Fabrication Techniques for MEMS-Based Sensors: Clinical Perspective PDF

Fabrication Techniques for Mems-based Sensors: Clinical Perspective Prof. Hardik J Pandya Department of Electronic Systems Engineering Indian Institute of Science, Bangalore Lecture – 02...

Fabrication Techniques for Mems-based Sensors: Clinical Perspective Prof. Hardik J Pandya Department of Electronic Systems Engineering Indian Institute of Science, Bangalore Lecture – 02 Introduction to Microengineering Devices Contd Hi, welcome this is the second module of our class 1 for course Fabrication Techniques for MEMS-based Sensors from the clinical perspective. Now, what we have seen until now is, there are several sensors that we can make for solving some important problems in the area of medicine or in the area of biomedical engineering. The same technology that we will be discussing in this particular course can also be used for fabricating devices, microdevices to be precise or devices based on MEMS-based technology that is microelectromechanical systems-based technologies that can also be used for other applications such as electronics, robotics, chemical engineering, mechanical engineering and so on. So, in our class 1, what we saw are few devices starting from the microheater. (Refer to Slide Time: 01:39) So today, I will just show you how the heater pattern looks like. Now the pattern that I will be showing would be different than what you can see on the screen. But the idea is that the micro heaters like I said can be patterned in a different way because it is nothing but a resistor. So, resistor if you want to have the resistance of a metal, if you want to 28 increase the resistance of a metal, you can increase the length or decrease the area. So, let me show you the microheater which is now with me. (Refer to Slide Time: 02:27) So, if you see here, this is your microheater. This is a microheater, you can see the pattern of the microheater on the glass substrate. This is the backside of the heater and we have used chrome gold, we have used chrome gold as a metal. So, this is how the microheater looks like. Now then again you can see that the length is high, the area is also high. So, the resistance would not be that low, but this heater was patterned with a particular application. Now, another thing that you have may have observed is I am wearing gloves, so as to avoid the fingerprints, so as to avoid the contamination on the device. Again this device is for demo and that is why even the recording studio is not a class clean room like the last 1000 class, 10000 class. This is just to show you the devices outside the cleanroom. But if you have a complete device, then the devices are of several types one that can only be used in a cleanroom environment, second that can only be that can be used anywhere else. So, we have to design the device, since it is a clinical approach clinical research, these devices should be able to go outside the laboratory and at the same time, it should not have contamination issues. That can be done when you package the complete device because again in the clinical environment, the hospital environment would be cleaner 29 compared to the dispensary. When I say cleaner, suppose the surgical room is present, it is around class 10000. (Refer to Slide Time: 04:44) So, then what we have seen, we have seen an interdigitated electrodes. Then in interdigitated electrodes, what we have seen that there is a heater and on the heater, there is an insulator, on which there are I D E, patterns. So, if you want to see interdigitated electrodes, I will show it to you here. (Refer to Slide Time: 05:01) 30 Now, if you see here, this one to which I am pointing this one, this sensor here, this chip has a microheater at the bottom and on that there is an insulator, on which there are interdigitated electrodes made out of chrome and gold, this particular chip once again I am showing it to you, this chip. So, we will see in detail about the fabrication of this chip with a better zooming angle when we are talking about these devices in detail. Now, my idea is to show you how it looks like when we will go into detail how we can fabricate it, at the time we will even zoom it further to understand how it looks like from the actual design point of view. So, what is the role of that, the role of those devices was that now on these interdigitated electrodes you can load let us a piezoresistive material, And if I create a diaphragm on the backside, so what does it mean, I have this electrode. So, you see here, I have an oxidized silicon vapor. So, I will draw oxide and then I have a heater, then I have an insulator, then I have interdigitated electrodes, this is what this particular diagram is. Now, if I have piezoresistor, a piezoresistive material such as P.PSS on this and if I apply a force or a pressure on this piezoresistor, I apply a force then it will not show a change in resistance or it will show a very poor change in resistance or very small change in