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as soon as digital innovations and learning a video journal interactive with discussion
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offering this program and all others and Apple Amazon and spotify podcast
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in association with this and I surgical neurology International
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with Anche Epstein MD as it's editor in Chief
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of Police to present another in the Sai Digital series of interviews with clinical neuroscience leaders
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today's interval will be with William Lauder
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who is the section chief division of neurosurgery at children's hospital of Orange County
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he will talk about novel untethered Micro robotic platform that he developed for minimally invasive Ultra selective microsurgical procedures and targeted drug delivery and this is the first in a
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preliminary report on the characterization of the tissue response to interpret rank them on navigation
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and they all align brain this is another and they as an AI Digital series unlike neurosurgery will be like in the twenty end of the twenty first century
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and are allowed in in addition to being section chief of the division of neurosurgery at children's hospital of Orange County and the Ready children's health network is a clinical associate professor
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in the Department of neurosurgery at the University of California Are
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But You're allowed to be interviewed by James Hausmann as the creator and CEO of S and I and National Digital and the editor in Chief of US and I Digital
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was formerly professor of Neurosurgery and the University of Minnesota Michigan Illinois and U C L A and the former Chairman of Neurosurgery and Henry Ford Hospitals at the University of Illinois at
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Chicago and Brief Introduction My Name is Bill Laden I Am a practicing pediatric and adult neurosurgeon been in practice for about twenty five years now as academically trained I started out hold on
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just a minute because my I had some noise in the background humans okay now let me just give a little brief introduction then today we're going to talk to be allowed and jose are you professor of
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pediatrics I'm an Associate professor of Neurosurgery and you're working at a children's hospital of Orange County
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University of California Irvine how long you been doing that twenty five years as of this month as understanding and and that you're going to tell Us about some detailed work and thought you've had it
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it really is a biochemical and and detailed physics electronic background how did you get all that
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well do I just was fascinated from my earliest days with the challenges of trying to get drugs to the brain where we needed them and to avoid all the pitfalls of systemic delivery and toxicity and you
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know watching all these patients succumb to brain tumors and other diseases would just keep you awake at Night Thinking about new ways to try and address the you know the barriers that we encounter
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trying to get the right stump sharing per minute so he can see a full screen okay
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then so are you you're basically self taught and all these kinds of things oh no no no do you have a PHD Yes Yeah no I started in Yeah I started up the NIH as an NIH fellow and then I moved with that
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lab to MD Anderson and I finished an MD PHD program there in tumor biology and then went on to do a postdoc in here and molecular biology with tumors being the focus of that and kept on kind of going
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did stereotactic radiosurgery fellowships in pediatric neurosurgeon fellowships was heavily involved and the evolution of the stealth machine with Medtronic's I was one of the Beta Testers for the
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original version and did most of the of the F D a data submissions from our institution for that one and here we are eight eight stealth machines later down the road and still going right so I I was
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able to hook up with this company bright the beginning of covet and it was it was an interesting thing again full disclosure I no longer employed by the company we're talking about here I have no
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financial ties to them whatsoever at this time so again I have no conflict of interest when I present as this is purely my take on you know some of the really good work we did stuff I'm really proud
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of but I joined this company back gideon have covet and work with an incredibly talented group of people who lead us down a very interesting road and I Hope That it's kind of you know think he will
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continue on as we move forward with this guy's terrific alright well why don't we get into the presentation because the people will see the the depths of your thinking and experience with it and we
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can talk a little bit afterward Okay I Please I'm just going to rapidly go through some slides and you know please please please stop me if you have something you'd like me to clarify okay reflect
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boom boom so I've always been fascinated by you know the evolution of the art of neurosurgery right mean two thousand years ago we have remnants of skulls that were terrified and we can tell from the
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skulls that patients actually survived right so even two thousand years ago Peruvian neurosurgeons were pretty competent at doing some procedures what the what the procedures were asked the question
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but also always found it interesting that You Know You'd probably pick Your Neurosurgeon by how many you know stol flaps he had on his necklace right you know how many patients had actually treated
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over the years so I think a lot of the stuff that we're looking at here really comes down to is transferring
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I have always been I've always been very intrigued with the evolution of the art of neurosurgery and starting with the ancient Peruvians two thousand years ago who had developed rather extensive
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instrumentation for trepanation Ce the purpose of the Treffen nations obviously are lost in history but the fact that looking at the skulls we see signs of the bone healing obviously means that the
