hello everyone and thank you for joining us during this tumultuous time I'd like to welcome all of you to today's presentation on the uses of history gypsy answer and neurological diseases today we hear from dr. chen zhu an associate professor of biomedical engineering at the university of michigan please bear with us as we rework our webinar set up the code mid-nineteen restrictions currently in place if you are dialing in from a phone and are having issues with your audio please consider joining the meeting using your computer audio if possible your collection connection is lost entirely you simply log in again through the link you received when you register you will receive a link to a recording of the webinar as well if you'd like to ask a question i'm dr. junju please submit it in the Q&A button at the bottom of your screen we will collect these questions until the Q&A period at the end of the presentation and now I'd like to introduce dr. junju dr. Zeus research focuses on developing new ultrasound techniques for the treatment of cancer cardiovascular diseases and neurological diseases she and her colleagues have developed history see the first image guided ablation technique and is non-invasive non-ionizing and non-thermal doctors use work spans basic science device development preclinical investigations and clinical translation of history up see doctors you or is yours Thank You Cal SIA for the kind introduction and I also want to thank everyone for joining me today so today I'm going to talk about history chipsy therapeutic ultrasound technology for treatment of cancer and the neurological diseases it is a quick disclosure I'm a co-founder and hold stock in history sonics a little history and background here for history trip see what is here's the trip see and there were a combo so history gypsy uses ultrasound to mechanically liquefy the target tissue into a cellular debris and Institute seat room actually came about in 2002 so that's when I was doing my PhD dissertation with dr. Charles King a universal Michigan and he I trakone a charm because all the medical charm is amazing so histamines soft-tissue in greek and a tripsy meaning breaking down so you really refer to a process where we actually mechanical breakdown the soft tissue to parallel with lithotripsy which also uses ultrasound to break up kidney stones so little mean stones in greek and it was motivated when I remember in 2001 we had a cardiologist came to us and said that and his name is dr. Lewton risky so he was asking saying that all the existing minimally invasive or non-invasive approach at a time and even now they are mostly thermal based who were use various of different forms of energy to heat up the tissue and constitutional courses such as radio frequency microwave or ultrasound but he was looking for a technology that's not invasive but allow the clinician she actually physically removed tissue to perform a real surgery as he described it so that's actually motivated development of his ship see and history gypsy uses high-pressure short pulses at low duty cycle below 1% and that's kind of distinction between history at sea and a high food so low duty cycle where duty cycle soldiers are on time divided by the children treatment time using a low duty cycle below 1% allow us to reduce and minimize the heating were high foo thermal therapy uses ultrasone continuous wave or ultrasound trains by a high duty cycle to actually purposely heat the tissue there are two kinds of historically processing in general one is the history process that we have develop at the Michigan were sometimes its terminus at cavitational history of see high pressure and really high peak neck pressure typically above 20 mega Pascal and microsecond lens pulses are used were the central frequency of the ultrasonic in the range of about 200 kilohertz to 3 methods the you said the low duty cycle and that caused trying allow us to generate a cluster of contagion micro bubbles and as the inertial cavitation that's generated with rapid expansion the collapse of the micro bubbles results in mechanical disruption of the cellular structure and a liquefaction of the target tissue and you know this whole his trip see results with the first paper that published in 2004 so another process termed as boiling history trip see develop a University of Washington and this slide is provided by dr. Tanya cockroach where they describe a process we're also using short horizontal pulses but using milliseconds long causes and with peak metal pressure in a range of 10 to 60 mega Pascal so lower Bowie's a really high positive pressure so it's a shock wave where with the peak positive pressure in the range of 60 to 100 mega Pascal and that allow rapid heating of the target tissue reaching a hundred degrees in several milliseconds and generating vapor bubbles and that process and generation of the vapor bubbles also allow liquefaction of the target tissue and the similar PI effects of eruption mechanical disruption of the target cells into a cell debris with process initially published in 2013 I wanna focus on the process the conditional history of C crosses so first I want to show a video just give you a visual I like videos and movies and you can visually see it and hear this I do is an individual cosine cardiac tissue and in a water tank so really allow you to see visually what's happening to the tissue here and the ultrasonic transducer is crazed about a centimeter away and focus to the location here and you can actually see one see stars and visually see okay you can hear the sound on some star so you can visually see the smoke that comes out an ass smoke is actually not real smoke it's the a cellular debris that his tripsy generated from the sheath so to see process and in water tank is a debris is so fine and it's actually moving up so this is a real-time movie video within a minute you can see about a millimeter diameter perforation welcome find was a generation through this individual quasi-neutral what issue any salt almost like a real surgery an eighty cycle real surgery where the tissue removal is actually achieved and