resistance. Why, because I am using silicon then I have silicon dioxide. I have a heater, I have interdigitated electrodes though, silicon is a hard material. So, if I want to see the bending if there is bending, then there is a strain on the piezoresistor. For that, I have to create a diaphragm. So, what does the diaphragm mean, it means that we will etch silicon from backside in this particular fashion? So, this is the diaphragm that you have created. And now, if I apply a force, the diaphragm will bend and this bending of the diaphragm would cause a change in the resistance / So, if I want to deposit a material which is a piezoresistive material on these particular electrodes, then I have a diaphragm on the backside this can be one of the application. Another application is instead of piezoresistor instead of this p.p s s, what I will use. 31 (Refer to Slide Time: 09:04) I will use gas sensing. So, if this material is used in sensing gases such as semiconducting oxide materials like indium, tin oxide zinc oxide, tin oxide, indium oxide, tungsten oxide. Then, if in the presence of gas, in the presence of VOC volatile organic compound, there will be a change in resistance because of the reducing because the VOCs are reducing gases, we will see in detail how we can use it. The application of this particular device now can be in many areas and two of which I have just shown it to you; one can be a force sensor, another can be a gas sensor. So, the device that you have seen now which I have shown it to you was a microheater on which there is an insulator on which there are interdigitated electrodes. Then what we have seen, then we have seen a device for Atrial Fibrillation. 32 (Refer to Slide Time: 10:35) So, again we need flexible force sensors. So, I have to make flexible force sensors and the tip of the catheter and we will discuss in detail about Atrial Fibrillation. So, when we talk about the tip of the catheter, then we again need flexible force sensors. So, what should the sensing material be made of? It can be just a strain gauge. (Refer to Slide Time: 11:01) So, if I create a strain gauge or array of strain gauge like this, then you can measure force correct. So, how can I create this array of strain gauge on a flexible material? So, to see the pattern, so, see the pattern, I have here another wafer which you will see, which you 33 will see how the chip looks like. At the center of this chip, there are four sensors if you see here. (Refer to Slide Time: 11:45) So, if you see this one, then in the center of this chip, there are four sensors centers. And what is in the center of the chip, these are four chips; one, two, three and four. At the center of the chip, there are four sensors. So, if I deposit if I create this kind of pattern, if I create this kind of pattern on flexible material, it will be a flexible force sensor, isn’t it? So, if you just look at me now and you see what I am holding? 34 (Refer to Slide Time: 12:31) You can also hold the wafer in the way I am holding. It is like this. The earlier wafer that we had was a microheater. So, there are two ways of holding it when you perform lithography, the best way of holding is always using a tweezer. (Refer to Slide Time: 12:44) This is called a tweezer. So, we can hold with a tweezer or you can even hold with the gloves like the way I am holding. 35 (Refer to Slide Time: 12:54) Now, you can see the pattern properly. So, on one side I have flexible force sensors, a pattern for flexible force sensors that I can use further. On another side, I have a heater this is the pattern for flexible force sensors. So, for the heater, we know how we can use it. We now know how we can use the flexible force sensors for the atrial fibrillation for measuring the catheter contact force. So, there are several ways how people are comfortable by holding the wafer, again the best is with tweezers. Now, depending on the dimension, depending on the primary flat and secondary flat, the wafer can be identified as p-type or n-type. You see there is a flat; one is the primary flat here, the secondary flat is at the bottom. So, it is at 90 degrees. You see here there is another flat degree, primary flat. If I see it is not circular, you see it is not a circular wafer, there is a primary flat here and then there is another flat let me just show it to you which is here at the bottom. This is 90o with respect to the primary flat, here is a flat. So, let us try to see if you can catch it. Yes, you see the primary flat and secondary flat. The secondary flat is always smaller with respect to the primary flat. If we know where is a secondary flat with respect to primary flat, then we can understand whether the wafer is 1 0 0 or is 1 1 1, whether it is n-type or this p-type. This is an advantage of the primary flat and secondary flat. So, we will see how the lithography is done, how can you create this pattern a lot of other stuff in this particular course. That is the idea for this particular course to educate 36 the students in