 Okay, well, thank you for the kind introduction and I'd like to kind of highlight a few of the studies and experiments that we're doing downstairs some of the projects that we're working on. It's quite active downstairs, but I've decided that we're going to focus on three technologies that I personally think are the most promising and the highest impact. And again, this talk is basically just to kind of show the story that we have as we go from translation to development of medical devices, preclinical testing and ultimately even the clinical use. So I am a stakeholder equity owner of Seronis, Maxwell Biomedical, Nanolinia and XN Health. Every technology that's discussed is in a preclinical testing phase at this point. So the way we're going to organize this talk, we're going to first start talking about the wireless pacing for low energy and perceptible defibrillation. We'll then switch over and discuss some of our recent findings with conductive hydrogels for patient specific therapy and then finally we'll finish up with a little blurb about Excalibur or cath lab on a bench, and we'll discuss that. And it's a really cool opportunity I think for a lot of folks to become involved in medical device innovation. So let's start with the low energy pacing termination of fibrillation specifically. In this case, we'll talk about atrial fibrillation. We all know ICD use delivers typically 10 to 40 joules of energy to defibrillate the heart and multiple shocks may be given we also know that ICD shocks can be profoundly traumatic to patients. And it's just not a matter of ICD is it's often you'll have patients who come in, who have atrial fibrillation, and they need to get defibrillated and obviously that is an outpatient, often an outpatient process that involves you know being hospitalized and even as a same day procedure, a brief period of anesthesia. But what if you could actually terminate the AFib without delivering a high energy shock without it actually even being perceptible to the patient, we know that the pacing outputs the pacing energies are about one 80th that even the lowest intensity shock energies that are at the threshold for detection in terms of pain typically it's about one joules, and the powers that we're working with with with the pacing is about one 80th intensity and essentially completely imperceptible as anyone with a pacemaker can can tell you. When we talk about our work, you know, Igor Afimov and his and his group and his group initially at in St. Louis and now in George Washington University in DC, have shown that the concept of low energy termination of fibrillation is not is not a is not a crazy one for lack of a better term, but actually you can really do this, provided that you can deliver energy outputs from multiple sites and you can see that if you if you do that the energy requirement for termination of atrial fibrillation gradually decreases and and you can actually have termination of cardiac arrhythmia, delivering just by pacing from different sites, but these are shocks that are delivered. These are shocks that are typically around one jewel and therefore they are actually perceptible to the patient. So our concept was, we use absolutely no shocking outputs we use purely pacing outputs, and this is for atrial fibrillation so we decided, let's try test this concept and let's see if this actually does work if we can potentially terminate fibrillation purely by pacing. So we induced atrial fibrillation by giving a systemic new stigma injection and then we gave a citricoline close to the sinus node and rapid pacing. Often you didn't even need the rapid pacing once you give the citricoline and the new stigma, the, the animals go into fibrillation on their atrial fibrillation. So we then delivered pacing therapy using a custom built pacemaker to pace from multiple locations at varying delays. So we have this topera firm map catheter that was initially used by Abbott it's mostly for sensing purposes well but we decided to use it. It's a large basket catheter so it works really perfectly in terms of putting it in the left atrium and having good contact so that was our initial experiment and what the way we actually are driving the pacing is this cartoon will will note it's not just burst pacing we're actually going sequential we're going around the heart and I'm going to let this play. One more time. So we go around the heart and as we go. You can see different poles are getting stimulated. So the order, basically you go in one direction and then you wrap around and you come in the opposite direction. Why do this well we know that by phasic shocks with defibrillation are more effective. And this is a way and actually computer modeling has suggested for pace termination of fibrillation the same fact holds that by phasic will be better than monophasic and this is our way of mimicking a bi phasic pacing train. So it's it's not simple overdrive facing and obviously to do this you need multiple electrodes around the heart around the atrial. Atrial fibrillation again, as I said, with the new stigma and acetylcholine, we observed the duration of the each episode for the therapy episode after one minute, we would provide the therapy with pacing. And in the control cases after one minute of sustained atrial fibrillation we would wait until the fibrillation spontaneously terminated. And this could take up to 10 minutes. If there was no termination after 10 minutes, we would then cardiovert the animal and then we would also use the time to sinus rhythm for each episode as a marker of efficacy of the treatment. Here's an example. On the left, you can see that so here we have the splines, making contact with the with the left atrium. And here is atrial fibrillation that we induced using the new stigma and acetylcholine. Here is the burst pacing that you can see, and you can even appreciate here it's not a regular cadence you see this. There's a there, the cadence to this and the locations and the activation you see is is different but if you were to drop a line right in