while history up see is supplied to within a balk tissue what happens is that that volume of and this is a single point treatment single focal treatment and the volume tissue is liquefied such that you can easily scooped out Oh extracted by a needle and if you're looking at a histology with the SLO debris in there and you can see at a boundary where there are intact cells and then within the treatment region the cells are disrupted there's no cell remembering no cell nuclei new cell structures really into this a cellular debris and it's very telling and I love this urge to show this a histology side is because at the boundary you can even see here there's a half of the cell and the other half is bisected by the microscope who are microbubbles was really high accuracy it's not like we can aim cell and say we're gonna cut that cell because what there's you know imaging accuracy and rich matrices not such but the fact is that it can actually bisect the cells of because our effective agent or effective scalpel here is actually micro bubbles so the first thing first when we started looking at this so it took us a while to figure out how does history chipsy work and there are two parts of it why is how is capitation January to divide history gypsy in a very controlled at a predictable manner and the second is how does history FC disrupt cells and this is you know all the work I'm presented here is really a work by not just by me as and by my group is in collaboration with a large number of people and for the mechanism of collaboration with Charles came team hall Adam Eli and there's just a key person at bright folks and the number of people we collaboration those are the key people here and first question when we started but working on his orchard see at a time I remember was 2001 that at the time his which capitation was really viewed as his random process that cannot be controlled so the first big question that we were facing was is how can we control the history gypsy process or how can we control the temptation generation and in our body you know outside along we operating error and long feature future data error but in our body we actually have a lot of gas in our body and they are nanometer gas pockets very stabilized to is really high surface tension around about 300 atmosphere so it's really high and without using so history gypsy process we don't use any injected contrast agents or micro bubbles so we are using those nanometer gas pockets that's already endogenous in our body and then we found out that if we actually using natural pressure if we can transiently trying on to exceed you exceed an echo pressure natural pressure means that the pressure outside the gas pockets would be lower than the in side of gas pockets using ultrasonic and that allow us if the pressure is high enough that can overcome the surface tension of the nanometer gas pockets that allow us to instantaneously expand and grow than enemies you gas pockets to micro bubbles hundred micron and we're talking about this explosive growth of a hundred thousand times using ultrasonic pulses and we tested and actually Adam didn't study well he was in might laugh at a Maxwell and then he tested that and show that if you you know looking at all kinds of tissue and in our body mostly our tissue is water-based so you look at a different you know broadcasts fresh cross across different concentration and kidney liver heart a wide range of tissue type and what he found out is that if the condition threshold using just one single pause of one cycle if we can actually exceed in a range of 26 to 28 mega Pascal that intrinsic a patient threshold if we can actually apply the polls microsecond one cycle ojisan a pause exceed a threshold that every single time temptation can be reliably generated by a single Auto sauna pause how you achieve their dignity pressure you know you you can achieve it when you have one cycle pause and purely by P kinetic pressure there's also a process called a shark scattering I'm not going into it but the key thing here is to have microseconds length pause with negative pressure effectively exceeding this entrancing cavitation threshold so by using that we learn how to generate cavitation in a very controlled manner and the second question is how does he searched series of cells in the target tissue and that was achieved and that was investigation until I played a major role in this work and in this video here what you are seeing here is a 3d tissue structure with one layer of clear tissue milk in jail and now I'm layer of breast cancer cells and those are the why white circles here so layer of cells and not let another layer of tissue mimicking gel on the top and this allow the cells should be sitting in a 3d tissue structure but we can see them under the microscope and then we use the high-speed camera to record the bubble cell interaction so the black structure here you see are the bubbles generated about history of C and it is actually at a boundary of the cavitation bubble cloud and there you know the each cell is about 20 micron here and several micro bubbles are actually custard in to coalesce into one big blob here but what you can see is when the bubble actually expand the cell gets squeezed and now when a bubble actually are collapse the cell actually get pulled away put apart so really is a high mechanical strain and stress that induced by the condition this rapid explosive mix growth and the collapse process that allow us to mechanically disrupt the cells and only ourselves within the cavitation region and immediately surrounding the condition micro bubbles and each part each pulse actually generates part of the cell destruction and then you require multiple pulses to really liquefy and mechanically completely restructure all the cells within the target region and another thing here is we use microseconds lines cause and razing is that'll hours true reliable each energy cavitation however and the bubble expansion crabs process the time takes about several hundred in microseconds they intake time for the residual bubbles to dissolve however if you expand their