the area of micro-engineering, particularly if we can solve some very interesting problems using these devices. So, then what have we seen? We have seen the flexible force sensors for atrial fibrillation followed by a cantilever, a piezoresistive, cantilever. (Refer to Slide Time: 15:13) So, when we talk about piezoresistive cantilever, I have told you that there is an S U 8 tip that is used for piezoresistive cantilever. And as the name suggests, there is a piezoresistor embedded within the cantilever. How can we integrate a piezoresistor inside silicon or on the cantilever we will see their factors. Now, as we know if there is a piezoresistor, if I bend this cantilever, if I apply a force, then there will be a change in the resistance. So, how each cantilever looks like I said, you can see the chip here. 37 (Refer to Slide Time: 15:54) You can see the chip, but at the end of this chip if I draw just a line like this and if you just concentrate on this particular chip, the line that I have drawn is this cantilever which you cannot see with your naked eye, you have to use a microscope to understand that there is a cantilever. So, how this chip looks like let us see here. I have cantilevers if you can focus on the disk, yes. So, you see or let us do like this, let us focus I will put in my hand let us try to focus this yeah. So, the small things within here, over here, these are the chips, and within this chip, at the end of the chip, there is a cantilever. So, it is so small. It is so tiny, super tiny and we cannot see the cantilever coming out. We can only see the chip; we can only see the contact that we can take the contact out of the cantilever. So, it is very difficult to see the cantilever. It is very difficult to see the cantilever with a naked eye even with the zooming factor of the microscope. We can see the pattern of the contact pads that is why if you see the screen, what we are looking at here is if you see the screen, the contact that you can see is this chip, which you can see. And this chip if I zoom in further, what do you see. So, you can only see this. So in fact, it is very difficult to see this as well, but still, you can see. So, what is this? These are contact pads, this one, and this one, contact pads. Here is your cantilever that we cannot see and this is the contact to the cantilever, contact to the cantilever. So in fact, contact to not only the cantilever, but there is a piezo resistor embedded in the 38 cantilever. So, if I zoom in further, if I just say a cantilever and that there are contacts for the cantilever, this is a cantilever and there are contacts for cantilever, then there is a piezo resistor, there is a piezo resistor and this is the contact to the piezo resistor. This one is the contact to the piezo resistor. And as you go down further and make a big contact, further down and make a big contact. These contacts are for the cantilever, this one is for the cantilever which has an S U 8 tip. So, this is super tiny as you can see, everything is super tiny, it is in the order of micrometers. So, you assume that when it is in micrometers, if it is like this if it is nanometre, you can definitely not see with your naked eye, correct. So, we have seen that this cantilever can be used for understanding the mechanical property of tissue. It can also be used for measuring and understanding the mechanical property of cells, it can be used to measure the stiffness of the material and we will see how we can fabricate and how we can use this piezoresistive mechanical cantilever from a clinical perspective. So, next was interdigitated electrodes that we have seen. (Refer to Slide Time: 20:34) We can place the tissue and we can measure the change in impedance. Again we will look at this in detail when we go onto tell about each device. 39 (Refer to Slide Time: 20:43) Then we have seen this chip. And like I said, now we are interested in measuring the electrical thermal, mechanical, electrical, thermal and mechanical properties of tissue. In this case, we should have a sensor that can measure the electrical property of tissue, that can measure the thermal property of tissue, that can measure mechanical property of tissue and to measure all these three properties, we should have a chip that consists of or that is integrated with all three sensors ; sensor 1, sensor 2 and sensor 3. So, we can call this a biochip. Why biochip? because this chip is used for phenotyping or for understanding the change in the tissue properties. And what changes? Electrical changes, mechanical changes and thermal changes of tissue properties, why is it important? how tissue property changes? why this whole idea of designing this tool comes into the picture and really is it important to make this tool or because just we know microengineering we are designing different sensors, a lot of questions should be there. Before you design any device, before you start working on any device, the main thing is: what is the application of the device, what is the gap in the current research that you are going to solve. By designing this device, am I going to solve a gap with the existing technology or is it really useful from the diagnosis point of view and if yes, how? So, always understand the devices from the application point of view, first understand the application and understand the problem and then your design for the device accordingly. 