I have one little quick follow up question for the presenter. So, you know, Evan kind of alluded to this how we're kind of getting more into a lawyer focused world and I feel like the grips of the legal concerns are kind of grabbing many of our institutions. So any tips or tricks that you can that you may be able to share to explain the importance of this kind of relationship to your institution and be able to kind of maintain your for your patients. I think there's different ways to go about this. One way I could say that everyone who wants to work with industry should be familiar with your own institution's conflict of interest policy, like know what it is that you are allowed to do with industry. Are you allowed to consult? Are you allowed to earn any income from your consulting? Does that income come to you personally? Does it go to your practice pool? Does it go to your university? Then get redistributed some other way. There is no point in trying to do things through the back door that can only come back to bite you. Just do it the right way. Find out what the legal requirements are in your institution and follow those rules. I really think that's really important. You don't want to get into any trouble. We're all trying to do the right thing, but doing it the wrong way can get you into trouble. I will say, Brian, it's a good question. I really only worked my career at two places, one in Miami and one in Los Angeles. I can tell you that a lot of it is institutional culture. I will say without denigrating anybody or anything, when Miami Children's, when I was there, was just very unfamiliar with what we're talking about, these relationships with industry. Basically, for the decades I was there, it was almost always a bit of an uphill battle. Most of that was just education, that this is good for the hospital. Why are you going to Flagstaff, Arizona all the time? It doesn't make sense. You should be here. But a little of it is seeing is believing. Then they started seeing all the ASDs that were coming to us, only half of which we could close. The other half went to surgery. All of a sudden, it was a great thing because it was generating revenue. So it's not just the legal part. It's getting the institution to recognize it. I think some of the more, my perception is some of the larger, more advanced institutions have been around a while. They kind of get this. I can certainly say that for Cedars, the whole institution is built on these kind of relationships. So they really, again, as Matt said, you got to over disclose. But as long as you're upfront and honest, but I realize that there is a great variability between institutions. And sometimes it just takes a lot of patience and education to get them to understand really how beneficial this is, not just for the patients, for your program, but for the hospital as a whole. Yeah, I would add on to that. I mean, when you read and when you meet with your conflict of interest people, a lot of people who are on these committees are people who would never actually be invited to have a conflict. Right. So it's like so it really so there is a clash of cultures. You're an interventional cardiologist, your mindset and the way you see the world and medical therapy tends to be more aggressive and out front and trying to push the envelope. That's sort of what we do. Right. So when you and these are not the people sitting on the conflict of interest committees, they're not I'm telling you, because I've lived this. However, if you go and you sit and you explain to them and it is conversations specifically, you know, one thing at a time, like for the for the harmony valve trials, for example, this is why this is important for patients. This is why it's important for the institution. Here are the finances in the catheter based valve world. And the aortic market is one point five billion dollars a year. There is no market for the pulmonary space, but here we have this growing population. And we at this institution have a chance to be in front of this. And this is what's going to require of me and my time. And this is what it means. And then what they do is they say no. But then they think about it. Then you go back and then they draft a conflict of interest management plan for each individual thing you want to do. And you have to update things as they change. And you get a letter from them and you sign it and you all agree to it. So you can do it. Now, that was hard to do maybe 10 years ago. That was a chance. Now it's nothing. It's the same. I just go in. The same people are there. I say this is what this is. This is why. And you can work through it. But it does. Again, all of this requires extra. It's all extra energy, extra time to actually get this going and then to sustain it. But once you do it and you're if you stay at the same institution long enough, these people start to know you and they know what to expect. They see success and results. They don't see problems that they were imagining. They're not afraid of. And it can change the culture slowly. Thanks so much, guys. That was a great, great question, Brian. We're going to move on just to Henry now. So Henry was going to speak a little bit about his journey through the device development process, but really honing in on the concept of creating a device based on the concepts and the needs of our community and our patient population. And then that the research and development process that goes into that. So I'm going to turn it over to Henry for that. Yeah, thanks very much, Arash. So, I mean, in a nutshell, I think all of us are sort of the experts of our field. We see what the devices out