post lands longer and you know millisecond is a much longer then the bubble activity can continue going but become really chaotic and the less controllable another thing about this low duty cycle used in the history of see process wine is to reduce heating but another important factor to have that long time between the microseconds lend historically post pauses is this allow the time for the cavitation bubble and residual bubble fragments should dissolve such that he does not actually impact the activity of the Temptation generated by the next pulse so now we learn understand how hear certain words and this slide shows the instrumentation used for his/her ship see so and what I'm showing here is actually one mr. ship C system manufactured by history sonics ah the history of C system in general in a way is similar to the - system so it contains ultrasound therapy transducer and in the centre of this it has ultrasound imaging probe is because the cavitation generated by mr. ship C can be clearly viewed on ultrasonic imaging so history FC is treatments typically guided by ultrasound imaging so also the imaging probe is inserted in the center such that she can actually view the therapy plane in real time and in the g1 system there is a mechanical arm coming out who is a motorized the positioner micro positioner that can be used to actually move the therapy transducer and the controlled by the joystick here and then all the driving electronics for the therapy transducer of some imaging probe and the positioner are all in this compact cart here so he looks at you know is slightly bigger than a typical or some imaging system with the software inside integrate the control of therapy imaging and positioning and the really the key part here is the drawing electronics for the therapy transducer allow us to generate that really high pressure microsecond dense pulse but such a system is really compact it can be easily moving and out of the operation room for procedure again for coupling is similar to a - procedure we just use the guest water for the coupling so I'm going to show a video demonstration of the historic SI system in action demonstrated by dr. Kate Owens who is a cardiologist and the hopeless is you will get an idea how this actually works this system is a complete ultrasound system here with the both in imaging transducer and a therapy transducer to deliver therapeutic ultrasound pulses over here we have a phantom or a replica of what they the anatomy of a human baby pretty you have a therapeutic cartridge placed in there's a target and then place the transducer piece you can imagine a transducer place a utilizing the micro positioning system we can take our crosshairs or our target and position that on to our so the crop a red cross showing the purples now that we've got our crosshairs on our target we're gonna go ahead and initiate therapy I'll get a confirmation on the screen I will say yes right structure warming on the interface that we see at the crosshairs and after two minutes of therapy we would stop and then we can remove our cartridge and we should see a lesion through the red blood cell phantom which would represent our atrial septum stranger he's showing the demonstration were using the a my the ocean unguided the history FC system true generator really precise the lesion through all the ribcage and everything of that human phantom so now showing how history gypsy works in the the instrumentation and I wanna talk about true applications in today's webinar why is for the brain and whines for the cancer so first for the bring applications again is really a work with a large team here and that I have the fortune to work with dr. aditya penny from the neurosurgery university chigan doc no Tim Paul Johnson suka fish Charles king at BAE and those are you know key people here so brain is really active research area for focus ultrasound and there are three a big mechanism so far there have been active research and also the clinical trials along Y is a thermal ablation so for using ultrasound delivered outside the skull transcranial ultrasound and get it by MRI we can can be used to actually achieve precise dermabrasion through the skull completely non-invasive which is really really from research and technical side is really amazing then the secondly is a problem barrier so ultrasonic transcranial ultrasound can also be used to open up the blood-brain barrier try on temporarily for drug delivery and 30 is using a lower pressure lower Imperial so noble neural stimulation and chocolaty disease include really a wide range of different neurological diseases II essential tremor is a one that's already proved in SciTech system a probiotic EA and crinkly have been treating and benefiting a number of patients clinical trials are also ongoing for isomer disease Parkinson's disease brain tumors and other neurological disorders for focus ultrasound transcranial focus ultrasound for the thermal probe pros I mean even though it's really amazing I can really achieve a non-invasive transcranial blasian because the score is highly absorptive and highly attentive of the ocean energy going through it with you know in order to generally heating inside the brain the skull can be overheated and that limits the treatment location and a volume of the mi guided focus ultrasound using the transcranial approach and really you know with you know several mechanism you can only treat the deep charges and also a small volume and now that actually preclude a majority of the court hacks were a brain tumor can often reside and we think the potential to manage of transcranial history chip see that we are working on is a history gypsy does not rely on heating of the brain they actually generate cavitation and it uses a very low duty cycle and we can use no duty cycle even below 0.1% and that allow us to mitigate the skull heating minimize the skull reading while still achieve effective capitation and treatment in fact within the brain and that allow us to treat a large range wide range of locations and large volumes so we develop a in our group the chain one transcranial historic C