40 So, if I want to see this biochip, how it looks like; I have a biochip in my hand and here we have to focus on, you have to see this area, if I see the camera, now you do not have to see the center, you have to see this one. All the three chips are in the bottom, you will see that there is a subtle difference because here you can see that it looks different than this one because now you have a gold pad and on that, you have S U 8 pillars, you have a gold pad and you have S U 8 pillars. If I can show in this particular fashion if you can zoom in further. So, comparing and looking at that chip where it was having microheater and interdigitated electrodes. Now, we are looking at this particular chip; there are three in the bottom and here there is a clear change in the design, you can see very clearly, you cannot clearly understand what are the patterns, but you can see that the chip looks different. And we will see in detail by zooming each chip what are the patterns within the chip, but these are the biochips integrated with three sensors the bottom one, biochips integrated with three sensors; this three and this one. There are 4 indicated with three sensors; one microheater, then piezoresistor and then.electrodes. And we will see how we can use it. (Refer to Slide Time: 24:48) We have a heater, we have the interdigitated electrode over which we have piezoresistor, over which we have electrodes on which there are SU 8 pillars, you can see in the center 41 and on the backside there is an etching of the silicon and this etching is done using bulk micromachining. If you go to the workshop, then you have machines. Here we are machining the things at micro-scale that is why it is micro machining. Why is it bulk because you are removing a bulk of silicon, you see if this is a silicon wafer, if this is the silicon wafer and I am etching the silicon wafer from the backside, this is silicon dioxide and I will tell you why I am drawing such a pattern always with silicon dioxide. So, if I say that the silicon is 500 micrometers and I am etching the silicon, I am etching the silicon to about 480 micrometers, then the bulk of the material is etched. And then for the diaphragm, this one can be from 1 millimeter, can be from 500 microns, 200 microns, 100 microns. This is the window, but this one what I am talking about this one the area 100 micron, 2 microns, 300 microns, 400 microns, 500 microns, it is in micrometers, we are performing a micromachining technique. So, etching of silicon from the backside is done using bulk micromachining, then there should be also surface micromachining. So, what do you mean by surface micromachining, how it is different than bulk micromachining? We have to see that as well and we will see it. Now, we will see the bulk micromachining from what is the difference between bulk and surface micromachining. (Refer to Slide Time: 27:26) 42 Then we have seen microfluidic chip for rapid drug screening and I have discussed with you why it is important. (Refer to Slide Time: 27:36) The importance of this particular device you can see on the screen is that now you can test multiple drugs for the same patient. So, you can load, if I just zoom this particular one, what is it? it is a channel like this, connected with a smaller channel, and I can load cancer cells in this area. Below this, there is an interdigitated electrode here, you can see interdigitated electrodes. If I zoom in further, it looks like this. And below the interdigitated electrode, there is a silicon dioxide and below silicon dioxide, there is a heater. You can see this one, there is a channel, inside the channel in this area. There is an interdigitated electrode which you can see from here, below the interdigitated electrode there is an insulator and below insulator, there is a heater. Now, I have loaded cancer cells in this particular channel and I am passing a drug, I am passing a drug 1, on this one and I am circulating continuously for some amount of time; let us say 24 to 48 hours, you can select anything, you have to optimize it. Now, how many channels I have? I have eight of those. I have eight; 1, 2, 3, 4, 5, 6, 7 and 8; eight channels I have. So, what will happen? I can test eight different drugs because I have eight different channels. So, now, you can do a drug screening; that means when the drug is effective, the drug is effective the cells would die and the impedance would change we will see in detail how this thing works. 