the middle, you're pacing from these electrodes, moving along and then from here you switch around and you start pacing in the same electrodes but in the reverse order. And essentially it becomes a mirror reflection image. And then after we're done here you can see that the animal is back in sinus rhythm. And, and so this was, you know, this was a very, very helpful observation. We only delivered five to eight microjoules per pulse, far, far less than the pain threshold of one 0.1 to one jewel. And you can see here that in terms of the time, maintain time to termination of AFib, there was a clear improvement clear difference in series of actually three experiments and three different animals on three different days. But here's the problem. The problem is, you know, not necessarily that anyone doubts the efficacy of such an approach. The problem is people haven't been able to do it. And why is that the reason is, as you can appreciate there, you requires a large number of pacing electrodes. And until now, that really has prevented anyone from from looking into the concept or the possibility of terminating fibrillation by But now, and working with ID and Baba Connie at who's initially at rice and now is at UCLA as a collaborator. We have developed these wireless powered pacemakers miniaturized essentially one by one centimeter and down the road significantly even smaller than that. These are powered using electromagnetic induction, much like you charge your iPhone wirelessly. And we use these electrodes can be then delivered to terminate the fibrillation. So these electrodes are about one centimeter, and they can be placed across they can be decorated across the posterior wall or whichever location that you decide in the left atrium. They're then magnetic, they're wirelessly communicating using em induction with a power generator that sits, you know, subcutaneous as an implantable just like you would any other implantable but it is wireless so you have wireless induction, you have wireless charging of the power generator, and you know, you're you're circumventing some of the major issues that we typically have with device therapy which is battery changes and the need for complications from lead failure or device malfunction or lead fracture. Here is another example this is more recent. Again, give the neostigmine and acetylcholine and I do want to bring this point up. Look how rapid this atrial fibrillation is. This is much faster than what we typically see in the cath lab because these animals don't have scar and also the neostigmine and acetylcholine can work basically by decreasing the refractory period. So you can activate more and more rapidly, given tissue. And so you get this really really rapid atrial fibrillation and if anything, this atrial fibrillation at this rate would be more challenging to terminate with with with the pacing protocol one would expect, but you can see that even with these and all of these studies that I show you that's the mechanism that we induce the effort, but you can see you have atrial fibrillation here. So the pacing burst starts right around here, and you deliver the pacing therapy. And then, after this, you notice that, while it was completely chaotic here, you, sorry. While it was completely chaotic here now you have organization on the right side. And this organization is actually something we call atrial flutter. Then the atrial flutter spontaneously terminates. Now in this, I have marked up this region here, where we actually feel that the termination actually occurred of the AFIP. And you can see, I've magnified it here and if you keep a close eye here, you can see that the local activation with every pacing spike that we're delivering for therapy is now driving that pacing spike is driving the local activation. In other words, you captured the tissue, you are now pacing the atrium. But the thing that happens is because you're pacing the atrium quite rapidly when you come off, you have essentially gone from AFIP and you've induced the atrial flutter. But you terminated fit, and the biggest proof is the fact that you are driving atrial activation with your pacing here. So that's, that's, that's one of the projects that we're working on. Another project that we find very, very interesting and intriguing is using injectable electrodes for improving pacing therapy and also to mitigate the risk of re-entrance arrhythmia. So how does, you know, how does this work? So first of all, we all know we just discussed the limitations of pacemakers as they are right now. Epicardial leads can obviously are placed transvenously and all these leads, you know, with regards to especially cardiac resynchronization therapy, their epicardial leads can have malfunctions. They can have dislodgement, the devices can get infected, things of that nature. And so our thought was not only that, but what if we could make something that does not use these leads necessarily, but as an extension of these. So in other words, you could consider using if there was a portal to be able to paste tissues that up to now no one could paste. And what we're talking about mostly is the mid-myocardial tissues, where most of, you know, you can often get a site for re-entry where you get delayed conduction and delayed conduction is the hallmark of re-entry and ventricular events, especially post-infarct. So a couple of things, if we can paste in the mid-myocardium, first of all, you're improving cardiac resynchronization to a level that is dramatically greater than even any of the devices we have right now, which have, you know, just four electrodes. If you inject into the venous branches, a conductive hydrogel, and if those venous branches, as you, as they feel retrogradually, then come in contact with the tissue very, very intimately, if you will, with the tissue that is now, say, scarred or delayed in terms of its conduction. If you could capture this entire region as it's going deeper and deeper into the mid-myocardium, you're effectively turning the mid-myocardium into a pacing