system so they're true often one is a two hundred fifty kilohertz they are these 500 kilohertz both are 256 element hemisphere Co array with 30 centimeter diameter and 15 centimeter focal distance so it's actually huge was 3d printing with this array are we contact you some initial experiments and first to demonstrate a treatment profile and volume as I described by using a really low duty cycle mr. Trippe C is able to actually treats through excised human skull - for a wide range of locations both the deep targets as well as locations close to the skull as close as five millimeter away from the skull it also can be used to treat a volume target and here shows a four centimeter diameter in vitro bovine tissue that was treated using a mr. ship see through excised human skull within 30 minutes and we also measure the temperature increase in the skull and showing that even up to an hour of treatment the temperature increase to the score is within four degrees which is not sufficient to cause biological damage so we are able to treat a wide range of locations locations near skull surface and freezer volume charge through excise humans fall without overheating skull there was a concern that because he's a gypsy cherish mechanical tissue disruption so there was a concern that in the brain he may actually cause excessive bleeding or edema so we actually conducted in vivo safety studying a cosine brain this is actually was supported by focus or just on the foundation and the collaboration is a focus on some foundation so in this study we actually removed part of the pig's skull just because a pig score is so flat and thick and not meaningful for the autosum to go through and then suture back the skin so the ultrasound was applied from outside asking into the intact brain tissue and generating different kinds of lesions single patch and they even broke em because we're from Michigan we we have a tendency of putting em wherever we can do it so MRI images show that the lesion generated by history gypsy within the in vivo cosine brain it's really we'll confined so you have you know showing those bleeding zone but they are well confined within the ablation zone treatment zone and this is a gross morphology where the pig would survive for three days and three days later whose morphology shows that the lesions also is well confined within the treatment zone so this demonstrates the initial safety such that we now observe any extensive bleeding or email outside the treatment region in the brain we started universe's initial safety study we started looking investigating transcranial history FC for different applications I'm going to talk about couple here one is intracerebral hemorrhage or hemorrhagic stroke and what it is is that the vessel in the brain actually disrupt and breathe out and cause caught formation and for those patients the current treatment is a 1 years medical monitoring so doing nothing or highly invasive surgery to resect the clutch and there is minimally invasive approach you wear a capture is insertion into the crotch and atropine in from political trucks to liquefy the crotch and drain out and this really minimized the damage in terms of not cutting through the brain but however you know it's really slow it takes several days for the car to be liquefied the trick now and there is a secondary injury occurring within those time and the patient had a catheter connected during a several days so what we have been showing is a using his Oh Trixie acquired from outside a skull transcranial history up see we can liquefy the crotch really quickly up to 16 millimeter per minute so this allow us to liquefy a large crowd within several minutes without damaging outside damaging a spring tissue sironia we actually purposefully live a rim of the crotch intact so that we don't damage the ring and allow the train age of the crowd quickly true minimize the secondary injury to the brain we perform also in vivo experiment in a poss-eye intro cerebral hemorrhage model to demonstrate initial safety and F is ability so we are seeing here you are seeing here is a my image where we have the clutch in injection into the pit boring and then Twitter leave a rim of the on Tricia Crouch there to avoid damage to the Sony intact brain then this is a historic ruling on Tricia college and the Tricia crotch we survived a pig for seven days and then tracking for any adverse effects and and they were doing fine so that demonstration usual safety and a feasibility for the intracerebral hemorrhage application and second years we have developed a my guided a transcranial history Tootsie system and this is a chain true transcranial history gypsy system and in this system we have same geometry 30 centimeter diameter hemispheric array but with 360 elements and highly packed so higher packing density this allow us to increase packing density and increase the animals number allow us to double the pressure output through the skull so we can actually achieve theoretically can we measure through the skull achieve 150 mega Pascal and allowing this high pressure range also allowing us it was a increased element account allow us to be able to treat a large volume generating habitation through a large volume using electronic steering only and we can create up to 100 milliliter with the electronic focus tearing only and that's about 6 centimeters in diameter so really a good range through the skull on top of that oh the system you see here actually this is all the driving electronics so this is a Ray and we also added receive capability to the history of CRA meaning that the history of C transducer transcranial history of C transducer can actually transmit and receive signal and this allow us to do capitation macking through the skull and the reflection signal from the skull also can be received a true mathis call surface then allow us to actually carriage Esther our condition mapping true a mile CT scan of the brain we conducted this we're in the process actually of doing in visual in vivo cosine bring study against apportioning by focus ultrasound foundation and in this study we are using the