43 But the idea is, now, what you can see, you can see that using this particular device you can test multiple drugs for the same patient; that means that if you take the cells from the patient. And if you load it in this channel and all the remaining seven channels for the same patient and you can try different drugs to see whether a drug is effective or not. Alternatively, you can load eight different patient’s tissues in eight different channel and you can try the same drug and see whether the drug is effective or not. Both ways it is possible either the same patient, cells from the same patient in all eight channels, you test eight different drugs or you take eight different patients cells from eight different patients and you try the same drug and see what is the efficacy of the drug, how the drug is effective to kill the cancer cells or not. It is a rapid drug screening device. So, how does this rapid drug screening device look like, you can see from the screen. So, I will just show it to you, I have brought one for you, just to see. So, I will put this back and take a tweezer and then pull out this device to show it to you. So, first, let us see this device in my hand. (Refer to Slide Time: 31:34) what you can see is that there are a certain number of channels, and then below the channel, in the center, there are electrodes, below the electrodes, there is an insulator, below the insulator, there is a heater. So, if I show you from the backside, you can see the heater clearly and then you can see that there are lines going like this which are 44 interdigitated electrodes. So, heater is there, but I am showing from the back because you cannot see clearly from the front that is why I am showing from the backside; heater is there, on which there is an insulator, on which there is an interdigitated electrode, on which there are channels and these are eight different channels. So, you can test eight different drugs. So, let me just show it to you here, you can see now there are channels and then there are contact pads. We can see contact pads over here, over here there are channels and below the channels, there are electrodes below that there is an insulator but you cannot see that and then there is a heater. So, on the backside let me hold it properly. You can see now, there is a heater and these lines that are going, lines here on the second side also, these are electrodes and you can also see the holes for the channel, this is the backside. You can see the heater first. When I say backside, from the backside you can just see that there is no metal here. If I touch here, there is no metal on the backside. So, we will see in detail again by zooming it further when we are talking about the microfluidic device for rapid drug screening. But in principle, these devices can be fabricated using the microengineering technology and this can be used for rapid drug screening. So, that was about the microengineering devices. But when you have drug to flow, when you have some fluid to flow in such a channel which about 1 millimeter or 100 micron or 200 microns any anywhere between 100 to 1 millimeter or 0.5 millimetre, then it comes as a micro channel. And a fluid flowing within the micro channel, we have to understand micro fluidics. That is why such devices are also called microfluidic device or microfluidic chips. These devices are also called microfluidic chips. So, when you talk about microfluidics you have to also understand whether the fluid flowing from that will be of smooth flow or turbulent flow. You have seen that when the river flows very fast, you see a lot of turbulence. Then you have also seen a river which is slow in nature, smooth flow. Then suddenly, there is turbulence. So, we do not want turbulence. So, the flow should be smooth to understand this turbulence we should further understand something called Reynolds number. So, we will discuss this when we discuss the microfluidic chip. 45 (Refer to Slide Time: 35:46) We can see a device that can be used to understand the antibiotic susceptibility testing, for what? For bacteria. We have discussed in the last module that the material antibiotics susceptibilities is an extremely important problem since a lot of neonates get affected by several bacterial infections; And the report now comes in 24 to 48 hours which is too long for a neonate to wait for and because of this lots of neonate die, a lot of babies die, that is one thing. The second thing is, even for us, even for the grownups generally we have to take multiple antibiotics, topical antibiotics and we do not want to do that. We want to create a technology that can aid the doctor to give a particular antibiotic within a shorter period of time rather than waiting for the reports to come back from the pathology lab, which comes in 24 to 48 hours or even sometimes 72 hours. So, for that can we design a microfluidic chip that can perform this kind of rapid testing or we can just have a microchip that can do rapid testing. So, we will see that particular work as well and for you guys, I have also brought you this microfluidic chip, again we will discuss this microfluidic chip in detail when we are