a door to begin thinking about manufacturing processes, okay? And we rolled that technology into a set of printers that were designed with the sub-discipline and mechatronics where everything in the printer was censored up, remotely controllable with software, and we were able to do software upgrades every six to eight weeks. And a community of users out there, because everyone's using it, the process got better and better. And that's a network effect from an entrepreneurial point of view.

And this becomes a platform to allow designers to make amazing products. And I have a little video to share with you what we did in the past. - [Narrator] We salute all those who believe good enough is never good or enough. Those who pursue excellence for themselves and for our planet.

At Carbon, we apply our craft using science and technology to push limits and realize products unmatched in performance. Our difference is one you feel and it is light years ahead of anything else out there. You feel it in running shoes that control energy with every stride, saddles that enhance your performance and comfort mile after mile, helmets that increase your protection every time you take the field, clear aligners and dentures that improve oral health and give you more than a few reasons to smile.

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We salute the leaders, dreamers and doers who keep creation in motion, who boldly imagine a brighter future and craft it every day. - So this represents arguably the first transition from a prototyping technology to a manufacturing technology for 3D printing. And it's a platform that depending on the resin can be applied to a lot of different markets. But when I begin looking at into the future, what's needed going forward, and this is what my lab here at Stanford is now thinking about, we need advances in the processes.

We still want it to go another factor of 10 faster. We wanna make smaller things than you can make by the traditional printer. We wanna resins that could be recyclable or maybe bioabsorbable for implanted in the body.

And huge advances in software needed to improve the design and operability of the process. So let me walk you through very quickly high resolution products. There's a lot of interest in the literature for making things at high resolution. The challenge is, these are often made as one-offs. They're not made in a scalable way.

My laboratory here at Stanford with some great students and post docs now made the printer with a resolution down to 1.5 microns. So in other words, it's a commercial printer, the carbon printer is 75 microns in resolution. A human hair is a hundred microns, commercial printer is 75 microns. We now built the printer at 1.5 micron. So red blood cell is eight microns.

So we're making really small things and it takes a lot to make that work, optics, software chemistry, all coming together. But what the result of that is, when you think about one of our iconic buildings, the Eiffel Tower, this is what's made on the commercial printer, it's 75 micron resolution. Now we start making things smaller and smaller, 30 micron. And now looking at 1.5 micron, you need electron microscope to see everything.

You can start seeing the ability of making really small things. And one of the areas we're really interested in applying this to is vaccine delivery. And so why do we want to do this? A lot of the migratory immune cells that you're targeting with vaccine are found at a hundred times more concentrated in the epidermis than you do in our muscle. But most of us are vaccinated with a liquid that went into the muscle because this space is hard to access. We've now made micro natal patches with this high resolution printer.

We coded them with a vaccine product using a simple patch that's now painless, it can be self-administered, and when you do all the detailed studies, and this paper was published just under a year ago, we get 50 times the antibody response, 50 times. You know as you can reduce the dose a factor of 50. It's kind of cheating because we're delivering the vaccine to where the cells are. But that's the point of focal delivery. That's the whole advantage. And so what we're doing now is making really amazing micro needles that look a little bit like that Eiffel Tower with a lattice.

We're trapping liquids in them, we're adding moving parts. And where this is going is now in a new area of sensors. You're probably familiar with continuous glucose monitoring that took the world 40 years and 40 billion of investment to measure one molecule.

We're now trying to attempt to measure dozens of molecules. And we're launching a new company in this space as a new way to give you advanced capabilities to understand between micro needles and these new biosensors from Tom Soh's lab, the ability of measuring lots of different molecules at the same time, opening up mental health issues, degree of the state of performance, all sorts of things maybe that might go wrong earlier before you detect normal ways. And so it opens up sport, wellness, and other things. So we're really excited about where this technology will go. And thank you for your attention. (audience clapping) - Okay, everyone.

I'm Renee Zhao, currently an assistant professor in mechanical engineering at Stanford University. So today I'm going to introduce our recent work on millimeter science and robotic system for non-invasive surgeries. So look at what we have, the current technologies for disease diagnosis and treatment. Usually we are looking at all tethered systems. We rely on tubes, catheters and guidewirers, sheath and probes.