transcript history gypsy system treating through an excise human skull and then into the pic bring so here again part of the skull picks core is fruit skins you to the back name in the mi scanner and transcript mi guided transcranial history up see were used and were able to generate precise dwell confined lesions in the in vivo pose I bring as shown on a my image and that's this is a two hours later after treatment again the vision is well confined and we didn't you know see excessive bleeding or edema so just a summary for the brewing applications we were able to show transcranial history FC can be used to treat a wide range of locations and the volume in the brain without overheating the skull and we demonstrate the initial safety and a fizz ability of using my guided transcranial history gypsy system and we also actually constructed a transcranial history gypsy system guided by a newer navigation system to demonstrate some initial safety but the testing and study is ongoing so the secondary application I want to talk about is the transfer treatment and this is really a group effort in collaboration with the surgery radiology universe Michigan and radiology department University of Wisconsin the Barcelona University Hospital and histrionics and we chose liver cancer as a first chemical target and when I talk about liver cancer here refers to both the primary and the liver metastases and the reason we chose liver cancer first target is because when the patient population is large and there is also a high percentage of surgically in operable tumors semele job 90% and because of that ablation is already a quick Oh standard treatment for liver cancer such as microwave ablation radiofrequency ablation but due to technical limitation and a lot of limitation even the current minimum a separation technology can also treat tunnel image we use to treat a limited patient population around the 15 percent also mr. chip see as a non-invasive non-thermal and non ionizing approach has a potential to actually overcome many of the limitations of the current ablation technology and I'm going to talk about history tripsy for liver cancer treatment in preclinical studies using large animal normal liver as well as small animal Liberty remodel and an with surface 1 clinical trial that was recently conducted you first his a gypsy in normal cosine liver human-scale a large animal model so this is seeing a collaboration with University of Wisconsin group with dr. Fred Lee Timmons Elwell down West and Paul Excel Lasky and really this has been a great collaboration that we have had in a year liner you have also have contacted the pig study at the university chigan so here are and also honor thank Fred and Tim to sharing some of the slides that I'm showing here so here we are showing first is ultrasound P mode image during the history of C treatment so that you can appreciate you how you know the treatment goes so above the arrow here is actually the cavitation January which is a bright spot so first we want to answer question can historically treat through inject chest and ribcage and here is treating through intact chest of the pig and a part of the ribcage and generating this will confine a cavitation zone and then the focus is the scan through a volume to cover a volume target so during the treatment you really can use ultrasound can see the capitation well and then after treatment history tripsy generated ablation zone can be visualized on MRI ultrasound and after on CT chew so this shows two on which there my image of the history trip see abrasions on right after treatment which is about three centimeter diameter spherical air region volume now was treated within 30 minutes of a history of see this shows a m-shaped we can control the shape and the size of the treatment zone really well on MRI ultrasound and because we are reducing disrupting this tissue increase air debris so we're really reducing the cell cell schedules which can be showing off some image so we can provide a real-time imaging guidance and a monitoring of the history gypsy process and this East entered debris that generated by history chip see they actually they were absorbed by the body really quickly so this actually shows that my image showing that immediately post treatment this is ablation zone none for weeks afterwards the ether de breeze we absorbed and clear out by the barbary body through the normal metabolism process and a history of see also another feature of history FC is tissue selectivity because the damage generated by history FC is caused by the cavitation induced a mechanical damage and different structures tissue structures has different thresholds for cavitation induce mechanical damage we found that tissue with lots of collagen and fibrin are more resistant to capitation inducing chemical damage such as file ducts your atheneum bow and vessels while tissue are more cellular such as a tumor are more resistant actually on easier to destroy so very susceptible to the history of sea damage and because of that we are able to actually preserve biodag normal blood vessels within the treatment area while the actual other tissue surrounding air are disrupted to a certain degree so we demonstrated that history can actually achieve precise ablation through intact chest and ribcage in large animal model then we started looking to the effects of history gypsy in the current model and we studied here so should see in northern shore model and this is a study where we collaborated with dr. crypto and mashaallah la merced michigan their group and then we did a different series studies the first study we did it was in rodent a rat liver tumor model that's off the topic and immunocompetent so they have in touching new system also you must study particularly there's true cohorts the first cohort of study were there is a tumor in the liver and we target the tumor and deliberation with a margin to cover entirely target death the entire tumor and in that group of rats nine of them the tumor after treatment and within seven to ten weeks we do not see any tumor on the mi know and have the volume that was treated