Associate Professor Pallavie Dhagat

What are magnetic nanoparticles and how can they be used in medicine? Oregon State Associate Professor Pallavi Dhagat and graduate student Phil Lenox explain the very sensitive techniques they are developing using magnetic nanoparticles to detect a biomarker for disease in just a drop of blood or look deep inside the human body.


Bonus Materials


Transcript

[MUSIC: Pastels & Palm Trees, Ethereal Delusions, used with permission of the artist.]

RACHEL ROBERTSON: Hey folks, just a quick note to let you know that we are trying out a new format for Engineering Out Loud. Instead of pairing two related stories in a longer podcast we are creating shorter podcasts that feature just one story. We’d like to hear from you about what you think. You can email us at engineeringoutloud@oregonstate.edu or send us a note to our Facebook account. Now, on to the show.

[MUSIC: The Ether Bunny, Eyes Closed Audio, used with permissions of a Creative Commons Attribution License]

HAUTALA: Any sufficiently advanced technology is indistinguishable from magic.

ROBERTSON: That is British science fiction writer, Sir Arthur C. Clarke. Well, actually, it’s a quote from Clarke. The voice was that was fellow podcaster, Keith Hautala, who agreed to channel Clarke for me to kick of this episode on magnetic materials for medicine which is the last episode in our season on Environmental and Human Health.

HAUTALA: Any sufficiently advanced technology is indistinguishable from magic.

ROBERTSON: A little reverb on that and it sounds ominous! This is Rachel Robertson and I liked that quote for this episode because we will be talking to two researchers who are on the cutting edge or the bleeding edge or whatever you want to call it. But basically they are inventing new technologies using magnetic materials. And what can be more magic than magnetics?

Specifically they are working with magnetic nanoparticles which are …

DHAGAT: very very small chunks of magnetic material — tens of nanometers of magnetic material. So, just to put it into perspective, they would be about 10,000 times smaller than a typical mammalian cell.

ROBERTSON: That was Pallavi Dhagat, a professor of electrical and computer engineering here at Oregon State.

DHAGAT: I direct the Applied Magnetics Research Laboratory. And the word applied magnetics means that we use magnetism and magnetic materials for the purpose of applying them to new technologies be it in electronics or be it for medical applications.

ROBERTSON: So, although it sounds like science fiction, it’s happening right now here at Oregon State. So, let’s get down to the science. The first thing to know is that not all magnetic materials are the same. 

DHAGAT:  So, when we get the nanoparticles we want to make sure that they are either superparamagnetic or ferromagnetic.

ROBERTSON: If that just sounded like supercalifragilisticexpialidocious, here a quick note about magnetic materials. Materials like iron, steel, and nickel that you would normally think of as magnetic (because you can stick a magnet to them) have an ability to retain magnetism and are called ferromagnetic. Iron oxide, which they use in the Applied Magnetics Lab is ferromagnetic. But interestingly, when you break iron oxide into very small pieces, like nanoparticles, it becomes what they call superparamagnetic and doesn’t have magnetic memory anymore. Ferromagnetic and superparamagnetic materials can be used in different ways. So back to what Pallavi just said, the first step is to test the nanoparticles to see if they are superparamagnetic or ferromagnetic, which can be a bit of a problem.

DHAGAT: The equipment that you can buy measures them at very low frequencies, in some cases we are talking about higher frequencies than what they characterize or measure them at, where the response is quite different. So we have had to develop a technique were we can characterize the response of these or the behavior of these nanoparticles at the frequencies that we will be using them at which is quite different from what commercially bought instruments will tell you.

[MUSIC: Pastels & Palm Trees, Ethereal Delusions, used with permission of the artist.]

ROBERTSON: So you might be wondering, as I was, what are these properties of magnetic materials that Pallavi and her colleagues are taking advantage of?

DHAGAT: What makes a material magnetic is spin, which is the property of an electron. So when we think we think about the electronics in your computer today it is the charge on the electron that makes everything possible. But there is a second property of the electron that's the spin and one of the current or emerging technologies is trying to see if you can exploit the spin property of the electron to make advanced electronics that would be more power efficient, for example.