For example, here is the upper endoscopy procedure where the surgeon would need to insert this tube all the way to the stomach. And this is another procedure, another example here called aortic valve replacement. The surgeon would need to cut somewhere from the femoral wing, somewhere here, and then insert the catheter and a guidewire from here and all the way it goes all the way to the heart. So this is actually, the guidewire is used for this procedure which is made of stainless steel. And this is another example of using the sheaths.

Have some degree of freedom to control the far end of the tip, but still very limited. We really want the very agile motion of the tip, right? But the degree of freedom is really limited by the motion from the far end. So imagine now if we have a technology that can do everything un-tetherly? And what we are going to get is what we recently developed, a milli sized robotic system that can integrate its locomotion and targeted drug delivery. So what we have here is a millimeter sized robotic system controlled by external magnetic field. And we use the magnetic field to control its locomotion.

And what is more interesting about this device is that we can use one magnetic field to switch between different functions. So we have the locomotion controlled by the external magnetic field, and we also can use the field to generate a folding of this origami robot. So when we think about origami, that means paper folding. That folding mechanism actually converts to a pumping mechanism for targeted drug delivery. So what we are doing here is to use the external magnetic field to control its motion and then once it reaches the target, it could easily switch to the pumping mode and then achieve this targeted drug delivery capability.

So here we are just using the magnetic field to squeeze the origami robot and then pump out the liquid medicine. And what is even more interesting about this very simple but robust robotic system is that due to its geometric feature, we can actually make it swim in water. So this robot really serves as an amphibious robotic system that can roll, flip on ground and can also swim in water. So what particles that we added to the water shows the turbulent flow it generated during swimming. And this is a slow motion showing how the spinning is inducing the swimming motion for the robot to swim in the fluid. And of course, we can couple these motions together.

And this is a video showing the robot is having this on ground motion in a pig stomach. And what is inside of the pig stomach is viscous fluid. And they can easily switch the motion from the on ground rolling and flipping to a swimming motion in the viscous fluid. And now of course, it can be coupled with targeted drug delivery.

And now let me give you a very brief introduction about the swimming mechanism of this robot. So basically this is origami robotic system that has its tilted panel that serves as a propeller blade. When we spin it, it generates this swimming motion. But we also have this structure that the whole origami system is a thin-shelled structure means that it has this internal cavity.

And we have this hole in the front, and also this lateral cuts. And this mechanical design, or we call it geometric design, allows it to suck water in from the hole and spins water out from the cut. And that actually generate a suction mechanism which is very interesting for other functionalities. So what we can use it for is actually, the answer to that question is similar to the answer to this question. If we think about how fish eat food, right? Fish does not have hands, it does not use forks and knives, right? How do they actually get food into their mouths? If we think about that, it actually opens its mouth in a very short time, like suddenly opening of the mouth, creates a negative pressure, and that causes this suction mechanism to suck in food.

So now we have a mechanism to generate this negative pressure by spinning. And ideally we could use that for the same functionality, right? So this is a small spinner trying to approach to this small little object, and then just by spinning, it creates a negative pressure inside and that leads to this suction behavior. And right now we can integrate all functionalities together. So this is a artificially designed environments that we use to test our milli robot that can curl, can roll and flip on ground and can jump into the water and swim to the target and capture this a little tiny ball and then reach the target location and then release it, and then it will swim back to where it original came from.

So everything is controlled just by the magnetic field. And so this is how the multi-functionality is integrated to this small robotic system. And I actually have the robot with me.

So after the talk, if you're interested in looking at the actual device, feel free to take a look. Thank you so much. (audience clapping) - Great, well, we're gonna move quite a bit more squishy from the plastic printing to the magnetic actuation printing, now to sloppy floppy biology. And it brings a whole host of challenges, but exciting opportunities. And I'm gonna talk to you about work that I did as a postdoc and where we're taking this at Stanford to be able to take cells from the Petri dish and working towards the whole scale of human bio-pump.

So our target patient population are children that are born with a particular heart defect. It's called single ventricle disease. So most of us sitting in this room have four chambers in our heart, two atria and two ventricles. And these children are born with only one functional ventricle. And this means that blood that is deoxygenated coming back from the body is mixing with oxygenated blood coming from the lungs and is being pumped out to both the lungs and the body.

And as a result, this mixed blood doesn't have enough oxygen, it's being not fully oxygenated. And so the end organs for these patients would not get enough oxygen. And sadly, in the past, these patients would only live a couple of days. But in the '70s, a series of phenomenal and courageous surgeons produced these amazing surgeries that would result in this circulation called the Fontan circulation. So what they would do is they take the veins from the body of these patients and connect them up to the arteries of the lung so that the blood coming back from the body no longer visits the heart. It actually goes straight to the lung bypassing the heart.