talking about the particular topic in detail, but now let us see how it looks like. So, in my hand, there is a microfluidic chip that can be used to understand antibiotic resistance. This is how the chip looks like. 46 Now, again you see this is all about the design and here we have used P D M S, this material is called P D M S silicon. We will see how we can create this kind of a channel. But suppose I want to now commercialize this one and I want to put it in each and every pathology lab so that I can rapidly diagnose which bacteria are there and then rapidly diagnose whether bacteria are resistant to the particular antibiotic or not. What should I do, because the wafer that I am holding now itself is costly, it is thin glass, I can use a glass slide instead of that. Now, there are gold patterns and then there is P D M S, again you will see that when you want to create P D M S channels in P D M S it is our pain. It is not so easy and then it is costly. In that case, we have to opt for some different technology. So, instead of creating a channel in P D M S, I can create a channel in plastic, I can do plastic moulding, I can stick plastic on the electrodes and the heater, I can make the entire device on plastic. It will solve a lot of problems if I have the entire device on plastic because it will be cheaper, it will be robust. Unlike this, it is fragile and can break into pieces. Apart from designing the device, the cost factor should be kept in mind to reach out to the poor people who are unable to afford it. This is always helpful when you want to understand any topic, say about drug screening or if I talk about antibiotic resistance or if I talk about atrial fibrillation or if I talk about cancer diagnosis tool. 47 (Refer to Slide Time: 43:31) This is a microfluidic chip for evaluating drug efficacy and here we will discuss about this device, we can mimic the in-vivo situation on the in-vitro platform. This is an in- vitro microfluidic chip. So, if I want to mimic this one, I can create a device that will have a similar kind of design that is within the body. This is a very simple microfluidic chip. Now, people are also working on chips on organ. (Refer to Slide Time: 44:36) So, if I want to create the microfluidic chip, I have to have a mould and this mould is of silicon and this what you can see, these are all S E M images, scanning electron 48 microscopy, scanning electron microscopy. These are all S E M images and these images are of the mould. And using this mould, we will create the P D M S channel. So, How does this device look like? This is the pattern in the picture. (Refer to Slide Time: 45:39) So, this is the channel that we are looking for on the S E M and then in between the channels, if you see the central region here, we can load the matrigel. On one side, we can load the cancer cells, on another side of the channel of this device, there are two channels, as you can see. So, one channel we can load the cancer cell and on the other channel, we can load the epithelial cells. And in the center, we can load matrigel and then we can test different combinations of drugs. So, how this works we will see when we are discussing this device into detail, this is the pattern of the device, pattern how the mould would look like now. This is just to show you how the pattern looks like, this is not a mould again. To create a mould, we have to create this kind of a pattern on silicon and then etch the silicon. When you etch the silicon, whatever is opposite to it will come in the channel. What does the opposite mean? So, if you see the screen 49 (Refer to Slide Time: 47:02) If I have silicon like this and I create something like this and if I have P D M S, my P D M S will look like this, when I peel it off, it will look like this. We want channels in P D M S. So, if I take silicon and if I etch the silicon in this particular fashion, then if I pour PDMS, then my P D M S will look like this. That is we have created, a channel in P D M S. So, what I mean by opposite is, this is the mould. Whatever be the pattern on the mould, the opposite will come here, you see there is a hill and here is a valley. So, you can see here that what we have is a valley. So, the opposite of that would be hills. If there is a hill which you can see here clearly, then the opposite of that would be in the P D M S. That is what I mean by opposite, we will see in detail how we can fabricate this device when we talk about the combinational therapy; The devices that can be used for understanding the combination of drugs. 50 (Refer Slide Time: 48:48) Then, we also talked about flexible MEMS for phenotyping tissue properties, and this is similar to that we have seen earlier. If you see this one, this one or this one, it has two sensors; one is an electrical sensor and another one is a piezoresistive sensor and this device looks like this which we have seen earlier. This is a device that you see on the screen as well. This is the device that I am holding now. This has a piezoresistor and it has an electrode and everything is in the center, and the rest is just a biochip. So, that is what we are looking at on the screen and it is on the flexible material, that is why we say it is a flexible MEMS and can be used to understand the tissue property. That is why we say that the flexible MEMS for phenotyping tissue properties. 