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next short talk is given by Jack Hampson. So Jack is going to talk about the preliminary in silicon model for conversion and infusion. Um, transcranial delivered drugs in cerebral spinal fluid. Get so there's going to be no cells mentioned, uh, at all. So I don't I don't know if that incites fear or calm. Um, but first, very briefly. I'm going to tell you about who, Who, who we are, what I'm a part of PMS May train stands for progressive multiple sclerosis materials training. And we are a pan European group multidisciplinary, comprising of two, um, industrial partners and six academic academic institutions. Um, it is part of a European Union horizon 2020 project and funded by a mercury grant. And what I'm going to talk to you today about is the in silicone or computational modeling arm of PMS that PMS that trains development of a transcranial drug delivery system for the treatment of M s. Um, so a drug housing device is implanted on top of the skull and through a controlled release protocol, uh, drugs will migrate from the device into the skull and diffuse across it, targeting the surface of the brain and cortico lesions characteristic of m s that form there. But here is a more detailed look. Sorry. This way. More detailed. Look at the area of interest. So what you can see here is the path. Uh, the diagrammatic path might look a little different to this, um, that the drugs will take from the device that diffusing by molecular diffusion through the skull, the dura, the arachnoid until they reach the subarachnoid space where things get a little more complicated and interesting. So you can see the compounds are taking a much more highly distributed route in the subarachnoid space. And that is because they're travelling not only by molecular diffusion, but being carried by bulk motion of cerebrospinal fluid. And this cerebral spinal fluid is moving in a pulsatile motion, which is driven by cardiovascular action, Um, and makes things a lot more complicated. Um, sorry, actually gonna jump back because of the flexibility of silicone modeling. We can actually take each of these layers of anatomy there. I know it's a diagram, but they are kind of a nice little neat stack for us. We can take each of those each of those layers and deal with them independently. And rather than start with the skull, uh, we're actually going to be starting modeling with the subarachnoid space. Um, for a number of reasons, One of which is the computational Modeling is particularly well suited to modeling, uh, fluid flow in a way that in in vivo and in vitro can struggle with. And also, um, computational studies in the spinal compartment have shown that, uh, drugs in the spinal subarachnoid space the dominant method by which they get distributed around the central nervous system. That the the subarachnoid space is encompassing is via this this pulsatile motion of the flow. So it's it's going to tell us a lot about, uh, localized or global delivery to the brain surface for any drugs that are found in the subarachnoid space. And because we're focusing on just the one part of the anatomy, our objectives short but, uh, dense with work. So we want to develop a methodology for stimulating the drug release into the subarachnoid space and to identify the mechanics of the drug transfer in the flowing cerebrospinal fluid. Um, so how do we translate this space? Which is quite complicated too. A computer model. Um, well, we we simplify quite a bit. Uh, here is a two dimensional schematic of what our model looks like. Um, pulsatile flow is being stimulated with an oscillating boundary condition with the velocity field oscillates between the positive X direction and the negative X direction with this being the average velocity in there, uh, we have an infinite drug supply for the time being, as we're only modeling a short time window, 300 seconds worth of system evolution, and we have a relatively small patch through which drugs can enter. And, uh, these these compounds have diffuse city. That's of an order of magnitude that you'd expect for small molecules in water. Um, it's not a compound. It's it's a representative compound. Um, it's not a specific diffusive itchy, and it's quite a short. It's quite a short channel. All in all, it's 60 millimeters, so we've approximated it as a rectangle. Um, so I'm going to show you too little animations. What you're going to see is the concentration field being, um, uh, diffusing through the fluid and being affected by the fluid flow itself. This is the 1st 25 seconds of evolution. Um, so it looks like basic. But what you're seeing is both streamwise flow, which is along the X axis and transverse transverse displacement of the compounds. Um, and it's a little difficult to see from here. It's not real time, um, pulsing with the frequency of about one hurts. Um, it's a little difficult to see, but the amount the distance of distribution, streamwise and transverse are not quite equal. And if I go to the next one, which is the last 25 seconds of our simulation slowed down just a little bit. You can see that the concentration field is being slashed around. But even after this, 300 seconds, it's five minutes. Um, concentration still drop off very quickly away from the drug source. And, uh, in this bluish band, uh, concentrations are only a 10/1000 of what they are at the source, and this is after five minutes. Um, now, I haven't quantified it with the graph here, but the distribution stream wise is about 40% further away from the source, then by then in the transverse direction, meaning that, um essentially, uh, the combined effect of conviction and diffusion that's taking place in the stream wise direction. It's having a considerable impact on drug distribution. Um, but again, this is a simple model. You might have noticed that the inside of your head isn't too d or rectangular. Um, so we need to make these models more, uh, subject specific and PMS. Motrin is primarily preclinical at the moment. So most of my