Using Micro-Electro-Mechanical Systems (MEMS) to Develop Diagnostic Tools

I'm U De Mercy, I'm the principal investigator of Bio Stick MAMs in Medicine Labs. I did my PhD at Stanford University in electrical engineering. I did a postdoc at Harvard Medical School at MGH working on bio acoustic MAMs or mostly bio MAs.

And now I'm continuing as a faculty at Harvard Medical School at Harvard MIT Health Sciences and Technology. And continuing with my research that I enjoy very much. The work that I did during my PhD was very much related to droplets and using acoustics to generate precise size droplets and control their location and position to deposit very sensitive polymers.

Now we apply similar technologies to encapsulate cells in droplets and then position them on the surfaces for various applications in tissue engineering to print cells on the surfaces to pattern cells. Also, there are applications where you want to see that you can encapsulate few cells or a single cell or from the same population and to see the differences between the same population from one cell to another there being able to encapsulate cells in droplets at high throughput rates like 10, 000 cells per second kind of rates becomes very important and very useful to understand biological problems. So my research currently has two legs, I would say.

One is this cell encapsulation work that I just talked about. How do we pack a cell in a droplet that's, and how can we do this repeatedly and reliably and without harming the cells? So after the cell is ejected or encapsulated in the droplet, we should be able to precisely located on a surface the cell should be functional and alive and viable.

It shouldn't be harmed by the effects of ejection and so forth. So currently we have a system where we use acoustic drop focused waves to generate these droplets from open pools where we can encapsulate down to single cells in these really small droplets that are comparable to the cell size. That's very exciting in terms of applying this to cell printing and tissue engineering.

The other side of my research is again using these MAMs micro electromechanical system technologies to develop low cost diagnostic tools. Mostly this research uses microfluidic approaches where we can introduce whole blood, very small volumes such as blood from a prick finger prick, less than 10 microliters that you can introduce to a chip. And from that blood we can encapsulate or you can capture certain sub-cellular populations from whole blood.

Why is this important? Why should this be cheap for global health applications On top of the mountain in Africa, you want to be able to tell for a HIV patient, for instance, how many CD four T lymphocytes this patient has. Because World Health Organization says that below 200 CD four cells per microliter, you have to start treating the patients In the developed world, you use hundreds of thousands dollars of vert flow cytometers to be able to get this data.

And it takes of course time to use and skill of course to be able to use these like huge table size machines. Our small chip can be introduced this small finger brick 10 microliters of whole blood and it'll capture the CD four cells using the surface protein affinities. And then you can rapidly count these cells that are captured because you know that there are CD four cells which are attached to CD four proteins antibodies on the surface of the chip.

By controlling the flow rates and shear, you can make sure that the specificity and efficiency for these cell types are optimized. And there's of course always non specific binding, but by our sheer approaches we minimize these effects and make sure that between plus minus 10%errors, which is sufficient to make a diagnostic or prognostic decision on top mountain in Africa. So this has interesting applications for global health as well as these low cost techniques that are disposable can impact the developed world because now these fast blood tests which are really low cost can impact the tests that we use in the developed world.

If they're optimized to higher levels of efficiency and specificity, which our initial data shows that they can be, then it'll definitely impact our lives. When I first finished my PhD, I knew more about microfluidics and that in MAMs more than anything else I could see, especially with the droplet application, I could see that if I could print cells and encapsulate cells or manipulate the few cells, single cells, that it'll have great applications in biotechnology area. And I was very interested in working on things that will actually impact people's lives.

I used to apply these technologies to semiconductor industry, but then I wanted to to be useful directly to people. So I, that's what directed me towards problems in healthcare. And then that's why I made a big shift and came to a hospital, mass general hospital to the postdoc.

And there, you know, I got exposed more and more to problems and it seems, and it's all clear that one of the biggest problems of the world today is global health and there comes illnesses like tuberculosis, HIV that kills thousands of people per day. And these people die not because the drugs are not there, but because there aren't enough diagnostic tools which is much more expensive than the existing drugs. So I know the technology side of the things very well.

I get, I got exposed to the biological problems and the more I learned about them, the more I could see that I could make an impact. And that's how it all grew from there. And it's still continuing now.

Like I seen biotechnology and in medicine there are like so many problems that actually directly cause our result into loss of people's lives and the technologies, the technology aspect of it and being able to apply it to real world medical problems is a great, I think path to follow. This is like how this whole biotechnology area I think is kind of growing and it's becoming very impactful. If you think about it, HIV cancer, those are big killers in the world.