there are capable of doing. We see what they're not capable of doing. We see the drawbacks of what's available and we can see the unmet needs that our patients have. And that's where all of us can be sort of if we're attentive to those things, can come up with ideas that can help our patients further. So I started with the idea that transcatheter heart valves that we currently have available are really very much adult valves. I mean, we can shoehorn them into some smaller kids, but they're really adolescent and adult valves. Nobody makes a valve that's very tiny, that's suitable for a toddler, you know. And so with that idea in mind, I met with some engineers and we decided to, you know, meet with our institution, apply for a provisional patent, start working on developing some prototypes of a pediatric sized transcatheter pulmonary valve. And, you know, the concept behind it is that if you think of all current heart valves that are out there, they're all animal tissues hand sewn onto some metal frame. You know, we're talking about dozens of hours of labor to sew these things together. And if you think that, let's say for the Medtronic melody valve, it's widely known that it's about 15 hours of labor to make one valve. And in the manufacturing process of trimming the fat and the connective tissue off the bovine jugular veins and so on, more than 95 percent of the raw materials are discarded in the manufacturing process. It makes these valves incredibly expensive to source. And all of the technologies that we see out there right now are all a first world solution, right? A very limited population benefits from these solutions because they are incredibly expensive. So when you add the expense of the manufacturing and you add the size constraints that they're all made in adult sizes, we thought if we're going to scale this down even further to make very small valves, how are we possibly going to do that and hand sew at even smaller sizes and achieve cost savings by doing that? So we had to rethink the way we are going to manufacture valves and we approached it by making them out of a medical grade polymer. And that way we can manufacture them in any size we want. We've manufactured devices down to 10 millimeters that work really well. We can make the leaflets incredibly delicate and yet very resistant and have a lot of consistency in our manufacturing. Which the animal tissues don't bring a lot of consistency to the table. Every animal is a little different from one from the other. The pericardium is not always the same thickness. The bovine jugular leaflets are not always identical and symmetrical. And so that's where we sort of departed from the standard animal tissues hand sewn onto a metal frame. And with that, you know, the journey has been a long, a long journey. And I would echo what others have said. All of this is extra. It's on top of your regular job. Nobody excuses you from your other, you know, obligations to do this kind of work. But I think little by little we're seeing results. You know, we started by doing bench top testing on the valves and showing that we can get reproducible results both on the valve performance and on the valve durability. Once we passed the International Standards Organization requirements for durability, which is 200 million cycles for a flexible heart valve. We then transitioned to an animal study and did chronic animal studies to show that the polymer wasn't calcifying or degrading and that sort of thing. And now we're sort of at the next level. And the next level is, you know, the stuff that is beyond what most of us understand and know. I mean, already a lot of this is beyond our general understanding. I'm not an engineer by background. I like to think sometimes that I like to pretend to be one, but I'm not. And so there's a lot of engineering that goes into this. But then the next steps beyond this are a lot of business knowledge that I also don't have. We don't learn these things in medical school. So how to professionalize the company, how to get proper documents created, how to, you know, issue shares and how to, you know, equity plans. And all of these things are very, very complicated. Dealing with intellectual property agreements with the university, licensing agreements back from the university once you have a patent. You know, all of these things are incredibly complicated. And I would say that one of the things that really helps us to surround yourself with people who know what they're doing. You don't have your life isn't long enough to learn all of this on your own in time to get any of these things done. So you really need to surround yourself with people who know what they're doing. I would say it is not difficult typically to attract engineers who like to think of these things. It's harder to attract people who then want to run with the company professionally, like a CEO or those kind of level people, because you come to them with a prospect for a company and a product that, you know, the sales are just not going to be it's not going to be a billion dollar company. And most venture capitalists looking at funding companies are looking at companies that are billion dollar companies. So if you're looking at something that's going to make a few hundred million dollars or a few tens of millions of dollars a year, you're in a different category right away. And as pediatric medical device developers, we're in a very difficult category. We have to find ways to fund companies in ways that are creative and different. So what what I did, and it's only my experience, it's not necessarily the right way or certainly not the only way, is I thought