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patients survived the surgeries so they had cleared a stop humidity you can see right here in the skull you're showing on the right hand side of the bottom where the edges are not sharp anymore right
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and they clearly indicate she had surgery he recovered and that his bone began to grow and remodel and I dunno what's over here but another said that your final or not but that that only that
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substantiates what you're saying the one who survive surgery and look at the bone flaps right with the little holes in that so you could wear them around your neck and you could show how good how good
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a surgeon you're is that what they did I didn't know that never heard that isn't that impressive yes I didn't have some very interesting I want to go with that guy he's got one hundred skoloff laps on
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his neck Yeah that's right where was that from and time since the Peruvian Yeah two thousand BC Yeah an ancient okay So you know part of the advancements has to do obviously with the advances that
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have come with US so we've seen amazing advances in imaging modalities We've gone from X -rays up to functional memorize and you know spectrometry and just you know each step of that has caused a
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revolution in our field right I mean if you think about the sheep feeder Angio fluoroscopy films that used to be taken for even intracranial work that overnight were replaced by a cat scanner and then
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cat scanners again replaced by Ember eyes on and on and on the instrumentation the introduction of an operating microscope might not even to mention sterile field but from there into stereotactic
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radiosurgery and neurosurgery and the endoscopic procedures each one of these is taking US up on another notch all of these two are also dependent on the materials that will work with the bio
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materials look at the evolution of metrical apparent neal shunts right to go from LaTex and to Have know the different materials that allowed us to succeed from VHS to VP shunts on and on and on and
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the pharmaceuticals the total revolution in the pharmaceuticals
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part of this minimally invasive neurosurgery has been the ongoing goal of trying to do our surgeries with smaller incisions less blood loss safer and in a rapid recovery times so surgeries that used
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to in ca involve weeks of hospitalization now are starting to be done on an outpatient basis as proof of principle what this concepts are leading us to again there are true giants in that field who
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have helped us along the way doctor cushing obviously started this off by becoming the true first neurosurgeon to really take on neurosurgical procedures and in his early days the concept of Fifty
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percent of his craniotomy is failing to survive stunning right imagine a personality who could get up every morning knowing that half of his surgeries were going to die but taking that within twenty
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years and training it into pretty much the modern art of neurosurgery as we know it today phenomenal right this Gentleman Doctor large XL is for me one of my heroes as well and I love the quote again
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from him this was an example of the mindset of the people that really made this work tools used by the surgeon must be adapted to the task and where the human brain is concerned no tool can be too
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refined amazing right here in front of his stereotactic system that he used for surgery and then went on to work on and ultimately develop stereotactic radiosurgery first starting with a proton beam
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proton accelerator system but ultimately ending up with what we know today as the gamma knife which to me has revolutionized my practice then just helped thousands and thousands of people across the
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world
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goals of stereotactic neurosurgery again improved localization improve accuracy right that allows us than smaller incisions to get to that point and then more complete resections or more complete
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achievement of the goal of that surgery was even still to this day look at up amirite post operatively and you can tell the difference between a stereotactic procedure versus an open procedure you can
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see that the channel on a stereotactic procedure leads directly to the target and it's all it takes to get there in contrast open procedures you see a funnel going there again really portrays the
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accuracy of this the the the concept of the stereotactic surgery you know initially went through it's own evolution with external landmarks been recognized as insufficient in the human brain not so in
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rats for example When humans skull shape itself was never sufficient so to be able to do rigid fixation to do intracranial landmarks by initially X ray later by a cat scan mRI and then combined
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technologies allowed us to enter the realm of true stereotactic surgeries I still remember doing you know frame based systems and you know have twist drill to do you know that lobotomies and
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protecting our containment procedures and other deep brain biopsies something I think that's lost to the new generation but this was amazing Stuff from my perspective and many people still use this
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but I guess now we're looking at robotics systems but the next step up again was the ability to lose the frame right to be able to use imaging technology and to take that imaging and three
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dimensionally locate your targets based on the external anatomy so that was a major color advancement and started tactic Forget frameless image guided surgery and that to me was a real eye opener
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because now things like endoscopy procedures could be done with much more certainty right now that you were able to use you are able to guide your scope with Endoscope I'm sorry with strap tactic
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tools directly to your target really really I think transformed the role of minimally invasive endoscopic procedures for tumors for CES for endoscopic therapy she philosophy is for biopsies and we're