And that means the blood now coming back from the lungs, it's oxygenated, visits the heart, the heart beats, it goes around the body, then goes around the lungs, and then back to the heart. So most of us with our heart, that the blood travels twice to the heart per once around the whole body. Whereas for these patients with a Fontan physiology, it's once. Now this actually allows them to survive for two to three decades of life, median life, which for a lot of interventions in medicine is incredible, right? We would consider a 30 year survival to be incredible if this were an adult. However, these are newborns and 20 to 30 years is not enough.

We want to be able to extend that. So what's going wrong with the Fontan physiology? Well, there's no right ventricular pump, right? There's only one pump. And we're asking that that blood to now go through the inferior vena cava and to the lungs as well. And what that causes a lot of backup of pressure venous congestion. And also the lungs expect to receive pulsatile flow from a beating heart.

And if they don't see that, they get a bit angry and they sort of close up. And these vessels get very high resistance, and that high resistance causes even more venous congestion. And with that high venous congestion, you have this very high pressure that backs up through your body to your liver and ultimately causes this end organ failure after two to three decades of life. So we want to change the trajectory for these patients. And to do so, we propose manufacturing a functional and living bio-pump made up of the patient's own heart cells derived from their stem cells that we can use to be able to introduce more pulsatility and energy to help the blood pass through the lungs, essentially acting like a second ventricle, but not in the heart. Now if you do the back of the envelope calculations to make this, it needs to have a thick wall, 4.4 millimeters thick.

We need 3 billion cardiomyocytes to make a single pump. That's the heart cells that beat. We need vasculature to keep that core of that tissue alive.

And we need valves to make sure that when this tissue beats it's producing flow in the correct direction. So we're in the business of manufacturing large amounts of biological tissue. And if you look at the ingredients that go into that, there's vasculature that supplies the cells, there's matrix that bonds the cells together, there are cells that bestow the function of the organ. In the heart, those are the cardiomyocytes that beat, these cells are not just willy-nilly growing all over the place, they're actually micro-architectured. So in the heart, they're aligned so that they're all beating in the same direction and working together.

And all of these aspects, all of these recipes need to be fabricated, a scale that is human relevant. Now, when you're manufacturing solid organs, unlike connective tissues like tendon or bone, when you go to the solid tissues like liver, heart, kidney, the cell density of these tissues is enormous. We can't sprinkle a few cells into a polymer and expect it to have the same kind of activity as hundreds of millions of cells per milliliter. And these cells are architected from the tens of centimeters down to the single micron.

And in order to keep those cells alive, the vasculature provides the oxygen and nutrients to maintain that densely cellular, very energetic tissue. Now, in the last decade or so, there's been amazing advances that begin to address some of these challenges and how we assess getting that many cells together. And one of these is called iPSCs, it's a way, it got the Nobel Prize in 2012, invented in 2008 by Shinya Yamanaka. And you can take a skin cell and turn it into your own embryonic like stem cell.

It's called an induced pluripotent stem cell. And the field can now use these to generate cells of all different types. Not only that, but if you culture them in the correct environment, people are showing that if you take a ball of these embryonic like stem cells and nudge them to become different tissue types, they start generating these things called organoids that resemble the kinds of multicellular architectures of our living body. So maybe for printing, we don't have to print every single cell. Maybe we can work out how to make biology do the hard part of the small scale. And all we need to do is assemble things at the large scale and make sure it has oxygen and nutrients.

And to do that, we use this really special method of 3D printing called embedded 3D printing. So instead of printing layer by layer, this is actually printing one material inside another. It works because this material is liquid like enough that a nozzle is able to come through and print it, and the material can self-heal behind that translating nozzle. We're not carving canyons into that material, but it's solid like enough at the same time that whatever we deposit there stays in place. It neither sinks nor floats, nor pulls itself in back to a sphere. So the key to make this work is a property called visco-elasticity.