And current micro technologies, current approaches could maybe benefit from early detection of cancer by capturing these cells from blood or making it really cheap, which will make it available to masses. So all these things coming together, I think this whole microtechnology applications in healthcare in medicine could impact the future of human beings. So that's how all these things kind of come together I guess.

And being in the Harvard MIT health sciences and technology where on one end you have the technology and on the other end you direct aspect, direct access to patients, direct access to doctors in Brigham and Women's Hospital where I work is a great environment. cause every person that you talk to have their problems and you could maybe it's coming from a different background, provide interesting solutions to those existing real world problems. So this is, I think how I see the whole perspective of how these medical problems meet the technology side.

And we try to impact people's lives in a positive way. In single cell cap encapsulation or in cell encapsulation, the major challenge is to be able to encapsulate reliably and repeatably single cells. So you're ejecting 10, 000 hundred thousand cells per second.

And how do you make sure that each droplet that you eject has a single cell? This statistics where you are changing the droplet size and minimizing the, optimizing the cell size over the droplet size, which goes into the old problem of packing spheres in a volume and what is the most efficient way to do it. So that's the biggest challenge in the cell printing area for from the technological side.

The other aspect of it is now you can say print and precisely locate these cells. How can you generate these three dimensional tissues and how can you keep them alive and how can you transplant them? There comes in the biological end of the problems where you want to now exactly mimic the tissue.

We have current approaches to be able to print an eyelet, a pancreas eyelet, and to be able to print using smooth muscle cells, a bladder tissue, directly mimicking what is in human or red bladder so that then we can make this tissue and test how well it performs compared to the real world existing native tissues. So that's the major challenge I guess by taking these novel technologies, how can you make this the ideal tissue that can be replaced, that can be transplanted, that's the, you know, biggest problem from the beginning because the control on single cell gives you the capability to precisely locate them. And then how do you kind of grow it from there?

So it's something transplantable there where the impact of human life comes. So that's on that end, what the challenges are in the tissue engineering side of the things in southern encapsulation and in diagnostics using microfluidics, the challenge is to be able to capture a cell out of billions of cells. It's like you have a sugar particle in a salt can and you're trying to pull out that sugar particle and that's like one in a billion.

So you, you're processing microliters to milliliters of whole blood and you want to be able to specifically and efficiently without any technological problems like clogging or any biological problems like non-specific binding, you want to be able to isolate at one cell out of billion cells in one microliter of whole blood, you have a few millions of cells. And for the CD four T lymphocyte case in that one microliter, we are after about thousand cells per microliter. So it's like one cell in a thousand kind of a problem where we have shown that it's doable.

But when you want to go after circulating tumor cells for cancer, then the challenge becomes one in a billion. So to some summarize it, the challenge is how do we capture this one cell out of billions of other cells around it? And what is the technological aspects?

What are the flow rates? What is the device design? What, what are the flow rates?

What, what are the volumes of blood that has to be processed and how do you make sure that the cells you capture are the ones that you actually wanted to capture? All these aspects kind formed the whole challenge that can be summarized in one sentence, which is how do you capture this one rare cell out of billion others? So it's really a needle in a haystack kind of problem, which is exciting.

And I think this is moving the technologies forward to address these problems is the current technological challenge. Being able to bring them to a level where they do the job that they're supposed to do is one thing. And then taking it to the clinic and making it a product has all different expertise such as being able to start a company, being able to patent these things and all those other aspects come into the picture.

And I think we as scientists primarily don't have all of those skills that takes the products from desktop to products. So there comes in again, the importance of collaborations with people who have different backgrounds. And there are many technologies out there that I think could be very impactful and useful.

They sometimes don't make it to the clinic or to the use of humankind either because it just didn't happen, wasn't the right time or other effects came into the picture that I just talked about. Or sometimes there isn't a direct link that you couldn't see that the technology could actually solve that problem. And the person who deals with the problem, or let's say the biologists or people in medicine are used to doing it one way for many years.

And the people on the technology side mostly if you're not having a biotechnology focus, are not aware of the problems in medicine. So bringing these two sides together is a serious interdisciplinary research. And I think in the past years, the whole emphasis both at NIH level and that we see in research labs and universities is to generate interdisciplinary research.

So people end up getting PhDs where they have to know multiple fields. For instance, for my PhD, I had to know acoustics, I had to know mems, I had to know microfluidics and I had to apply this for polymers. So now you see kinda very depth of knowledge in one field where you had to know actually three other fields quite well to be able to solve that problem.

So I think the answer is in interdisciplinary research combined with people with business skills to make it available to use of the people, it's a whole big process and some inefficiencies that come in at certain locations. Cause that low percent of tech transfer.