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removing clots all kinds of things but again now where do we go from here how do we move forward but I always thought this is a great picture of twins obviously one of these twins has severe
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hydrocephalus and the other one's normal the ability for us to start thinking about treating these children even before they're born again taking advantage of endoscopy procedures augmented by
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stereotactic registration ultrasound all of these things all become possible when you put all these pieces together and remember what your goals are is looking at this picture here on the left can you
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go back to that a minute or naw Naw left his side sagittal view his skull you see the outline of the brain here yes I'm assuming what you're saying here is his total ventricular Magadi even going into
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the temporal horn yes with less frame substance and what what ages is shy oh I would say this as kids pretty far along I would probably get six months seven months I mean you know in my mind this I'm
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thinking when I see this I want to know how could I possibly get an endoscope in there and you know put a catheter into this kid into the ventricle bent it just into the fluid for an outright this is
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this is kind of where we are and where people are actually not just thinking about it people are actually doing this stuff now Because we have these amazing imaging capacities because we have the
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biomaterials to use you know leave them in human all of these things coming together allows us to think beyond everything we've done before and that's my whole point is where do we go from here so I
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had the distinct pleasure of being able to work with this project where we were looking for an untethered and untethered system to use a micro robotic platform to be able to go into the brain or
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around the brain and do procedures perhaps do a mite for surgery to a biopsy to a surgery deliver a drug for example so the question is what would it take to be able to achieve this now in a truly
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minimally invasive procedure the thoughts again been to make a small incision that sort of a bandage surgery right when you're done he put a bandage on it you'd be done and the patient could go home
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so
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The other goals will be set out for this were to not be restricted by the conventional stereotactic approach we didn't want to be restricted by a linear approach only we want to be able to have the
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freedom to move in any direction we wanted to be able to avoid structures and get to structures that otherwise would be hard to get to are dangerous yet too or even impossible to get to we also wanted
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to make sure that we had the potential of leaving nothing behind to do the procedure finish procedure and come out
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hope that's clear that was our our goal to set up to do this
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okay are We I'm intrigued by the I'm entering by the Inner Uterine photograph come and talk about that at the end sure we ended up giving this the name of Kleber a project lot of different names went
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down this boat we ended up calling that so we were looking at a system that had multiple parts to it We will go over this and little detail we had the Micro robot itself then we had an external system
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that would guide the Micro robot and then we had the function of the robot itself what would it do so we're going to kind of break that down and I always love this illustration I've been using this
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for a million years write the silver bullet we've all been looking for the silver bullet but we all know that the silver bullet you don't just push it into the head right silver bullet is actually
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very complicated when you think about it silver bullet is made up of parts right we have the bullet the tip itself that's therapeutic agent right that's the secret sauce we have the casing the casing
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is the thing we contain the therapeutic component in right it has to protect it it also has to stop it from affecting other parts until it gets to it's target so it has to deter degradation has to
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deter immune surveillance behalf to limit Bystander effects right bitches contain the the unit then you have to have the actual delivery system you have a firearm for a gun Jabba delivery system in
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this context that allows you to start from your entry and get your target point in in our case back again so the silver bullet it's a great thought but it's very complicated when you break it down and
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I think if you really think about most attempts into the Siena space that fail it's because they people haven't realized you have to have all of these components have to work perfectly together or
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else the idea of the idea of fails right all of these have to work every step of the way terrific example great so the Micro Robot was the starting point of this in the Micro Robot again delivers a
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therapeutic action it's untethered so it is completely free within the system it's biomechanical is biocompatible It has a heart is a neodymium magnet the strongest magnets known to man and again it's
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particular external outline is determined by it's function wright said design matches function we wanted to design it in a way that if it's going to carry a payload that the payload can be agnostic we
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wanted to be able to accommodate any therapeutic that you would be interested in delivering and again we wanted it to be completely removed at the end of the procedure so these are some really big you
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know these are some really big asks of a device but this is what we sought out to do
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again here's an example function meets designed this particular design as we call it a screw bot was on the order of maybe a centimeter in length and one hundred nanometers in outer diameter it has a
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screw pattern on it because it turns out that it's much easier to use torsion to move through tissue like brain than it is to like push something through think about a screw going into a piece of wood
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vs pushing a nail into a piece of wood so this was our early design of a screw bot and again it has the neodymium magnet this heart we can change it's size and shape and even the pitch of the screws