that if we started right away going with an idea on the back of a napkin to a big company and I talked with them. But by the way, when you do that, you have to be under a non-disclosure agreement to have those things firmed up so that you're those conversations are protected. And when we did that, most companies said, I love what you're doing. I think this is a great idea. I could definitely see how this could benefit patients. But, you know, and then there's the but, right? It's like being let down for a date or something, right? It's like, you know, it's sort of like, oh, God. So what is it? So it's the market. It's always the market. It's always the market. It's a small market. It's never going to make a lot of money. And they're beholden to their shareholders. They can develop a medical device that they can sell hundreds of thousands of a year or they can make a medical device that they can sell a few hundred of a year. And where are they going to pour their energies and so on? Taking a medical device to market, especially a class three, which means an implantable permanent device, is in the tens of millions to one hundred million dollars. Yeah, at least. Yeah. Yeah. And those are the things that that make people shy away from investing in a company that has a much lower return on investment. The cost is still high, but the return on investment is much lower. So what we did, again, just what our approach was, was to start with grant funding. And we started initially with some small foundation grants, kind of getting pilot level data. When you get those kind of data, you can start to apply to other grant, other foundations to get larger grants, larger grants, eventually NIH grants. We got an SBIR, excuse me, STTR, but similar phase one NIH grant. Then that's about a two hundred twenty five thousand dollar grant. Then we moved on to an SBIR phase two grant. That's a two million dollar grant. Now we're starting to talk a lot more money and a lot more ability to do things with that. That was our point of cutting the tie with the academic institution, taking our what was really a lab that I had in the university where I was doing all the benchtop testing. I'd acquired all the equipment for this and we're doing all the prototyping and working with postdocs and those kind of things in the lab and taking all that out into now a private company and renting the space privately where we are doing all our testing and manufacturing where we have a clean room, we have all of that stuff. So that's where we made the cut. We now license from the university our intellectual property and we're developing additional intellectual property that will be sort of held within the company. So that's kind of our journey in all. We've raised about three and a half million dollars and it's all been grant funded. We haven't had to have a single penny of dilutive funds from investors. But all of that is still just a very early, early step despite many years of work. It's still not going to get us to the 50 million we need to get to market. So the next step is going to have to involve investors and we are now in that process of the very first raise with investors. We've already got several angel investors, you know, write checks and all that. But then you're in a different mode. Now you're sort of meeting with investors and talking to them about your idea and what you're doing, why it matters, why it's going to help patients. And again, that's not something we have training in. We don't we don't learn about this in medical school. And it's really just trying to be very honest. You're not you're not trying to say that this is going to change the world. You're not trying to say that this is going to make anyone filthy rich. You're saying that this is an unmet need and here's what we're trying to do with it. Here are the pitfalls we're going to try to avoid. And here's here's our business plan. All of that, again, requires a lot of work. A lot of people who I can say I've been very fortunate to surround myself with who know a lot more about this than I do to help advance this. And that's been my journey so far. I will finish by saying that the statistics are that about nine out of 10 startups fail and that you have to be aware of that because that's a lot of blood, sweat and tears you're putting into something. It could be a decade or two of your life and it could fail. It could very well fail. In fact, the odds are it will fail and it's not failing necessarily because the technology is bad or because the idea was was poorly conceived or anything like that. It could fall apart because of some intellectual property problems with the university and lack of funding from investors or people not getting along and splitting the company apart. And it could be anything like that. So manage those relationships well, work with people as honestly as you can. I think all of us who are in this are not in it because we want to buy an island and retire. We're not going to ever have those kind of returns on the kind of pediatric devices we're developing. So just, you know, we're not about it into it for the greed. We're into it for trying to help our patients. And as long as we're clear about that and our motives are clean, I think we just do the best we can with with the situation we have and the patient's needs. So that's kind of a quick summary. Henry, I'm exhausted just listening to that. Now, let me just say something like I've been on the valve development journey, too, and I'm still suffering on the same path where you are in the mitral space a little bit. So I know how incredibly painful and it can be, especially when you're