electrode, what we call a planar wavefront activation, planar pacing, so that the entire myocardium is now simultaneously activated. We just did a study on this actually on Monday and we don't, we have some nice images, but we still have to clean them up a bit. But what we found in that situation, and you'll see a little bit more detail here, is that when you paste, you can actually create even in areas in the mid-myocardium, deliver that energy and you get an entire wavefront that even in the depths of scar is now activating simultaneously in the heart. And that eliminates the delayed activation. That eliminates these delayed potentials that we often see, which is the hallmark in the necessary condition for reentry, which is by far the most common cause of sudden death has been tricular arrhythmia is caused by reentry. So how does this work? Here's a little, so we inject the two components of this hydro gel into the venous epicardial venous branch. They, soon as they are mixed here, soon as they're combined, then you can tune how long it takes for the material to gel. And you can actually also tune the conductivity of this material. Right now, the material that we have is about three times more conductive than normal myocardium. You then take a standard pacemaker, you attach it to the base of the hydro gel, and then you deliver the pacing out. And you are checking at that point to see, are you going to be activating as a point that's spreading out? Or are you going to be able to simultaneously, since all of this is essentially one electrode, are you going to be able to actually activate the entire myocardium, including those little regions in the scar tissue that cause the delayed potentials and the reentry. If you can activate everything at the same time, you have been resynchronized or you have brought back the same homogeneous conduction pattern that is typical of native conduction and not disease conduction so you don't have the wave breaks that are caused by scar that caused reentry. So the concept of pacing this entire tissue, this planar wave front, eliminates or potentially could eliminate any delayed conduction or normalize that delayed conduction so that you eliminate that substrates for reentry. So here's, you know, a little bit more of a materials discussion of what is going into the cross linking to create these conductive hydrogels. What we decided to do is we injected these hydrogels into the AIB, which may look familiar to many of us as the Venus partner of the LAD. And the reason we did this is straightforward. If you are having in for this technology to work, you have to be able to localize where the scars. Okay. And at least in the case of ischemic cardiomyopathy or ischemic scars brought on by coronary blockage. This is typically a well defined vascular territory that is scar because the occlusion is that some well defined location in the in the coronary arterial vasculature. Every arterial bed is then drained by a specific Venus bed. So now if you say you have an anterior infarct and that anterior infarct was involving I don't know the mid LAD. The Venus drainage of that tissue that was involved by that infarct is being drained by the anterior and turventricular vein, which is the Venus component or the Venus partner of the LAD. And therefore, if you inject in the Venus branch that corresponds to that arterial branch of that same territory, you are by definition injecting and introducing these hydrogels, and this pacing ability into those exact same tissues that are scarred that are the focus for reentry and have the substrate for the delay conduction. This allows you to tailor perfectly your therapy to the infarct. Now this is probably not going to work as well when you have conditions such as sarcoid or non ischemic cardiomyopathy where you have patchy diffuse scar. But for the vast majority of patients with ischemic cardiomyopathy with scars that are due to a vascular bed being occluded. This technique will allow you to once you know that the region of the scar you go into the Venus branch, and you inject the hydrogels, and you start pacing, and we've, we saw that you know you can actually pace areas that have in the mid myocardium, even over dense scar. Again this experiment you have to take my word for it we did it on Monday and just was a little too short for us to be able to get all the data out. So, let's talk a little bit about these ionic hydrogels. You know, they are conductive, they must be bio stable, they must be cytocompatible, and they must be mechanically robust and the data that we have to date suggests that all of these criteria are are are valid. Right at this point, you can see that the myocardial conductivity is about one third of the conductivity of the hydrogels. Now, there is a concern that if you are now conducting more rapid than native conduction, well then that can potentially be a cause for reentry to and that, yes, that is definitely something that needs to be looked at, and needs to be studied. But keep in mind when we have planar wavefront activation, a very large amount of the myocardium is being simultaneously activated. And so there is that you are essentially creating a homogeneous activation time. And even if this is three times fatter faster than normal myocardium conductivity, if you are activating a whole block simultaneously you have homogeneity in that region. And so the chances of reentry are probably going to be less, but again, this clearly has to be studied a bit more in future studies. So the hydrogen, as I said, we mix them, you can tune the curing period. And then we directly inject the hydrogel into the AIV. This is our experimental setup. This is with sinus rhythm. This is us pacing actually with and through the hydrogel. So it works and afterwards, when you take the hydrogel out, it's quite resilient, it takes the shape of the blood vessels, the venous blood vessels that it was injected into. And so here's I think my favorite slide of all here, other than determination with with pacing of a fit. Here you see a