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pending on what we want to use it for but again we wanted to be able to move through CSF We want it to be able to move the brain but we also did some preliminary work in liver and eye and kidney as
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well that makes sense so as one hundred microns you're talking about Sara woods
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and fifteen times the diameter of a red cell right yet so we're looking at a grain of rice is one way of thinking about it I think rightly a grain of rice is a that's not a grain of rice we eat at all
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it's point one puts color point one millimeter right Yeah I'd say a one millimeter I'm sorry I'm Sorry such I felt like one to ten one to ten millimeters depending on what we're doing with it right is
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it so we take a human hair how does that comparing know if it's bigger than a human hair is really think of the the ones that I found most useful are the ones that really were like a grain of rice
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okay Erna
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and the second part of this platform now so we have a magnet inside the Micro robot we now need a system to take advantage of that we have an external magnetic propulsion system MPs and that system
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for applications on the head we're going to array it around the head in such a way that the external magnetic field affects the magnet in the Micro Robot is able to move it in three dimensional array
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to it's goal so that as you would imagine represented a challenge in it's own right this is a very early rendition of a thing we call the death star Because this was extremely dangerous and hard to
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work with we took a number of these six inch neodymium plate magnets and would connect them one do with each other and like force them into position to come up with the spinning array that we were
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hoping would be a useful way of moving the internal Micro robot but think about this for a second now this is a fixed magnetic system there's no on and off button on this thing so as you can imagine
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this was not something that I was very happy with as a neurosurgeon to not be able to have my off button to be able to you know turn on and off the array as I needed to so again this was a very very
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early system that was rapidly replaced by what you'll see here the evolution of the real MPs that we used so we started back twenty twenty one with an array this was like a workbench research tool
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that had six electromagnets each one controlled independently obviously with an on -off switch controlled by our own proprietary controller unit and software unit this evolve now to the first clinical
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version the MPS version one and then moved to version two and again I'm blocking here with my screen but the MPs version three was the clinical version of this and I'm going to give you a little bit
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more information about this as we move along but you can imagine how each generation we realized we needed this so we didn't need this or we needed to improve on this ultimately we were looking at a
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system of eight magnetic coils to be able to accomplish three dimensional control and here is the final kind of layout of the clinical version each one of these carts had four electromagnetics
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embedded in them and they would come and they would lock together they would lock together and were designed specifically to integrate with existing by plane or fluoroscopy system that makes sense so
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why join a philosophy that you've got an image it at the same time how do you do that that's a great question about that how about that the the MPs system was designed specifically for each by plane
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or fluoroscopy system right so it integrated perfectly around the gun in the plate of the two by play of the two planar systems
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you can see art cards locked in here yeah the bicycle system oriented around it so now we could visualize the bio not in three dimensions at any point in time that image would go back to our control
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unit which would compare the position of the bot to our plete a PRe planned trajectory and would affect the magnetic array to move the move the bot in that direction let me ask you a question here how
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do you demonstrate it in three dimensions are you reconstructing your image electronically if you got by planar that the biplane is giving you the shades in real time but how do you how do you
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distinguish tissue from CSF Great Question so we've we started this off with an M R I image of the patient's head and then we stereo practically fused the amirite with the fluoroscopy intimate we were
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sitting at the control panel with the emery image and with the fluoroscopy image that we're now co registered
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and that that avoids the problem the brain shift because nothing's really nothing's moving so you can continue to use this you can use this continuously and you may have you may have when you
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introduce it and maybe getting ahead of you but that's are you introducing into the CSF does that change an altering the dynamics of the CSF compartment Okay in this space but that's a great question
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that Will Remind me that because I I don't have a true answer on that one but I have A I have a suggestion for you then again on this the you know the key and this was again the accuracy of this right
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right so in this one graph here you can see where I wanted the system to be accurate plus or minus one millimeter across the whole length of the detract of the trajectory that's and I demand and it
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was a super high demand but you can see on this line here you see the error bars of plus or minus a millimeter that we were for the most part very capable of doing that and this was traveling in the
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brain tissue itself great outstanding Yeah that was that was a true it was a brief comment on this moving in the brain is actually easier than moving in cerebral spinal fluid in the brain or you know
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if you've turn off the power you don't go anywhere but in the CSF You're always dealing with pulsations and you're dealing with gravity in a in a liquid scenario so most people who tried this before