it was reabsorbed by the body entirely and then we also interesting enough we also did a cohort of rest with partial to migration so in this cohort we treat you to 50 to 75 percent of the tumor so as you can see here the yellow arrow shows actually the target the volume where the blue arrow was the residual tumor that we left behind intentionally and it was interesting enough because we want to see what happens to the residual tumor but you are surprised that time weeks later this tumor you know bozo treated any residual tumor left behind both are gone there also resulting the complete absorption of that volume and when we look at a histology we see minimize region of calcific some calcification fabric some scar you know that what you see you would seeing a scar tissue typically with normal liver surrounding it just a you know millimeter region and no tumor cells so that was a really you know great results for the surprising so that motivated us to actually looking through the immune response that induced by history of see so this shows the immune cells we measured at day three and day ten after historic see treatment of the tumor in this study we also treated it as part of the tumor fifty to seventy-five percent and what we see is that they ten the CDH t-cell are there is a significant increase of cd8 t-cells compared to the control there's also increase of other immune cells HMG be one cities HT cell or cd8 t-cell cd4 T cells neutrophils tumor specific t-cells dendritic cells we see increase compared to the control and the compare to radiation therapy and radiofrequency thermal ablation approach we see increased a more potent immune response that generated by his urgency compared to those and we also look at the systemic immune response so in this study we are dr. Joe's group the in Pangaea - tumor there's you know one tumor that was treated by has a trip see and now the other one we didn't reach and we look at the immune cells in both the tree to his side and the contralateral side that didn't receive any treatment and it was really interesting the contralateral side didn't receive the treatment at they Chan we also see increased significantly increased CDT seeing patrician and other immune response immune cells as well in the in the untreated side and a step further we inoculated in mice with pulmonary metastasis so newspaper much assets to this mice again by chose group and then we conducted a hesitancy treatment of the primary tumor so law is not touched and ten days later harvest the lung and we found that the lung metastases being a history tripsy treatment group is also a significant lower than the control group so this all point to poaching immune response post local and a systemic induced by history gypsy and so our current hypothesis is why would we see that and the hypothesis we have is so history tripsy mechanically disrupt the cell membrane but unlike radiation using ionization or thermal approach that heat up using heating like an teenager protein the history trip see is a mechanical process were the tumor antigen now proteins here in touch and while we disrupt the cell membrane and release the tumor energy out and now expose it to the body and not only locally in the treatment region the easterly debris also goes to the blood stirring myself getting reabsorbed by the body so it really you know exposed to the tumor antigen to the body should stimulate the immune response and tell body that the cancer is here now the immune immune system can attack and also there is a semi logical cell death they induced by history trip see that trigger other pathway of the immune immune path signal pathway and altogether stimulates this potent local and systemic immune response so with all that knowledge we have learned from the pig study and from the rodent tumor study there was a phase 1 clinical trial that was conducted last year by led by dr. John without Yahweh in Barcelona and in collaboration with Fred and Tim from in Wisconsin and the system used by history Sonics produced by history Sonics and trial sponsored by history Sonic's and so this is a phase one trial where the patient population why say their liver cancer patients eight patients eleven tumors was tumor size in the range of 0.5 to 2 point 3 centimeter only one tumor is a primary liver cancer hepatocellular carcinoma the others are metastases and the the initial look we're nisha looking at a safety study with the primary endpoint would be the technical success whether we are able to we were able to actually treat a grand ablation volume where the plan operation wanna me is a tumor showing on ultrasound the image demonstrated by ultra image here with a centimeter of margins surrounding the tumor and they were in all eleven tumor is a hundred percent technical success was achieved and in one tumor that was that small tumor 0.5 centimeter really small cannot see some well there was a missed targeting other than at one case child the eleven tumors were effectively treated and by history FC and confirmed by the MRI image and the secondary endpoint is a contraction of the BJP's tumor volume and within two months demonstrated by MRI we have seen that it really the tree to the tumor the volume just like we have seen in the pig and rodents the tumor study the reabsorbed by the body and the quickly contracted so average of 88 percent of the tumor other treatment Wharram contraction within three month and what I find is most interesting and exciting is that in true of the age patients were also obscure prefecture was observed demonstrated by a global tumor volume so they're distant tumors that's not reiated also showing the tumor volume on control and reduction on MRI and also there's a global tumor biomarkers such as CA and AFP a job in those two patients so what I want to add here those patients are on stage patients they have metastases in their liver on all of them and so this this e facture really is a kind of unexpected from our end but a confirmed part of the immunologically we have seen in the rodent liver tumor model so to summarize for the cancer treatment you know we have shown history