51 (Refer Slide Time: 50:08) Now, let us talk about one more technology called immunotherapy. So, immunotherapy is the therapy that will activate your immune system as the name says immunotherapy. It will work with your immune systems and again immunotherapy has several divisions, we will just talk about one particular division in which we need to understand whether the immunotherapy drug will be effective or not. So, you can understand a very simple thing here and then we will discuss in detail later. Now, when there is a tumor which you can see this particular figure and there are cells that flow in the blood vessels, then within the cell there are something called as t cells. We will discuss about t cells later on. And depending on the tumor if the immune system is working well, then there is a change in C D 4 and C D 8 concentration. Now you understand this thing, C D 8 are called killer cells, C D 8 are in t cells we will see what is a t-cell. C D 8 is killer C D 4 is helper cells. So, if the immune system responds well to the tumor, the killer cell should be higher in number. So, the blood is taken from the patient and C D 4 to C D 8 ratio is measured by using something called a flow cytometer. Now, if I want to create a similar kind of environment which is my in vivo environment, on to in vitro platform I can design a microfluidic chip which will mimic this in vivo situation. 52 I will create the channels and load the tumor in the center of the channel; you can see the magnified view of the channel with dimensions in figure F. (Refer to Slide Time: 52:43) So, here I will load the tumor and from here, I will pass the T cells. Now, immunotherapy is not so easy to understand, but just to help you out, there is a cancer cell and there is something called the immune checkpoint. So, one is called P DL 1 and T cell correspondingly, there should be P D 1 what is around a cancer cell P Dl 1, this is T cell, what is on T cell? P D 1. This P D 1 will interact with P D 1 1 and it will think that the cancer is normal that's because normal cells also have P Dl 1. So, T cells cannot distinguish between normal and cancer. In this case, if I block P D 1, then P T cells will just kill cancer cells because it cannot find, it cannot have a bonding between P D L 1 and P D 1. It cannot have interaction between P D L 1 and P D 1. So, what will happen? the T cells will start killing the cancer cells and more T cells will be generated or we can also work on engineering T cells. That is a different topic. now, we are not interested in that. We are just interested in that if I can use a drug that can block P D 1 and that is why the drug is called anti P D 1. So, if I block the immune checkpoint one of the checkpoints on T cell and then if T cells cannot have interaction with P D L 1, the T cells will kill cancer cells. So, in this case if my C D 8 will start increasing, killer cells will start increasing. The number of C D 8 increasing; that means, my drug is effective. So, I can use this anti P D 1 and similar kind of drugs. 53 (Refer to Slide Time: 55:05) And test it by flowing this across this channel loaded with matrigel and tumor. And every time I flow after 48 hours, I measure the C D 4 to C D 8 ratio; that means, I first flow just T cells and measure C D 4, C D 8, then I float T cells treated with drug. Let me write down here. T cells treated with drug and then I again flow in this channel. After 48 hours, I again measure C D 4 to C D 8 ratio correct. Then, I try with T cells treated with another drug 3, drugs 4, drugs 5, drugs every time I measure C D 4 to C D 8 ratio I keep on measuring C D 4 to C D 8 ratio. Whichever drug is more effective, I will get a better response for C D 4 to C D 8 ratio. If there are three different drugs, you do not know which drug will be more effective for a particular patient. So, if you know with the help of patient cells, if you extract the T cells from the blood and you could treat the T cells with drug, you will know whether the patient will respond to particular and immunotherapy drug or not. If there are three drugs, let us say there are three, F D A approved drugs. And now, we just give one of the drugs to the patient, whether the patient will respond to the drug or not, we probably do not know. So, if we can design a patient-centric device, such that you can load the tumor or you can load the cells of the patient in the channel, you extract the blood and from that you extract T cells and you flow T cells without any drug next to this cells cancer cells or tumour within the microfluidic chip and you measure C D 4, C D 8 ratio. 