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US had failed in the CSF Space and I think are truly our greatest accomplishment was to be able to move in a semi controlled fashion in the CSF Space Withstanding let Me ask you a M a M a ranch grant
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type question to Dummy I'm just looking at their machinery a guide here there's to be an upfront investment so you had to have somebody who thought this was a great idea and invested in truth we had a
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whole series of venture capitalists and then we also had buy -in from several universities and academic centers Yeah people were really invested in this as tremendous system as a highly sophisticated
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really and I still had a lot of it is not to diminish what you know but you have a lot of the either physicists or bio engineers to help with this and we had the whole repertoire we had the biology
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team we had the software team we had the hardware team though the whole we had it was a it was a very large undertaking we had about fifty people working on this in Los Angeles in Germany and in
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Israel so it was a it was a very very impressed again I have said this many times how proud I was to be able to work with so many of these incredibly young and absolutely brilliant people what was
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truly fun with them is you know when you're really young you don't know what you don't know right so you don't have any limits so you could just tell these people to go try to do something that you
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would think is impossible and then they'd figure out how to do it that's what was so excited about this every day you'd come to work and they'd want to sit you down and show you what they've done and
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just when you might thank God did you have to take some same time off from working at a chaka children's hospital to do this Yeah I had pretty much gone down to about half time as far as effort goes
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but it was it was convenient for me because Los Angeles was only about you know an hour's drive away so I would spend two days or three days a week up in Los Angeles the lab there and I had the I had
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the opportunity to travel to Israel a few times to be able to work hands on here so it was it was a great time for me so this is a dream that's come to fruition I think so let's see here if I can
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mostly can't get that one might appeal to get this one and
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see if the videos plane
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I'm afraid it's not going to play Guys I'm sorry or Maybe it is it should play it on your your computer your screen and should pressure play Yeah there you go on the left screen there that's alive
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fluoroscopy of a sheet and you can see the The Micro Robot moving in the brain in a nonlinear fashion untethered and then the Orient ourselves ahead to the nose in the head is up up in the left hand
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side is alright I think it's actually yeah exactly so this is a sagittal view Yeah I got it in and you can see it moving you don't see the outer shape because this is screwed but you don't see the
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outer shape because it's radiolucent you only see the neodymium core right Yes right near and and you're leaving a track of words going so it's in the Perama Yes exactly and then just to clear the
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point initially there was a lot and towards the end again when it resumed there was a real hope to be able to access the intracranial space via a lumbar cistern access so we spent when I joined the
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team there's been a lot of effort trying to do this but it was not till you brought your Neurosurgeon in that we were able to actually find me able to accomplish this this is a CSS this is a buyer not
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moving in the CSF Space introduce early right from looking at an image of the spine or what is year of the spine let's watch it again I this is this is kind of fun right again this is not this is not
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in tissue this isn't CSF space see this Waggle Yeah I Saw it Ok there You're going to be moving up along the chord entered early ultimately into the posterior fossa now this is one hundred microns and
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so you're in the spinal separate ignited space and you are able to move freely even though their nerve roots are there and so forthright Yes sir and that was really interesting to God We could spend
32:22
an hour on that alone we also had the advantage of a little flexible camera calling enabled cameras not F D a approved in America but we have many videos have been able to put the camera up into the
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into the intrathecal space and watch the ball move and it would just kind of tumble over nerve roots and vessels on it's way up listing never caused any injury we did opens a path never saw any
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bruising it was truly yeah spectacular right but to be able to actually watch it was fantastic you should have a picture that somewhere so we can look at that I mean that's I love to share that YUp
33:01
the the naval camera was the blew away my endoscopy equipment how about that outstanding and let's see if we can move forward area okay so what do we want to do here this is our first goal and human
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was to be able to access the intrathecal space via Cisterna Magna Puncture
33:27
there you're going to act so to be able now introduced into the CSF space and once there to capture it move it along a pre -plan navigation pathway to a target for example in this case the pawns upon
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reaching the goal to be able to initiate the therapeutic function
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and then on completing it
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to bring the robot back to their starting point
34:02
manage him and the Plebeian questionnaire there Arachnoid bands distributed throughout the summer outdoor space yes roll through them or roll over them or something or the most for the most part yes
34:15
you can Xerox if you get stuck somewhere you can just to reverse a magnus or something I dunno and redirected for the most part we would waggle waggle and get it free and we had some stronger Magnus
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locally that we could use as a second layer of of return and finally the third option was a surgical approach reagan endoscopic approach but We were always able to accomplish this with just the
34:38
external system at least to this point but here's a proof of concept this is a live sheep fluoroscopy we've injected some dye into the space so we have some anatomy here and you can you can see now