baseline. What we've done here is we have opened the chest, you have the AIV in front of you the left ventricle in front of you, you check baseline activation, then you start pacing on the epicardial surface with the metal. You also do what we call point pacing. So these are both point pacing with the hydrogel and the metal and we would expect these to be the same activation they have the same relatively same conductive properties. Then we also did a hydrogel line, which was not injected just a long line that we placed on the outer surface of the heart. And then finally, we injected the hydrogel that was another arm so yet a B and C and this was the arm that we injected the hydrogels. And that's where it goes. Our hypothesis and what we found in necropsy afterward is indeed that the hydrogels go into and take the shape of these tiny branches of the veins that are draining the infarcted region that is the source of the delayed potentials. Also, we know that the mid myocardium, at least at the septal level is where the conduction a good part of the conduction system rest. And for us, a first step to say, Okay, are we actually pacing in the mid myocardium or is this just surface pacing was exactly the way we did that was to compare the morphology of pacing when you have epicardial hydrogels, not in the vein, not percolating into the mid myocardium, and you pace from there and you compare it to what happens when you pace with the hydrogel that's percolated in the mid myocardium. You would expect if our hypothesis is that this is approaching the mid myocardial conduction conduction system this is pertingy system that the cures morphology would probably be a bit more similar than native. And so here you go you see on the top panel here. This is the native cures so p wave cures p wave cures. These are not synced in time, I just want to be clear so you're not necessarily going to see an electrode or signal here for this but focus should be on what this qrs looks like. This is the native qrs baseline. When we pace from the hydrogel point. And I can tell you that these all the hydrogel point, the metal electrode, and the lines were somewhat similar to each other. You can see that here you had an initial upward deflection, and now it's going down. So again keep in mind for all these tracings this is your normal, this is the best way to summarize it for metal electrodes for point hydrogel and line hydrogels. The morphology that you get is if you can appreciate it here is quite different than the morphology that you have at base. However, with the hydrogel pacing, what you see is with the pacing artifact there's a slight delay note that slight delay isn't here this in our hypothesis and this is something that's in the community is relatively well expect accepted is if you pace, and there's a slight delay that actually you're probably going into the conduction system and this is one of the things that these days we see with left bundle pacing when when you have a pacemaker and you're trying to actually capture the left. You see the slight delay as the his purkinje system is activated and therefore there's no surface activation, and then when you have that morphology of the trs. It is substantially more similar to what we have in in the case of the metal electrodes, or the point hydrogels or the linear hydrogel, non injected into the AIB. And all this but is it safe I mean you're you're including Venus branches you're doing all kinds of stuff well, you know, from a practical perspective, every time you put an epicardial LV lead in into the, you know, to do a by V your you're putting a lead that is essentially close to occlusive, because we typically go all the way distally until we can't push that lead out anymore so we we're doing this right now in the Venus system, and this is the Venus system that the experiments are being done it. And so that clinical picture kind of does give us a little bit of confidence but we decided to look into it, even in more detail and, as it turns out, you, if you look at the level of inflammation and necrosis. We did an injection we survived them for two weeks, and then we did the autopsy you see that there's a lot more inflammation that the vast majority of this inflammation is occurring where the injection was being delivered where all the instrumentation was being done. In this, in this region, right, this is the region that you know you're instrumenting and things, but the more distal areas as you're going farther and farther into the AIV farther more distally into the AIV. You see that there is essentially no changes no necrosis essentially very little damage. And so this was an initial indicator that we probably are going to be okay that the Venus, you know we're not going into the major Venus branches we're going into the side branches. We're not necessarily, at least based on this locally even there was no effect on myocardial necrosis. So here's the catheter delivery system. It's a dual plunger system. It allows even injections of the precursor to solutions. And it becomes the two lumens go into a single lumen catheter and then the mixing occurs here. And then you curing is pre programmed and as I said, tuned, you prevent the backflow you wait for the curing to occur. And, and that's it and that's how you, how you do the pacing and so more to follow, but stay tuned on this. And then the final thing I'd like to talk about today is catheter lab on a bench. This is an idea that I would like to shout out to Matthews john and Allison post in our, in our lab who came up with this idea, and I'll be introducing you to everyone here at the end of the I think every one of us at some point as physicians has had a period where they said, Well, you know, I have an idea. What if we did something like this, or what if we did something like that to help of a specific pain point in the course of our care of our patients. Well, you know, drawing something on the back of a napkin and then actually prototyping it are two very different things and, and this is where we hope to provide