of C can be used to safely treat your plan ablation volume in the liver through inject chest and ribcage there is a rapid absorption of the tree to the volume and this allow the early imaging identification if there is any company treatment and we also have seen at scope olfaction used by history of C and Yu Shu the immune response both observed in the animal and in a human there's still a lot of a space for future development here um so that's that's the end of my webinar and again takes a village to all this work it's really a work by a large group people I really thankful and fortunate to work with a large about people in versus Michigan my collaborators risk University's counsel mr. Sonic's team the Barcelona team and the Virginia Tech team and founding resources so this is a picture showing not all the collaborations were a good number of them we had a history of C summit last year in September and thank you all for your time to be here with me and I'm happy to take any questions and also you can contact me this is my email and our website for more information and by the end I also really want to thank the focus all just on the foundations you gave me the opportunity to be here to share with you thank you thank you so much for that very fascinating talk and so we're going to open the Q&A special now so if you have a question please submit it the end of Q&A button at the bottom of your screen looks like we have a very engaged looks like we have a very engaged audience today and so I'm going to try to get through as many of these questions as we can so the first question for you Jen is how close to bone and air structures can you safely target using history gypsy so we have treated you know I don't have really a specific number in the brain treatment the the skull is of five millimeter and the day in the liver cancer wise I I would say somewhere around my experience is somewhere around a centimeter family we should be in five millimeter to one centimeter is a region that I have seen in animal studies that can be safely used very interesting okay so we have multiple questions interested about phase aberration Corrections when you are trying to do history gypsy through either the skull or through the intact rampage so we have a first of all with all the liver cancer treatment that you have seen we actually didn't do any operation correction and and we can so I'm going to talk about first is when you go through rib cage and let's go to the wave from the beam profile you will expect you have increased side lobes and reduce a main lobe but one great thing here is a cavitation is a threshold phenomenon so what we have observed is a as long as the side lobe is below the intrinsic capitation threshold and the main lobe is above a cavitation threshold then we can change cavitation within the treatment region and now housed in the side lobes and what we have been doing is that we use ultrasonic guidance to slowly to ramp up from low to high until we seek how do you generate you to buy the mineral and then we use a pressure level right above the threshold you know by and they only exceeding in the main low and you said to do the treatment is true true trying to avoid the cavitation now generated by the side lobe so that's what we use for the liver treatment well we can definitely do aberration correction and that's that's the next thing so for the school you're going through the skull we can do two step one is or we can use the established method which is using the CT scan on to extrapolate the skull thickness and the speed of the song in the assuming a speed of sound in the skull and use that to do modeling and the to do aberration correction now a which is basically was being done right now is a was a current a my guided focus ultrasound treatment another thing we have been doing is we because we have transmission received capability now so that we can actually receive the cavitation emission signal by all the animage modules on our history trip see array and that allow us to calculate the time of travel true between the the competition site to focus I to the re elements and they use a to do aberration correction there are other things as well those are the main things we have been looking at great so you touched on this a little bit and but we had a question how finally does the peak negative pressure need to be controlled to avoid undesirable effects what happens if you go about the upper limit so the the cavitation what we have seeing if the pressure is too high first of all again you know really you can really measure that pressure I'm due to the inside role when you have different patients coming in right you you can have patient with a BMI above 35 though you can have a patient that's always a BMI below 20 and so to actually accurately measure the insight or pressure is it's difficult so we have been relying on the real-time feedback of the ultrasound imaging showing the cavitation to tell us when the capitation is January to the one we are right above the threshold and if the true higher amplitude of the kinetic pressure is used or just in general high pressure is used there a couple things that may happen one is you can generate a temptation outside of the treatment zone and especially if it's near gas pockets then you can you know power for example then you may generate cavitation in locations outside and cause some undesirable damage and the second is if true higher amplitude is generated and treating through the rib cage and if the duty cycle is not sufficiently low and now also can accumulate enough of the energy deposition that may cause a potential thermal damage to tissue surrounding that rib so there are some side effects but we really are trying to control the treatment such that you know is right above the threshold excellent so there is quite a bit of interest on your liver cancer clinical trial specifically on the patients who showed an AB scope effect and so could you talk a little bit more about how those patients make them different from the rest of the population in terms of whether they had other treatments on or before in history