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the bow not been introduced around the stem and then navigating this waggling up the space
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to the pawns and then get another die squirt so you can see the anatomy and then bringing the bot back out
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pulling the introducer out that shows you retrieve the bot yes and you leave the needle in bullet now you pull it out or you can play it and what it does is answers my first question you've done a
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needle in there even though there's some leakage it really doesn't alter it significantly southern Missouri to visit again if your wheat I did always procedures prone right so I have my introducer
35:44
system so the introducer is at least what twelve no twelve centimeters now you can CSF under normal circumstances would not be exiting that but I had an irrigation system as well so I would always
35:59
make the point of replacing fluid of during the procedure and upon exiting a magical wild question here in Michigan take a little while but that's all right
36:11
I'M just thinking about all these possibilities as you keep talking you could direct us in the orifice of an aneurysm ugh you are so abroad that Yeah no so the sub the sub rack Noise space this is on
36:28
our less right you know all the endovascular where we talk about is putting envelope embolic material or coils into the aneurysm which is great right but what about the Spasm afterwards the the value
36:42
I saw this was to be able to bring a buyer not into the into the cistern and to park it on the vessel and so you have imagine you have your endovascular catheter and you're eliminating aneurysm and
36:55
you're bringing your bonnet now onto the outside of the vessel and you can feel they literally can lock up head to head and release drug onto the vessel from the outside as well as from the inside and
37:08
tactic that was I really thought that would be you know you've seen the literature people have placed in defense tricks into the into the sub rack no space there to deliver drug and there is some
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compelling data of people doing that but to be able to target the exact vessel at the exact site at the base of the spasm and leave the other vessels alone I I thought that would be an amazing kind of
37:33
down the road application or you have a tool to do that where I boy were way down the road here have a jury until for example there's a there's molecular biological work saying that that an aneurysm
37:45
is is initiated by macrophage infiltration of the vessel wall with some inflammation and what you can do is you could theoretically they are stop that because there's one by giving them a drug which
37:59
says it'll you prevent that you can stop them from form you can stop the expansion the formation and the other work shows that it will regress so I'll stop the cascade why not but with what with
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selectivity that you could never get in any other way right literally It can if you put a magnetic tip on the catheter endovascular catheter the two would actually click right as if you could just
38:23
hold it there and deliver drought over what half hour hour so begin the possibilities there I thought were very compelling standard energy as as one stand in A if you're going to doing a blood vessel
38:36
when we won't go into it we're getting down the road doing Great okay go ahead to be clear though we never envision using the system endovascular right right and then the forces that we have to bear
38:50
at when we're at this point were sufficient to work on the venous side but we didn't feel safe using the system on the arterial side now so you you could imagine you know brain this in honor of on the
39:03
venous side of a vascular lesion or the venous side of a tumor but we weren't we weren't working on trying to get it up to arterial face of the early Concepts of this proof of concept of this I'm just
39:17
bringing this in
39:20
as a Prelude into Dandy Walker JR said of Dandy Walker his assist on the back of the brain which results in Hydrocephalus in at least eighty percent of these patients and obstructive Hydrocephalus for
39:32
example but if you look at what we just accomplished here the ability to put a bio not right into the cistern or Magnus space almost right adjacent to the Dandy Walker membrane and create on that
39:46
system a surgical tool putting a blade onto the tip of the robot and firing it at the Dandy Walker Cyst finished reading the CES and then bringing it back out again you would be directly
39:60
reestablishing the normal outflow anatomy of that patient absolutely astonished to just turn affect one character so that was our first clinical goal for doing this and elect to show you an example of
40:12
this so we talk this was the original workbench the six am system and here is a magnification of what's going on in this system here so look at this this little bot has a blade on it we took a an
40:25
optimal logic gold blade and we embedded it onto the tip here again new neodymium magnet inside of it so here we're using the external magnetic array to move the bow not towards the blue target which
40:40
is serving as our cyst and upon reaching the appropriate spot
40:47
we launch it we finish straight the cyst
40:51
and then we pull the bio not back out again and pull it out
40:59
and now you can you can see now you can see the dye now see I chant
41:05
that makes sense send a terrific idea so that was our first clinical goal so I felt the noise
41:14
from there we started you know that was ER that was our terrific concept now so we ultimately submitted to the F A and I'm very proud to say that in January the FDA granted US our ID for the use of
41:27
the bio not for the Dandy Walker System and that would have been our first clinical application so you've already applied for a clinical application for this we had and we were granted the ID by the
41:38
FDA so if they are able we would we would be able to begin clinical trials so it isn't only limited to Danny Walker or You're going to guess it's just limited to Tanya Walker Okay this first for the
41:52
start right from the start okay because again this is a class three device there's no precedent to it the FDR was incredibly supportive of this but there are also you know their job is to keep Us safe
42:04
right so you had a whole plan with them to do to patients with this first to review the data through another to ultimately to get to an IETF ass where we could then move forward and move into the
42:18
things we wanted to treat which is drug delivery outstanding okay so we now started looking at you know obviously in parallel we are already working in our small animal models and our large animal
42:31
models for drug delivery systems so what we saw with this system was the ability to achieve a targeted delivery not a global delivery for other diseases but as Ultra targeted ultra accurate delivery
42:47
which circumvents blood -brain barrier circumvents brain tumor barrier right it prevents off site toxicity or side effects it also prevents systemic degradation and it limits and immunogen aluminum
43:02
sorry immunogenicity right you don't expose it to the immune system Wait so viral vectors for example that are often made ineffective after injecting them systemically a few times the ability to avoid
43:15