This material needs to be a little bit solid like so that it holds the printed material in place, and a little bit liquid like so that I can move a nozzle through it. Think of mayonnaise or toothpaste. Now we wanted to test whether human iPSCs, these inducible pluripotent stem cells would be able to serve as a matrix that was viscoelastic. So to test this working with a post-doc at Harvard, Sebastien Uzel, we cultured hundreds of thousands of these aggregates and we've compacted them in a centrifuge to form a paste that we could extrude onto this little platum and measure the properties of this stem cell paste.

And we found that as you increase the stress on them, the viscosity goes down. That means that it flows more freely as I push on it. And that really helps us do the printing. It's also viscoelastic. The solid line here is how solid like it is.

The unsolid part, the open circles are liquid-like, they're roughly similar in magnitude with a slightly more solid like than liquid like until I push it to a critical amount of stress, about 10 pascals, and it gives way. Just like to get your toothpaste out of a tube, you could hold the tube upside down all day and nothing would flow. But if you squeeze it, it comes out, it flows onto your tooth brush. I'm such a 3D printing nerd.

(audience laughing) Onto your toothbrush, And you can hold that upside down again, it's self healed, it's becomes solid again when it's on your toothbrush. So basically, we have a toothpaste of human stem cells. So let's take a look at what this looks like up close.

Each of these is about 2000 stem cells forming this little aggregate, little pieces of couscous which get pushed by the printer as it's coming through. You're looking underneath the printer nozzle and you see that the cells re-zipped back up again. and not hurting the cells.

However, if that print head is extruding a jello like material, gelatin, you can see that it comes out and it pushes the cells aside. And we can create space in those cells that we can uniquely use to be able to provide the oxygen and nutrients to keep those thick and densely cellular tissues alive. So taking a Zoom out, we have about a billion human stem cells here that we're extruding. It's sort of like a, you see that sort of consistency to it.

It's got that little bit of solid like property. It's really like a human stem cell slurpy. And this printer is now depositing gelatin into that.

You can see it's translating through the material, it's not causing damage or cracks. And the gelatin is able to be remained in suspension. And now we raise the temperature of the tissue and that causes all the stem cells to lock together to become solid like, and at the same time it causes jello that melt in the mouth stuff to liquefy. And we can push out the jello and leave ourselves space that we can now connect these channels to a pump and perfuse that tissue with the oxygen and nutrients it needs to develop.

Now in tissue engineering, this is a game changer. Tissue engineering is a four decades old field and has really struggled with vascularization. And this allows us uniquely to keep thick tissue alive. And we can print not just one vessel, but a whole range of branched vessels from a single inlet to a single outlet that we can use to keep thick tissue alive.

If I took a tissue with no vasculature inside of it, the outside stays alive, but the inside within 12 hours is dying from a lack of oxygen and nutrients. But because we're able to perfuse this channel network through these pumps, it's able to actually provide a full thickness viability, full thickness survival of this tissue. And we can work with all sorts of different cell types, be them pluripotent stem cells, little mini neural tissues, as well as beating cardiac steroids. So let's take a look at one of those cardiac examples. So we cultured hundreds of thousands of cells, these aggregates, using established protocols to make them start to beat. And they're about 80% cardiomyocytes.

And if you look at them under the microscope, you can actually watch them jiggle. They're beating just like a human heart would. Now, if we use these as the row of material to manufacture a larger scale tissue, we're gonna have a problem. They're not talking to each other. So instead of beating like a synchronous heart, they're just jiggling around. So we wanted to see if we start culturing them for extended periods of time, whether they would start to fuse.

On day one, there's not much motion. You can kind of pick out the individual aggregates. But by day 10, you can really see that they've undergone this fusion. And you can see the tissue now beating is in a synchronous and much stronger fashion. So putting this together, we can now have a high number of cells that's thick and we can write the vasculature down into that with the gelatin, wash out the gelatin, use that space to then flush the tissue with nutrients.

And after 16 days in culture, you can see this tissue that says it's centimeter tall. You can see it throbbing and beating and it's pulling on these springs here that are actually training it like it's at the gym, it's working. And by doing that, you actually align the cardiomyocytes. They sense that force and they're able to align in the correct direction.

And we can introduce drugs and test drugs into these channels and see how those affect the heartbeat. But of course, the long term goal is much more complex in a single Y channel. We want to be able to take more patient specific geometries and be able to create spaces that we can use to perfuse unvascularized tissue at scale.