54 Then you treat these T cells with a particular drug, let us say first drug and you flow it and you measure C D 4 to C D 8 ratio. Then you treat the T cells with second drug and you again flow it in the channel and you measure C D 4 to C D 8 ratio. Then you, take T cells and treat with the third drug, flow in the channel, again measure C D 4 to C D 8 ratio. If the drug is effective, if the blockage is well like anti PD 1, there are other immune checkpoints as well, I am just taking an example of one immuno checkpoint. Then what will happen, based on the C D 4, C D 8 ratio, we can know that the patient will respond probably better to this particular drug rather than the two drugs inside. If you can do that, then you can use this device as a patient-centric platform in case of understanding the or evaluating the efficacy of the drug immunotherapy drug. And this is very important because immunotherapy now is given at the next stage like chemotherapy, radiation therapy immunotherapy. It is very interesting for people who really want to understand how cancer works and what kind of a therapies are there learn what is chemotherapy, what is the side effect of chemotherapy, what is radiation therapy, what are the side effects of radiation therapy, what is immunotherapy that we discussed, what are the side effects of immunotherapy. Now, the point is when you do research on immunotherapy, you will see that 68 percent of patients respond well, 32 percent do not respond well. So, why 32 percent are not responding well when these are F D A approved drugs. So, can we design a device that can be used in a fashion that we just discussed? So, again, to claim something we should have very strong data. This is another area which people are working on and I am just talking about a subdivision of immunotherapy. Immunotherapy is vast area, any therapy is always fast we have to understand a small portion and try to solve that portion, try to understand further. So, as an engineer I can, I know what are the problems, but the point is I do not know lot of medical terms and that is why a very important thing is whenever you guys design, whenever you guys develop any device, always have a clinician as your partner. Because, doctors are the people to talk to if you want to work in the area of clinical research; as an engineer or scientist, you can help them to solve the problem, what is a problem and is it really a problem? After we do our study, we talk to the clinician we get the response from them we understand the problem and then you develop your device, 55 then you design your device, then you perform your experiment, then you show the data and then the device will be actually useful. So, that is how you generally work in the area of biomedical or clinical research. So, the point was, can you design this device and the answer is yes. And we will see how we can design such devices and, again this is microfluidics. So, we call it as a microfluidic chip. So, there are two more devices after this and we will discuss this in our third module, two or three devices left to show it to you in terms of microengineering devices and that will finish our lecture 1. After that, we will start understanding technologies to fabricate my micro sensors and micro engineering devices or micro sensors or MEMS-based sensors. And we will see how we can fabricate those devices. So, we have to understand a process flow, we have to understand recipe. It is very simple. Let us see how micro technology also relies on process flow, it also relies on a recipe, like our life. For example; if you want to make sambar, with rice, it tastes delicious. So, the process flow to make the sambar is known, I also know, you also probably know, but the recipe that we use, the way I will make my sambar will be different than yours. And probably, the way that our grandmother used to make sambar will be more delicious compared to what we will make because they know correct recipe. The process flow is same, recipe is in the same way. When you want to fabricate the device, firstly, you should understand process flow. What is my first process, I should take a silicon wafer, what is the next process, I should clean my silicon wafer what is the next process, the process flow we know, I should etch, this metal how much time, what should be the thickness. What should be the bonding time how can I mix my P D M S with my hardener? These are all recipes. If we do not know the correct recipe, your device will not be. So, it is very important that you correlate the things in your life with research, it is easier to understand, process flow and it is actually called recipe guys. In microengineering, this are called recipes and the process flow same thing like our life, same thing like cooking. So, just understand and merge both the real-life applications with the academics and your research, your study will become easier. So, with that, just go through all the things that we discussed today and we will discuss remaining devices in the next module. Until then you take care, bye. 56