all of those problems again I had I had a brain tumor in my ear you're going to get to this I'm sure a rare brain tumor in my in my Basal Ganglia or or so I make no claim as I could I can navigate
43:30
this ascent the center of the tumor and it can release drug so forth and so on that would be specifically designed to be toxic to that metabolic a set of circumstances which made the tumor exactly and
43:44
you know to Me I was always looking again for ways to amplify the signal right now so the concept of a replication competent tumor virus or the ability to have a an enzymatic or a catalyst to turn on
44:01
a prodrug so you could have a systemic pro drug delivery which is only activated at that particular locus something along those lines where you could amplify the signal because again the bio nuts very
44:13
small payloads very small perhaps only a milligram of a drug or be calculated maybe ten to the ninth infectious particles of like an AD no associated virus now on standing up we also then we're
44:27
looking at the concepts of how do we want the system to release right yes we talked already we wanted to be an agnostic system to be able to adapt to anybody's needs so to that end we really needed to
44:40
work on some proprietary functions so an inhibitory aren't as SRM AES or antisense as as our turn out to be rather tricky when you try to concentrate them so twice to concentrate them without losing
44:54
their efficacy required a serious investment on our part same thing was true with Adna Virus and Adna Associate virus the ability to concentrate them but meant but To I maintain their their
45:07
effectiveness was truly challenging so there's a lot of work that we had to do to be able to adapt them to the system but truly it was all doable we just had to work on it release systems were also
45:19
interesting I like to bring them out there were two options that kind of came to mind depending on the application and if you think about strawberry field and you throw a bug bomb in the middle of the
45:33
strawberry field to get a burst and get a distribution pattern you don't get to control it very much and it's probably not going to get to all the places you want to go but if you have a school on one
45:44
side and the hospital and other side you worry about where your you know your your toxins are going to go in contrast if you have a you know a biplane that flies over the field and sprays the field on
45:55
along a specific pattern you have much more control you have much more likelihood of hitting your target and avoiding you're off targets The and I have the option of an immediate release or had the
46:06
option of releasing as it moves so you could paint you could paint a pattern of release as it moves into so we looked at those options as well and depending again on what your target was and what your
46:21
therapeutic was to match the two
46:25
fed is Terrific okay as an example I just kind of comparing some of the differences here get moving my trimble bit and
46:36
if we look at a modality like small drugs small molecules Bernat could probably deliver about a milligram in that grain of rice and that's to the target itself right not just into the systemic system
46:51
but directly into the target in the brain in contrast drugs that have been used systemically that have actually really been measured as far as their penetration We're only getting into the microgram
47:04
range when it actually gets to the CNS dishes so your three logs for logs down of concentration from systemic ultimately into the CNS that if that makes sense right see the concept the concept of
47:18
putting a milligram of even a basic chemotherapy agent into the middle of a tumor is like an atomic bomb going off right correct you we have to think at a molecular level exactly when you move on to
47:30
like a esos and you know plasmids and all the ability to still deliver milligrams of your molecular agent in contrast to looking at delivery into the CSF now right that you know we're still if you put
47:45
one hundred and twenty milligrams of an SL into the CSF You're diluting that right away and one hundred and fifty CC's of CSF made of that how much now it's going to cross the Pierre or the PIN number
47:57
and actually go into the brain we know that it's it's you know log orders down from there so neither guaranteed in any in any disease if you give the drug which it has an arena in Arena Slayer enter
48:10
Monsieur early or even in the CSF what is going to be the appropriate concentration at the at the cell that means in thus a target which got a great hobby systems and get into the cell itself try to
48:25
make the effect and and basically nobody knows that that's the point and I think we are seeing now over the last few years we're seeing a lot of the real big Pharma players pulling out of their CNS
48:37
drug developments because of this problem they have the great drug it works great in Vitro they just don't know how to get it to the target in a concentration that works at the target without seeing
48:51
systemic toxicity you know with you know with a esos and all that with liver disease and renal disease and and all these other problems IT pretty much just given up on it because of this problem right
49:03
here excellent Yeah it's right right exactly the problem so let's let's look at the solution here this is a rodin system where we injected these are an associated viruses that were labeled with GFP
49:16
green fluorescent protein we colored them here okay the the pink is also GFP we just colored in the contrast this we actually had developed this software herself because nothing like this really
49:27
existed to be able to actually measure the the distribution here but on the right panel is a classic basal Ganglia injection of the same amount of Ad necessity of viruses on the left panel the left
49:44
Panelo is with a bio nut in the basal Ganglia releasing the drug rights to the right loin as a catheter delivery the left one is the bio not release and we're going to look and compare st equivalent
49:57
doses of virus incredible that's that's a great piece of the work right there yet in this we just published so this is this is in the literature the you know we're not having any back flow up the path
50:10
up the track right right now going back to this tusk was an incredible finding we were really I mean the first few times we did this but it clearly impressed US right absolutely so you were talking
50:25
about tumors and I'm a pediatric neurosurgeon what timber what I like to see US impact before I die right so brainstem Gliomas remain an absolutely incurable disease with nothing on the horizon for Us
50:44
we've talked about the approach that I showed you the Posterior Fossa Cisterna Magna approach into the CSF Space and the ability from there to navigate around to the area of the pawns or the Medulla
50:58
and then to be able to deliver drug this was going to be our response our proposal for our first tumor system and I think from the previous discussions you can see why we thought this was interesting
51:13
so again in the way we see a number of people using the you know essentially catheter -based system stereo tactically placed right from you know traversing all of the tissues to get to the basal
51:29
Ganglia I'm starting to get to the brainstem Glioma there's a number of approaches for it but again think of all the tissues you have to traverse to get there and ignore all the inherent problems with
51:39