So this is kind of the central dogma of our lab here at Stanford is how do we generate enough stem cells to build these building blocks that we can use to manufacture functional tissue? How do we vascularize that tissue to achieve viable and cells that can mature over time? And how do we do all of this at a scale and speed as Joe talked about, speed is a very hard thing to achieve in 3D printing. And if you're working with living cells, then you have to finish your print fast enough that the cells are still alive at the end of that task. And so we work across a range of different scales looking at synthetic organoid engineering using advances in genetics to be able to manufacture tissues more readily and rapidly using the vascularization that I showed you as well as new types of 3D print heads that can manufacture things faster and with multiple materials.

So this is our lab, this is our socially distanced emo photo when we started in the pandemic. (audience laughing) And this is us moving in our new bio printer into the space. It's a four and a half ton machine that took 18 months to build by the company and watching them turn it on its side. This four and a half ton block of granite was absolutely terrifying. But it got in, it survived and we're having a lot of fun here at Stanford.

And with that, I'd like to acknowledge the work by Jennifer Lewis and Sebastien Uzel. We worked on this vascularization method as well as the members of my lab working now on scaling up all the work that I just showed you. And thank you for your time.

(audience clapping) - Yeah. - So each of the three presentations we just saw were variously based in chemistry, mechanics and biology essentially. And they all look complex enough to require their own interdisciplinary expertise. But can you comment at all on what is interesting or special about Stanford, if anything that allows or simplifies what seems like some obvious interdisciplinary levels of expertise that would enhance each and every one of those in and of itself, if hopefully that makes sense.

- Sure, I can certainly start. So Netra who's in the audience here, is the one that's driven the work in the lattice micro needles that you saw. Hart Ecker's in the room here too, he's a software engineer at Carbon. What's cool about Stanford and I was 25 years at the University of North Carolina at Chapel Hill top 20 University, one of the few that doesn't have a school of engineering that's at North Carolina State University, 25 miles apart. My group back then was 90% chemistry students at Chapel Hill. Here, I wore mostly natural, right? A lot of engineers, bioengineering, mechanical engineering, material science, chemistry, software.

It's an amazing, everybody under one roof. And we're in a building that is less than a hundred yard from school of medicine, less than a hundred yards from school of engineering. That culture, and students wanna be translational. There's a culture and we're a customer to OTL and other places like I've never seen in my career. It's pretty amazing.

- Yeah, I would say the environment and the culture of Stanford really encourages interdisciplinary research like our collaborator in the medical school, which is really awesome. Always open to new technology, new engineering device. So this has been really, really helpful.

- Yeah, I think there's not too much to add to that other than, as Joe was saying, name any other place that's got a world class engineering and world class medical school in the same place right next to each other? And actually, I don't think it really exists anywhere else other than Stanford. And it's a phenomenal place to do the kind of bioengineering work we do. We have a surgical fellow, we have a medical student, we have bioengineers, mechanical engineers, all in the same lab and I couldn't do it without all of those skills.

So it's great to be at Stanford. - Microphone over here. - [Audience member] It's okay, I can talk louder. - Right there. - Okay, Martin Bergen.

With the patch for immunization and stuff like that, how commercially ready is that? I mean, will the needle go away and flu shots and all these other things as a result of that? I wondered how you can make that many pinpoints in a manufacturing type of environment. - Yeah, so our back of the envelope is that a room with about 200 printers could be a gigafactory meaning a hundred million patches in four times a year for just 200 some printers. And so the throughput is really there to support that. Bill Gates directly is now funding the lab.

We are focused heavily on measles and rubella. He's got global interest and the key is with a patch, when you think about it, it could be self-administered, the stigma, pain goes away. We're actually delivering a vaccine as a solid state product, not as a liquid. Looks like that will mitigate a lot of the cold chain issues that they're keeping it frozen upon distribution. So those things come together and it's more efficacious 'cause you're delivering it to where the cells are.

All those things, we're very excited to make this very translational, but there's a lot of microneedle companies that are dead on the road to success in that space, but they've been using the old ways of making things. We think this new approach for fabrication opens up an innovation platform to make it happen. - [Audience member] When will we see it? - So we expect to be in some IRB oversighted trials here at Stanford in the first half of next year. Some ISF sampling work, and then moving into, we're already moving into animals now. There's a lot of veterinary and stock, pigs and livestock applications that we think will help us propel it more into humans. That chair.