ROBERTSON: Devices based on spin are called spintronics. Get it? Electronics use electrical charge. Spintronics use spin. And in the same way that electronic charge can represent ones or zeros in a binary system (by being on or off), so can spintronics — the spin can be either up or down. The first spintronic devices were in computer hard drives. Spin can also be measured because it generates tiny magnetic fields.

In the Applied Magnetics Lab they have been working on developing devices and applications that exploit these properties of spin to advance technologies like cell phones and memory storage, but we will be focusing on the medical applications. And it turns out that magnetic nanoparticles are well suited to such applications. Graduate student, Phil Lenox and Pallavi explain why.

PHIL LENOX: One of the interesting things about the human body is that it is not magnetic. I guess it is sort of somewhat obviously, but we are not ferromagnetic. And so, one of the ways I like to think about this is if you could imagine the human body is transparent you would think that it would be really easy to use visual based microscopy in to order to actually look at different things within the human body. Unfortunately we are not transparent, you'll note, and so in order to actually conduct microscopy we have to come up with a variety of techniques that we’re actually able to detect further and deeper into the human body. So, a lot of times that's were magnetic nanoparticles in terms of imaging they can be very powerful from that standpoint, in that you can detect them but not the rest of the human body.

Also, magnetic nanoparticles being nano sized can make their way into different areas of the body that potentially would be difficult otherwise. So, for example, for cancer treatments being able to get these particles deep into potentially cancerous tissue and then destroy the cancer cells, deep within the cancerous tissue.

DHAGAT: So, just to add to what Phil said. These nanoparticles, depending upon the composition. There are certain compositions that are considered safe and are acceptable. There would be other compositions that maybe be advantageous but where we haven't quite established the safety of these particles. Iron oxide has been commonly accepted and approved by FDA. So those don’t harm our body, so if they are introduced into the human body they are just excreted from the system. So depending upon the composition, some are known to be safe for use and others are still being investigated.

ROBERTSON: Now we’ll turn to the applications for magnetic nanoparticles that Pallavi and her students have been working on. We’ll start with biosensing. The idea is there might be some molecule in the body that you would like to detect. For example it could be a marker for disease.

DHAGAT: So you can tag that molecule with a magnetic nanoparticle and, just as Phil said, nothing in the body is magnetic so you can detect where that nanoparticle is without any kind of interference from the body, and use that as a way for sensing where that biomarker or that molecule of interest is. So you can use it both for imaging if it were introduced into the body, so you would be looking at in vivo application, or you could be using, let's say, if you wanted to detect, take a sample of blood from a person and see whether the person has a certain biomarker that would be a tell-tale sign for disease then run that sample past your sensor and see whether you have these molecules present or not.

ROBERTSON: The concept of attaching nanoparticles to molecules is not unique to magnetic nanoparticles, it’s also being done with non-magnetic nanoparticles. And attaching nanoparticles to biological molecules is the same in either case.

DHAGAT: The key there is what we call selectivity, whatever you coat with has to go bind with what you want it to bind to and not anything else. So if you are targeting, let’s say, tumor cells which have certain receptors that are present on the tumor cells and not on healthy cells you want to make sure that you are binding is a perfect complement of what is on the tumor cell. So, it's like a lock and key mechanism -- it only goes where it is supposed to go, nowhere else. And so that is an outstanding challenge in the sense of how selective can your binding mechanism be and that's where the fun is in terms of collaborating with people across biology or in chemistry, who design these nanoparticles very, very specifically tuned to the size we would like them to be, with the composition that we would like them to have, and with the functionalization that we would like them to have. So, that's an engineering aspect of designing the whole system together.

ROBERTSON: Pallavi’s research is unique from what others in the field are doing in that it is very sensitive, so you can use small samples -- just a drop of blood, for example. This allows for the miniaturization of devices. So, it would be possible to build a hand-held device that could be taken into the field. I asked her how they are able to accomplish the advanced sensitivity.

DHAGAT:  It's a technique that's based on ferromagnetic resonance. So, you’ve as a child have played with a magnet and wiggled around a coil and seen that it lights up a bulb, right? It's essentially the same principle except that we wiggle that at gigahertz frequency which allow for a larger signal and then we ensure that we pick up that signal through some of the schemes we have devised in our detection technology that we are able to pick that up no matter what. So that we don't miss anything that's bound to the sensor that we are able to rotate the magnetization around when it resonates and no matter where that magnetization is somewhere in that rotation we are able to pick up that signal.