totally emotionally invested in something that, you know, can work and will work and will do good. And, you know, so just congratulations on your sort of your endurance and sort of seeing your idea through. And we are all hoping that someday, you know, it actually comes to fruition where we're using it commercially because you're tapping into the critical issue, which is a material science issue. It's not it's like moving away from tissue products that into something that's going to be more durable, maybe perhaps clot resistant and infection resistant. And all these things is just so key to everything that we're trying to do in our patients that we have to take from small to big. They have to grow. So you need something that that doesn't necessarily have to become alive, but it just needs to be better to have a better durability profile than what's currently out there. So I've always believed that you're really on to something there. And I hope to God that you can see this through to the end. So we're all pulling for you. But for people on this call, like what he's describing, you have to understand he works full time as a doctor, too. So it's like that. It's imagine all this. And, you know, Henry, how many pitch meetings have you been to? How many people have said no to you so far? Oh, yeah. Lots of people. You spend so much time talking to people and everyone uniformly. Nobody says this is a terrible idea. What are you doing? Nobody says that. Everybody says this is a fantastic idea is going to help a lot of people. But right. And it's always that problem. Right. So and then I would tie this back to what Evan was saying earlier and what we were saying earlier about the need to work with industry and the reason that it's critically important, because one hundred and thirty billion dollar corporation like Abbott can take on development of a pediatric or a congenital heart disease product, Medtronic. And Edwards can do this because they have massive profit margins elsewhere. Right. So this is why you have to work with industry to make sure that Medtronic and the Edwards of World stay engaged with us, because if you work with them and you lend them your energy and your time and your expertise and you help them get through the trials, your patients are going to benefit from that and they can sustain it. They can sustain so long as you're engaged with them and they they're not going to make a ton of money, but they might not necessarily lose a lot of money either. They might make a little bit of money in the pulmonary space relative to the aortic space. So so in order for Henry's idea to be sustainable, eventually it will need to be folded into a gigantic corporation to get. But there's a threshold that you're going to have to hit, right, that you're going to have to get it to a point nowadays in today's climate that you're basically going to have to be in humans before they before it really tips the Medtronics of the world over and say, OK, this is now worth our investment because we don't have to put the 50 to 100 million in to bring this along. We can, you know, partner with Henry to sort of help him get through the large scale pivotal trial, for example. So that's. For us, for our patient population, inventing for our patient population, I think eventually is going to land at a big if it's a congenital heart disease focused thing at a big corporation that has profit centers elsewhere that sustain the corporation. Right. So I think it's important. Yeah. Yeah. What you're saying, it's really important. That's right. The end strategy is an acquisition by one of the large players. The challenge that Matt is talking about is very, very real. There have been cycles of investment by these large corporations. And there were times when they would invest really in an idea. Yes. Easy. It was so easy. Twenty, fifteen, twenty five years ago. Right. Like you would you would have been gobbled up immediately for a lot of money. That's right. But the times are different right now. That's right. And others have invested at an animal trial or something like that. Now they're telling us that it's not even getting into humans. It's getting into sales. Yeah. Yeah. And some of them is not even selling. Yeah. They want to see revenue. You have to be a company, you know, so you really have to plan to go all the way through to be a manufacturer of a medical device, FDA certified, all of that before they may even look at an acquisition. So it's an extremely long road that may change. Maybe in 10 years it'll be different and they'll they'll be a flurry of activity of investment in early stage things. But now they're investing in much later stages. So you do have flashes of that, Henry. You do have flashes where like in 2015, they call it the summer of Mitra love, where there were a lot. There were four Mitra valve companies that sold that just got in this sort of really it was like a beating frenzy where industry just got drunk on this idea. The tavern was so successful. Mitra was going to be five X and four companies at that time that summer went for a total of two billion dollars. OK, and these were early. Some of them hadn't even gotten into humans yet. Maybe one or two had had had had a first in human case coming up. So you can have you can you can see these companies can get, from my perspective, can be sort of drunk and start being like they got to catch a wave and they can make these investments. However, it's just it's not like what's on the other end of that is potentially a five billion dollar a year business. So if you are so you're willing to spend five hundred million dollars on something, if it's