- (indistinct) What prevents it from busting through the artery or the vein wall? Like the demos you gave, was it a plastic sheath that was going through and how would it work actually in a real human being? - Yeah, so we already have the ex vivo experiments using a pig blood vessel to test, well, basically the clots were from pig blood, so we generate clot from using the pig blood and we are testing also using the ultrasound to see what's going on in there, and testing the performance of the spinner in terms of its how a interactive inside with the clot in the real pig blood vessel. So that's what we already have done right now and the next moving forward we're going to test it in a live pig. That's what's the plan next. - Go ahead.

- Also on the spinner, I'm just curious, you said several times it's controlled by a magnetic field. How sophisticated is that magnetic field of what level of feel, what level of control, how precise, how cheap? - Right, sure. So there are different ways of generating magnetic field.

Currently for the videos I showed, some of them are used directly using the Helmholtz coil which is a three-axis magnetic field that generates homogeneous magnetic field in all three dimensional spaces. So we can change the magnitude and spinning frequency that controls the swimming speed of the spinner and also the driving force of the spinner when it interacts with the clot. There is another way to generate the magnetic field that we want is by directly having a robotic arm controlling the spinning of a permanent magnet.

So that creates a gradient field, but we can control the gradient field, how much it decrease and how large the field can be directly applied to the position where the spinner is and to control the spinning motion. And that actually works pretty well. So in terms of cost, manipulating the permanent magnet would certainly be much lower cost considering if we generate a homogeneous magnetic field using a device that would be some device like MRI machine, which is really big. So I think what the future direction to go is to developing a robotic system that is compatible with manipulating the rigid body motion of a permanent magnet to control remotely the spinners motion in human body. - Is there anything in the course of your guys' research that you anticipated to be true and you surprisingly realized wasn't? Something that would normally be true or that you hypothesized to be true, that you found to be not.

- Okay. - Isn't it? I've got a ton. (audience laughing) But I'm old.

(audience laughing) - Well, that's an interesting question, but I wanna mention something that's actually went the opposite way. So initially the suction mechanism of the spinner, we didn't expect that. It was really by accident we found out that that geometric design actually gives us a very good fluid dynamic performance. So that's where we started to pursue further and then using that mechanism to deal with clot removal and also kidney stone removal. Yeah, that's kind of the opposite direction.

(audience laughing) - I think from our end, I don't think we quite anticipated how expensive the work would be. (audience laughing) 'Cause stem cell biology is very expensive when you're working on a Petri dish and it scales fairly linearly with the number of cells you wanna make. And because the questions we're asking are how do we keep thick and large tissue alive, I mean, that was the dumbest idea to go straight into that. 'Cause it takes a ton of resources. But we're actually, necessity is kind of the parent of invention and that has had us thinking, are there ways we can make stem cell culture cheaper? Why is it so expensive? And we think we have some strategies we're working on to be able to dramatically reduce the cost of stem cells. Which interestingly enough, and I wasn't expecting myself to get interested in this field, but if you wanna make large amounts of tissue out of mammalian cells, there's another area where that's very interesting and that's in these synthetic meats that some of you may have heard of where you sort of culture animal cells and make a burger out of them.

And the difference between making a heart tissue that beats and making a burger is kind of whether you cook it. (audience laughing) It's very similar. And fortunately, there's a lot of people in the world focused on making cells much, much, much cheaper. And so it's very exciting to see kind of where industry and academia is gonna play a role in that and it'll help this work a ton.

- [Audience Member] So on the cost issue, I'm curious how much of your time you spend worrying about funding, and is the center of gravity in the disciplines here so strong that NIH or the foundations you list or others who are able and willing- - So just to make sure I heard that, how much of our time do we not spend about funding? (audience laughing) Oh, yeah. - [Audience Member] So you're testing them more than they're chasing you. - Yeah, you have to chase them.

- It's enormous effort, Jim. It's... - [Audience Member] Does Stanford make it easier than elsewhere or do you know, or how do you about that? - So these folks, younger folks, it's so competitive right now, and I grew up academically in a different era, it was a bit easier and I'm restarting my lab here as I mentioned, they're doing it for the first time. It's an enormous lift to go from zero to be at steady state and they're in middle of that. This is some of the most amazing science I've seen and it's extraordinary at this highest levels, it's extremely expensive. A average student is about a half million dollars for their PhD.

That's easy. And that pays salary and some supplies, let alone a major equipment. So it's extraordinary. A lab will run easily a million and a half dollars a year and there's a thousand labs here that do that at that level.