ROBERTSON: The Applied Magnetics Lab has been able to prove the sensitivity of their system, using a well-known biological interaction between biotin and streptavidin, and they are open to collaborating with others to tailor it to a specific application. Phil is taking the biosensing technology one step further by creating a device to detect the nanoparticles that have bound to molecules in a sample or within the human body.

LENOX: What I'm working on is called a magnetic particle imaging scanner or magnetic particle imaging device and basically you can kind of think of it a little bit like MRI. So, MRI is a technique that we are somewhat familiar with at least. You go into a big cylinder and basically it's able to see different regions of your body. The way MRI works is by detecting the actual atoms in your body — so, detecting the actual hydrogen atoms within your body. Magnetic particle imaging works fundamentally differently in that we are directly detecting the response of magnetic nanoparticles that have been introduced into your body.

DHAGAT:  So, magnetic resonance imaging (MRI), by the way, also uses magnetic nanoparticles, they are used as tracers because they enhance the contrast of these images. And the technique that Phil is talking about, magnetic particle imaging — MPI instead of MRI — the advantage there is that unlike MRI where they use the signal from the hydrogen atoms, here you are detecting an MPI you are detecting the signal from the magnetic nanoparticles which is larger. So you get a larger signal in your images which is obviously better.

ROBERTSON: MRI may eventually be a thing of the past. Since 2005 when the MPI technique was first published in Nature, companies have been developing it to image the human body, and there are already commercially available scanners. It has an additional advantage over MRI in that imaging can be done in real time. So, you can actually watch blood flow through the heart, for example.

DHAGAT:  What the distinction between Phil’s work and what the large companies are doing is that Phil is trying not to image the human body, or larger organisms, or small animals, but trying to scale it down to where he can image things inside the human body so tissue inside the human body.

The advantage there, people image cells all the time, right? They do it with light. But light is absorbed in the tissue, penetrates to a very small thickness so either you have to take the sample out. It's a biopsy that is very, very thin so that light can penetrate an image. And you can certainly not image very deep inside the human body while the tissue is still in the human body. So, there are two advantages. First, that if you can take thick samples and image them you are not destroying the 3D network that the cell lives in. And the cell behavior can be very different its native environment — in its 3D environment — than if you were to take a thin biopsy. So, because magnetic fields are not disturbed by the human body, they penetrate deeper and that's the reason why you would be able to image deeper.

ROBERTSON: Phil dives into how it works.

LENOX:  In order to actually build up an image what you have to do is you have to first select a small region of your sample that you want to detect, and detect, ‘Are there nanoparticles here?’ And then whether the response is ‘yay’ or ‘nay,’ you then move on to the next little area of your sample. And then you again try to detect, ‘Are there nanoparticles here?’ You step around all the different areas within your sample and by doing so you are able to then build up an image, a tomographic image, of your specimen.

So the process then of actually detecting whether ‘Are there nanoparticles here?’ at any given location is two-fold. The first is you need to elicit a response from the magnetic nanoparticles there. And the way that we do that typically is we apply an AC magnetic field. So that is to say, that this is a time varying field. So you can think about it as a tickling field or an exciting field, basically all this is, is field, a magnetic field that changes with time. So, it goes up and down and up and down and up and down, if you want to think about it like that. And magnetic nanoparticles have an interesting property where they don't respond quite the same as how they are excited. So, if the field is going up and down, up and down, well, the particles stay up a little bit longer than you might expect and they stay down a little a little longer than you would expect.

And basically this kind of distorts our signal. You can think about it in a way that's characteristic to just particles and not the rest of your body. So, the rest of your body might respond a little bit to this magnetic field, but they won't respond the way these particles do. And a key point is that we are looking at detecting that distortion or that way in which the particles modify the signal and then we pick that up. And basically we pick that up much the same way that Dr. Dhagat was talking about where you take a magnet and you move it through a loop of wire, you move it back and forth through a loop of wire, and it lights up a light bulb or something. We basically do that on a much, much smaller scale with a much, much smaller magnet which is comprised of nanoparticles.