going to complement your Mitra portfolio and could position you five years down the road in a five billion dollar market for pulmonary valve replacement. That does not exist. I mean, you may be in total. It's one hundred and fifty million dollar market annually. If you take all the pulmonary valves globally, maybe it's a little higher than that, which sounds like a lot of money. But for a big company like that, that's not a lot of money. It's not you. You can take your 50 million and invest it elsewhere and get that money back and buy 10 X in five years. So they do. So you run into the bean counters, you run into the actuaries, you run into the you know, you run into the people who define markets like the sort of J.P. Morgan health care assessment people who are prognosticating about where these markets are going to be. And so you go to talk to somebody and they have that report and you're not even on that report. Like a general heart disease, even on the report. Right. So it's so right. Like we had. So, again, bringing it back to what Evan and Henry were saying earlier, this is why you have when you have a company, a good company that's making good product to help your patients. You like I always felt like during the Harmony trial at any minute. And there were so many if that tale is ever told completely, there were so many points in that trial, from my perspective, that it all could have been met. And China could have completely walked away and we would not have harmony about because it's just, you know, you run into these valleys that are going to cost them a little bit more money to invest. And there are forces within that company saying, what are you doing? Let's put this over into Tavergen three. Why are we wasting time there? So. So, again, I think it's like what can help mitigate that is active engagement from our community. And, you know, that's sort of the way that the way that I've seen it. I think it's important to point out that what you and Henry are really talking about, which is really important, but but it's only one pathway. And I'm I'm engaged in that pathway right now. Right. I'm at a startup. So I'm kind of living Henry's tale right now with this little company that just started from scratch with the exact problems and pathway and ultimate, you know, hopefully coming to market and acquisition, everything you just said. So that is a pathway and it is everything Henry said. It's a lot of time with a lot of risk and it may never see the light of day. I think it's important to mention that that I've also been involved with with a different sort of pathway. And I don't know if this is luck and I don't know if it's widely applicable, but but I've experienced it. So it's got to be possible. And that is sort of coming at it the other way, which is actually much more of my experience with these companies, which is finding something that would benefit our patients. That's an idea that you can get them to invest in the big company. So you're not building the company. Right. So this was, in a way, Piccolo, but in a much bigger way, Altair. Right. So you got this company living on the house money because they're the biggest company in the world. And they're just honestly looking to do something else. I mean, there wasn't much more to it and maybe feel a little better about themselves. And honestly, I just pulled up the old email. Gareth Morgan asked me to pull up the original email. So, you know, in 2015, we were doing all this wacky hybrid stuff and we just took a chance and we went to the head of their R&D. We had a little, I didn't have much of a relationship with this company. Just I was just somebody on a trial. And we just went to them and said, hey, you know, couldn't you guys make something like this? Would you have a meeting to talk about it? Honestly, that's all it was. And they just had a meeting with us, their R&D people. And I don't know a lot of the inner workings, but it was just the right time. Maybe we were just lucky. But I think I will tell you. So that was 2015. And that thing was approved, what, last year? You know, lightning speed, right? Five years from can we talk to you guys to development testing? Because these huge companies have huge resources, as these guys have pointed out. And if that was like me saying, I'm going to build something that looks like Altera and start my own company, there's a pretty good chance that would have never seen the light of day. So there are I just want to open everybody's sort of mind to there are creative ways sometimes. And you got to be lucky to do stuff. Piccolo was not much different, right? This was the ADO2AS over there in Europe, sort of dying on the vine. They weren't really using it for much. They hadn't really gotten into premium PDAs. It was just some little plug that wasn't getting used. And then some of us over here recognized the utility of that and sort of brought Abbott along, kicking and screaming to a trial. I mean, to the point where we were going to fund it ourselves. But again, multi-billion dollar company, put the pressure on them, make them feel like they really need to do something good. And again, I think if somebody had come up with a Piccolo and tried to start a startup, probably never would have happened. But it's been sort of a win-win for everybody. So I just want to sort of raise that, that sometimes it is worth talking. And I know you guys did, you know, the big companies and you'll get turned down more than you get turned in, but it's worth a chat.

maintaining relationships

industry collaboration

conflict of interest policies

institutional culture

device development

funding challenges