gypsy and/or if you have any additional preliminary finding particularly immune analysis that would be very interesting I feel sorry to say that I don't really know this is really the early study that was that was done with unexpected results I have to say so I would refer and and the the the study was done I'm not a clinician so to refer those people who are interested in s to contact dr. roubideaux job a doctor friendly Tim they always Wisconsin so they are the people who have more information on the clinical trial and all history sonic so those questions I I'm sorry I actually don't have answer of course and so we have quite a few questions as well about the size capability in terms of your targeting so what is the smallest and largest lesion you can create with histor tripsy and what is I guess the imaging resolution in terms of tracking whether you're on target or not no sir upper limit wise really there's no upper limit if I think the upper limit would be the treatment time eventually the clinicians will lose patience patience okay so hey so we the the treatment volume size can you can treat your volume by either electronic focus steering or mechanical steering electronic focus steering that really there's a limit there because eventually you run out of pressure and a steering range but when combined with mechanical focus steering then that can be used to treat you as a larger volume as you Wow the smallest focus on our treatment zone is defined by the specific transducer the whole cone volume of specific transducers so really depending on the design a higher frequency will give you a smaller focus own and a smaller a lower frequency will give you you know a bigger focus on so you know if we are talking about the small cocoa zone we have ever created we say sutures in our lab we actually have a paper published rate for anyways interested it called micro trip see where we were able to use higher frequency mr shipp c to create actually lesions on the order of a hundreds of micron so it really depends on the the transducer okay we also have quite a bit of interest on looking at what the chemical characteristics of tissue are that effect threshold for cavitation so specifically there's some interest in clock versus normal tissue as well as calcified tissue right so I what I didn't report here our GU battery has done really a quite a bit of a work in terms of some prices so we have been able to use his gypsy to tree true mechanic to really like dissolve costs into again is there debris smaller than a micron both crops that's fresh as well as we tragic cross that's more aged we have trying to use this route see to treat calcified plaque so we try some really hard crack that from cadaver and when we found out it's at a calcified a human pack is really hard to treat and not just calcified is calcified plaque mixed with fabric and collagen together so that is someone seem to be very very existent to history damaged but interesting another interesting I want to point out that we we also found out that treating the cross and because typically the cost mechanical poverty wise seem to be the vessel will seem to be more resistant than the cross so we were able to in our study able to remove the cause while steer the vessel structure remain intact well that provided a perfect segue into the next question which is actually about this exact issue so if you are a bleeding either a tumor or I guess just generally in the brain and you're releasing all this debris into an intact blood vessel could there be issues with downstream clotting and or do you think that may actually affect whether the tumor is able to regrow quickly because it still has a blood supply well what we have so so first is that we when we see blood vessels remain in touch what we found is when we treat the tumor tumor vessels you know they are leaky tumor vessels those are really easily destroyed so we actually have seen we don't see tumor vessels remain intact we see normal vessels remain in touch and and also in terms of the memorization that was actually a major concern when we were conducting the thrombolysis treatment and it was actually very interesting and I was trying to conceive I can show a video here what we have seen in the formalizes study is a we were na we checked along we checked the brain because we were so concerned about potential embolization that can be caused by the you know just pieces of the pieces or fragments of the cross and it was interesting enough that in the study that we conducted in the pig we were not able to find any evidence of an embolization in the from Bryce's study and I want to share a video here and so what you are seeing the video here is actually a vessel phantom where you have the flow from left to the right and I'm going to actually unit study with 3 being a croc trap this year so I will start with video here so a cross fragment will be feeding into here and if you just go wipe away right but what happens here is what we see is this fragments actually caught fragment getting trapped within this cavitation zone january shaded by history of sea so it turned out that mr. Trippe see actually in you know breasts or created is more text actually has motion tracking of crud fragments and preventing any you know large fragments going down strange to call summarization so so this actually is what we think why are our complexes study we never seen any embolization in a lung volume in a brain so I hope that but I do agree that I need further investment like a we serve socially intend to study this further so I cannot see it conclusively you know that in the tumor treatment shape it's also the case but this is what we have seen the comprises study thank you so much for this this has been a fantastic talk I think we're going to wrap up for today so we don't keep you online all day for the audience members if you have questions that weren't addressed we will attempt to do that via email and if you have further questions please feel free to send them in to info at f-- us foundation work and for today that concludes our webinar thank you and for being with us here today