a service essentially to the community to the medical community, where if there's a clinical and there's well defined requirements and there's an idea that you have. We certainly can try to help with the prototyping the testing and the validation of that. And the ideas, everything remains yours, but we provide we can provide this service for you. And we have actually done it already and we have published. So, again, a step back. We had a paper that we were in which we were looking at different ablation characteristics for for ablation catheters. No need to really get into the details of that but suffice to say you can change the settings on the catheter the power the duration the force with which you are ablating you can have irrigated or non irrigated ablation energy deliveries you can have internal irrigation and external irrigation but for our purposes. The thing to keep in mind is that an ablation catheter resistively heats tissue, and it does so with an AC current output at about three to 500 kilohertz. The depth and the width of the lesion is dependent on these on multiple features that I was talking about. There is however one other variable to we talked about I just discussed the power, the force, the duration, but typically RF energy is delivered in a monophasic unipolar. I should say not a monophasic but in unipolar fashion, and what I mean by that is that the energy comes from the tip of the ablation catheter. And then it dissipates to the back patch your your, your, your indifferent if you will electrode becomes a back patch. So as the energy from the tip of the ablation catheter is going away it's dissipating the concentration of that energy is dissipating as it goes towards that back patch. That is in the mid myocardium and you're trying to ablate it you're trying to ablate tissue in the middle of the myocardial tissue. In that case what if you want to be able to create a deeper lesion. Well, one of the things you could potentially do is instead of putting a back patch for your indifferent electrode, you bring a second ablation catheter and that becomes your indifferent electrode that becomes the ground electrode. And when you do that now you are not dissipating that energy you are concentrating it, and you're enabling deeper lesions to form and you can see how that essentially works here with with bipolar the lesions are deeper it traverses the entire mid myocardium. So we decided that we were going to look and study different catheter properties and different ablation properties with bipolar versus a unipolar ablation. And so this is exemplar at this is just an example that I'm offering for what we do at Excalibur but you, we have a simple setup for bipolar ablation. In our second generation we actually circulating we had a circulating temperature water bath, and this this work was actually published by Matthews, and the rest of the team at on and heart rhythm, and you can then see that in our most recent gen three the unipolar ablation capability and the ability to monitor temperature to monitor collateral tissue damage during ablation was there and you can see. The whole setup for you, and it's in a bath, and we can actually control the amount of force that's being delivered to the catheters to the ablation catheters we have direct visualization, we can control the power that's being delivered, we can switch from bi phasic, I'm sorry from bipolar to unipolar pacing or ablation also just by removing catheter. So we have very good control over what we're doing, and you can see in real time a very detailed granular analysis of different results on the tissues when you alter some of these pacing, some of these ablation variables. Now, for the more most recent. There's a, we want to have and we do have precise catheter control of precise bath temperature and flow control, and we have a stationary and different electrode, and right now we basically can look at different properties, different ablation variables, again, as I was discussing earlier, and analyze in real time, what is happening and it's it's really remarkable to see the tissue changes. In front of you in real time, I think that anyone who ever touches an ablation catheter should at some point early on, preferably see what the ablation what what this does to the tissue. And so this is a perfect opportunity for that and to have future studies to have better understanding for example one of the other things that we are looking at right now is the concept of insurance lesions where an EP very frequently we will have we will do an ablation we'll see a good result and we'll say okay let's just stay there and give another burn as an insurance lesion. Do these insurance lesions work or not well we looked into this and stay tuned it should be out in press here hopefully in the next few weeks but the bottom line is that I would advise you not to do an insurance lesion. And these are the publications we've had recently, and, and, you know, it's it's it's been ramping up, and we look forward to having a 2022 that is even more productive than our 2021. And of course, this couldn't happen without help grants. The McDonald grant has been extremely helpful at the earliest stages to give you that initial money that you need to start those first few experiments to build on that. We've been collaborating with electrical engineers at at Rice University, and we have a patient specific multi sites in order to create kind of a patient specific type programmable multi site pacing to terminate the atrial fibrillation. And of course we look at the sensed events and correlate atrial sensing with the substrate of fibrillation so that we can give the appropriate pacing therapy. We have an R01 NIH R01 looking into this this this concept, and we have been blessed with philanthropy from a number of foundations are collaborators across the country but mostly obviously focused in in Texas. And here's the team. Alison post, Matthews john scholar buckin drew Bernard and pi arms of the 90. And that is it. Happy to take any questions and thank you.