colleagues are using mice models. So subject specific in this case is is mouse specific. And, uh, here is a T two weighted MRI image, and we also took CT images. And from high resolution images like this, we can perform commute segmentation and three D reconstruction, and we get a lovely three D representations of the distinct parts of the anatomy. And then we can click them together for one to have a better phrase and prepare them for, uh, physical stimulation. And the other side of that kind. The other part of, uh, transport that we need to model is diffuse city so diffuse it is very scarcely mentioned in literature for a number of reasons. It's, uh, it's kind of hard to do. It's not always necessary. And there's so many drugs and so many tissues that that you'll find a diffuse city in that. A lot of the time, it's just approximated as being quite slow. Um, so we've developed an experiment. We designed an experiment using this France diffusion cell. Um, whereby we can quantify the amount of, uh, compounds passing from this upper chamber through, um, a biological sample, a tissue sample into the lower chamber. And by sampling this, we can measure the concentration in the lower chamber over time, giving us this concentration first time graph. And if we fit that to known laws of diffusion, we can back out the key parameter, which is the facility, and that would give us a subject specific and compound or compounds pleural specific model with which to work with. So it's going to jump very quickly from a to direct angle to something that looks quite close in vivo and is, uh uh, obviously, this this is supposed to work for for humans eventually. So the ongoing work with determining, uh, in vivo realistic anatomy and determining diffusive it ease of key compounds in key tissues. We hope to perform that on human tissue next and human scans following this. Um, thank you. I'm sorry if I went over time. Um, I might have. Thank you very much. This this is very interesting. You have any questions from online, or Yep. So, um, this is very interesting concept for someone like me who is a condition. I'm thinking of getting the drug to the right, the right organ and just in the front side effect of drugs. But I suppose the first thing is, obviously this skull is a huge body part. Have you thought about how the drugs are absorbed through the bone? Um, thought about yes, like so. Actually, this this particular this particular, um, slide shows, shows a mouse skull here and that that is what we're going to be, um, measuring the diffusive any of the compound through first through mass skulls. So we're not sure how how it happens or how well it happens. We do. We do actually have reason to believe that that it does happen that things can pass through. But the exact mechanisms are unsure because, like, the human skull is even more complicated because the ferocity changes as you go through it. Um, but yes, it's something that is within the realm of modeling at the at the very least. Yeah, yeah, that That was one of my questions, which I wanted to ask. And so that little gadget you put on the top of the you had obviously there will have you thought about doing that. The skin, uh, will be one of the barriers you can. You have to get across or as in. So it's under the scalp. Yeah. Sorry if I didn't say it's under the scalp. Yeah, I think this this particular device is frequently used in transdermal applications. And we got the idea from a colleague of mine. So, uh, we're just using it for other stuff, which doesn't seem to have been done much at all with what you mentioned in terms of the gradient. That how quickly, Uh, wondering in that insert, because you will need to go through another two or three layers. You will have to have a pretty high level of, like, a high volume, higher concentration. So what's interesting about the diffusion is we used, We used We used a quantity of one more per meter per meter cubed and the distribution um, it will be linear. So if you had, like, 10 times that the concentration profile would still look the same. And you still have, um, you know, 1000 of that concentration, the set, the same distance away, of course, fluid velocity in the region and the specific diffusive it will will change all that. But But, yes, there are the parameters that we're going to have to sweep through, like a lot of different configurations, like high density, low fluid velocity and vice versa. But in terms of the pulsatility obviously will relate to local areas where the vessels are running. Um, is that going to Not exactly so. What's actually happening is, uh, as the heart beats, um, the arteries will swell in the brain, and they'll push the entire volume of the brain out words. It's not necessarily the same amount in all directions. And what that does is it pushes cerebrospinal fluid somewhat towards the spinal compartment, which is a little bit more a little bit less compliant. And then when the, um, vessels relax again, the three spinal food rush is slightly back that way. Um, so it's actually the whole volume is changing, as opposed to just the local, um, space around the arteries itself. Yeah. So the martyrs uh, vascular, uh, fertility is not going to be a major. I haven't seen that. And I haven't seen that reported in in studies that have measured the pulsatility. Thank you. Yeah. Yeah. The last question is a as in the chemical that's used. Yeah, 100%. So? So compound a in in school will be potentially different. Compound be in school, which will potentially be different. Compound A in the urine, you know, So it's technically unique to the compound in the media. Um, they could be the same, but you have to measure it to find out. And they can range between like, like with solids. They could be They could be one by 10 to the minus 12 m squared per second. And then they could be 100 times higher or 1000 times higher in a liquid. But but, um, yeah, it's It's not always easy to determine. Um, thank you very much. Very interesting talk. And now we are back in, uh