DHAGAT:  An application could be a hand held scanner, for example, where if you were probing for, say, cancerous tissue that was close to the surface then without having to do a biopsy you could use this scanner that is based on the principle of magnetic particle imaging and be able to detect that tumor. And of course that tumor would be tagged or labeled with magnetic nanoparticles, as we just mentioned, and be able to detect the signal from those magnetic nanoparticles in order to construct an image of your tissue or understand what is going on in that tissue.

ROBERTSON: Beyond sensing and imaging, magnetic materials can also be used for treatments. Pallavi explains how this is possible.

DHAGAT:  You can play around with the composition, obviously, of the nanoparticles. You can also play around with the shape of the nanoparticles which changes the response or the signal that we would get, for example, but you can also change the magnetic behavior, or use the magnetic behavior of the nanoparticle to advantage. So in the two techniques that we have talked about so far, the biosensing and the imaging we want the particles to be what they call superparamagnetic in the sense that they don't remember their magnetization. You put them in a field, they become magnetic, you remove the field they are no longer a magnet.

ROBERTSON: Just a quick reminder that this is what we talked about at the top of the show — how iron oxide is normally ferromagnetic, but when you break it into small enough pieces it becomes superparamagnetic.

DHAGAT: You can also make the particles to be ferromagnetic in which case if you apply a field and remove the field they have some net magnetization left to them, so this is like your refrigerator magnet, right? We've applied a field, it became magnetic, it remembers that magnetization which is what allows you to stick it to your fridge.

So you can have nanoparticles that are magnetic and use those for different applications. If they are ferromagnetic you can use them for example for treating cancer. It is a treatment called hyperthermia.

ROBERTSON: And just to clarify. That is hyperthermia not hypothermia. They sound very similar, but are actually opposites.

DHAGAT:  And one of our colleagues over in pharmacy is developing these nanoparticles and using them for hyperthermia and showing that hyperthermia used in combination with chemotherapy is more effective than one technique or one treatment alone. So we have helped him characterize his magnetic nanoparticles, for example, where he has been designing them to have certain ferromagnetic response, so that's another way we have been helping our colleagues.  

ROBERTSON: They have also just started a project with Oregon Health and Science University to understand more about how blood clotting works with applications for treating cancer patients. And now for my final question for them.

What interests you in particular in these medical applications?

DHAGAT:  Me personally? I think it is just the fact that you are applying engineering to the benefit of human kind. That maybe that through the work that you are doing, the research that you are doing that we may be able to bring a better understanding of things inside our body, and treat diseases or diagnose diseases early. And that would be a very rewarding experience.

ROBERTSON: Okay, how about for you Phil?

LENOX: Yeah, I think that's very much similar for me. I come medical household. My dad's a doctor and my mom works in the operating room, so I grew up with being used to the idea of medicine helping people and that being a very important role for people to play. When I chose electrical engineering I definitely didn’t have that in my originally but it's been really cool to circle back and have the opportunity to maybe work in the biotech field. I definitely agree that it's nice to be working in a field where potential to help people is very high and you can almost be certain that what you are doing will eventually in some way help people. Whether directly or indirectly.

DHAGAT:  Yeah, and just the fact that you couldn't be doing this alone. Right? An engineer alone couldn't be solving this problem, you need the chemist for the nanoparticles, you need the person who wants the nanoparticles to tell you, ‘this is how I would use the nanoparticles.’ So I think it is just fact that we have access, first of all being at a university, to all these different areas of expertise. And just the idea that you are an expert in your domain but because you are working together on this system you learn so much more beyond just you own little thing. That is also very rewarding experience.

ROBERTSON: So, that’s it, my friends. The conclusion for season 3 for Engineering Out Loud. I wanted to mention that Phil received a Best Student Presentation Award at an IEEE conference for his work on the magnetic particle imaging scanner that he talked about. Nice job, Phil.  And if you were interested in the topic you can check our website for more materials.

This episode was produced by me, Rachel Robertson. Our intro music is The Ether Bunny by Eyes Closed Audio on SoundCloud and used with permission of a Creative Commons attribution license. The other music in this episode was Pastel and Palm Trees by Ethereal Delusions (who is an Oregon State music production student) you can find him on Twitter @quixoticBPMoose. For more episodes visit engineeringoutloud.oregonstate.edu or subscribe by searching “Engineering Out Loud” on your favorite podcast app.