It's a lot of effort to do this and they're teaching. And then we have clinician scientists that are 60% in treating people and expected to run a lab. There's amazing colleagues here that pull all that off. - This is a question for Mark. So when you're working on 3D printing, the heart or aspects of the heart, how beholden are you to the idea that you wanna recapitulate as close as possible the actual human heart? Wouldn't you just want to get to the point where it's good enough functionally? And while you're at it, would you ever consider making improvements on the design of the actual human heart? Are you open to that? - That's a great question. You spent a lot of time with George Church.

(audience laughing) That's a great question. So first of all, the device we're trying to make already doesn't look much like a heart. It's designed to fit in place where surgeons to do that Fontan circulation, they put a pipe, a passive tube to connect the inferior vena cava up to the pulmonary arteries. And so we thought, why do we take that same geometry? So it's an established process, the geometry fits, but make it a beating pipe made up of human heart cells. So that already is a different sort of design.

In terms of making a heart that's better, I mean, shoot for the moon and maybe you'll reach the second floor. But yeah, I think that's kind of where synthetic biology plays a part. I have an engineer's mindset, so I don't necessarily play by the rules of developmental biology. I think we should use all the tools in our arsenal to be able to craft and make biology, do what we want it to do. So can we make a better heart? We can try. Yeah, it's a great question.

- Yeah, hey guys, thanks. I had a follow up question for Dr. Skyler Scott along those lines. Yeah, thinking about applying your technology to the arterial side and to the even much larger number of folks who have congestive heart failure, who need help on that side, can you talk about other technical challenges that might be required to deploy it on the arterial sides? Yeah, I was thinking specifically about innovation and synchrony with the- - Yeah, that's a very insightful question.

So that actually speaks to why we chose to solve this problem with the right side of the heart that feeds the lungs. You only need about 10% of the power to serve as the right ventricle compared to what the left ventricle has to work against. It's much harder for the heart to beat it around all your body than send it locally to the lungs.

So we only need about 0.3 watts that can barely power an LED to be able to provide sufficient energy to the right side. To go to the left side, we need a lot more pressure. It's about 10 to 12 times the pressure that we would need to supply, and that means a lot more energy, and it's also much more critical. So in the Fontan circulation, if that pump that we're building fails, it becomes a tube. So long as it doesn't rupture, so long as it just stops beating it, it's a tube.

So it can still perform its passive function. If you're replacing the left side, you'd better make sure that that's gonna work for a lifetime, and that's gonna be very, very challenging. And in terms of arrhythmias, that's a very important problem, right? Sudden cardiac deaths, terrible affliction that can can happen at any moment and it's caused by arrhythmias of the electrical system of the heart not synchronizing the heart.

Now fortunately in this case, our tube that we're building is not connected to the heart. So if it has arrhythmias, it won't spread to the heart. And secondly, if it has arrhythmias, it defaults to a tube. But again, if we're to work in the heart, I think the safety bar is gonna be much, much higher and much, much harder. So I'm gonna try and work with the right side and if we can get better cardiomyocytes, if even better than the ones we have in our normal heart, then I think that we're in for a shot for left sided. Yeah, great question, are you a doctor? - [Audience Member] Yeah. (audience laughing)

- [Audience Member] I actually work on vaccines, not cardiologist. - But it sounds like you're a real doctor. (audience laughing) As my wife would say. - [Audience Member] And even after, and you mean real instead of imaginary? - I'm an MD versus not, so. - I had a question about the spinning or spinner robot.

As you mentioned, it uses origami function like with this special geometric design that allows it to do all these different functions. I was wondering like origami is being applied to a lot of different fields of science and engineering. So I was wondering like is there something special 'cause due to its size that allows it to stretch and compresses, that's one of the main benefits of that technique.

So is there something special about the material or like the way it's structured? - Sure, yeah, this is a good question. What we are utilizing here is not only the folding capability of origami itself, it's also it's geometric property and how it interacts with the environment to achieve the amphibious motion, including Unruh motion and in water motion. And in terms of the material, we could develop the origami robot using biocompatible materials. Basically, it can be a stiff material as long as it's thin enough, and it has self hinges to allow for that degree of freedom for folding.

So yeah, hope that answers your question. - [Audience Member] Yeah, thank you. - [Audience Member] How about a final round of applause for our teachers? (all clapping)

2022-12-12 04:31

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