that these are some of the examples of some of the approached people have been using my thought was either to navigate around to the front of the pawns or travel through the cerebellum through the
51:51
peat uncle directly into more post early oriented tumors until we have cut and have the option of both options Rather than these conventional stereotactic approaches interesting okay you know I read a
52:07
paper I may have to evey I just came across it about week ago where where there was a brainstem lesion tumor that had a specific genetic defect that they were able to cure to unity that's what do I do
52:22
not know that paper that's I plan to send it to you because this would allow you to deliver the drug to their tumor you to biopsy it and so forth I mean there there's a paper that I'll try to find it
52:34
right and that's the point as the we have more flexibility as to where we can go because we aren't restricted to linear trajectory right rehab the village to move in all planes so that it allows us to
52:47
get the puck to tumors that otherwise would be very hard or difficult or just too dangerous right anyways I'm going to end it with here with another one of my heroes IT says Mr John Halter who was a
53:02
high school educated machinist for the Yale Lock company who single handedly built the first ventricular parallel shut to be able to deliver it to his son who was born with Spina Bifida and
53:14
Hydrocephalus back in the nineteen seventies and As I was finishing my training in Philadelphia I was getting to be a little more academic and starting to do my reading and read about him and I looked
53:25
him up and he was still living in the Philadelphia Area and I invited him to lunch and he showed up with his cardboard box I opened it up and it's full of all these black and white photos like shut
53:36
number four and I just goosebumps right just blew my mind that this guy could do this and you know people like this who have to remind us that really are no limits to what we can do if we just open
53:53
our minds and and really work hard to do it again that was just Can't say enough about it so I will leave it at this this is our system very proud of it I hope that someday it will translate into new
54:09
and better clinical options for everyone but I hope everyone will be motivated by this and think what could you do if you think this way stealing emerged any realize now is are you continuing to do
54:24
research on this obviously you've got a F D a approval or soon wired clinically I mean that's the first thing to do sure so unfortunately I am no longer working with the bio not system they are they
54:37
have taken this in a slightly different direction at this point and I hope again like I said that this will ultimately come back around again and we will move forward with this but that'll be will
54:50
will determine that at a later date you have potential here I mean we just mentioned a few of them and I was just passing through through your talk the potentials your are are tremendous and he
55:04
obviously in combination with other technology how do you do this if you want to go into a blood vessel an image at US and so for me there sir but but it does it does for example ante in the recent
55:17
work we had a recent video talking about the after interventional radiology for the treatment of aneurysms there is a retreatment a recurrence rate of twenty per cent yes and it's because what happens
55:33
is the the the the the the the device's stance isn't tight against the wall and blood goes in between the wall and the device and then to fright those kinds of things happen and so so they've got some
55:49
ways to go to improve that absolutely but delivering drugs directly and drugs that would die you could you could We can put a year that is a device which includes the neck of the aneurysm just using
56:03
aneurysms cause I'm an aneurysm person but you can leave you could leave these drugs to do definitively in the aneurysm Sac it will work and again I I I encourage people who are interested in this to
56:17
visit the Bonnet site and see you know their new thoughts and where they're going with this and again I think all of this is just another door that opens for possibilities for Us to do the things we
56:30
dream about doing to address CNS Pathology Lemme let me take you out of the CNS for a minute let's say I am I Dunno if I've got a pancreatic tumor that exactly this thing and I put it put it in the
56:45
pancreatic duct and I migrate the pancreas right Yes to the elation yep now no pancreas we we've looked at pancreas we look at liver with a kidney we've looked at the eye all of these things I think
57:01
again to remove the restriction of having to only move in and out in a linear fashion the ability to move in a curvilinear faction allows you freedom of treatment that really expands your opportunity
57:14
I think that's the point we really want to force home here that are not restricted united States arnold since you're limited but does it still doesn't mean it wouldn't apply so widespread applications
57:29
are people working on those yet or did you buy and I'd think about that or are you the person doing it no I I my interests of glad to talk to you about my current work but I think there are other
57:41
people that are using other systems to be able to move non linearly into these spaces to deliver drugs again like I said either endovascular early again venous side delivery is kind of compelling but
57:56
even though and to interpret them all as well this is an emphasis that I think is gaining ground now as we realize that surgery is itself is not going to get us where we want to go and systemic drug
58:07
delivery itself is not going to get us where we want to go well I suggest to it's in a
58:14
hope that we hope that you can give us some updates as a work on this proceeds I am just not going to happen in a week obviously but a year from now we can look at it whenever you make some advance
58:27
give me a Buzz and I look forward I AM also hoping I am looking forward to submitting a provisional patent this week on my newest greatest kind of perception here and I think you'll be you know
58:41
knowing your interest in endovascular pathology I think you may find this very interesting so I look forward to sharing that with you in the not too distant future okay we really appreciate your doing
58:52
this don't send off Yet I just an outstanding achievement and very exciting and we look forward to it thank you so much and mostly I want to thank you for supporting me you know along the way and you
59:06
know I was the only neurosurgeon that was partaking in this effort and to have your encouragement meant a lot to me well that's great I haven't been in a group before where people said hey this crazy
59:16
guy I dunno what I'd have hola do anything with him or not but it turned out to be worthwhile if you also know some people are doing innovative work that we should you think we should pay attention to
59:29
in Essence digital I'd like to do that because I want to get to those people who are creative innovative ideas and maybe it's early stage research I'd like to highlight that because that's how we're
59:41
going to get future I so look forward to that like I said I will have something for you here in the not too distant future myself OK okay if you know some people Emerald we can get them involved okay
59:55
Thank you so much I would like to have or have an example for your riker be prepared to take a screenshot there's only one reference and this is the paper and use that for your record and further
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