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KU Cancer Center Researchers Develop Novel Lab-On-A-Chip

February 25, 2019

Yong Zeng, PhDAndrew Godwin, PhDMei He, PhDResearchers at The University of Kansas Cancer Center have created a novel, cost-effective 3D lab-on-a-chip tool that can analyze tiny vesicles, like exosomes, secreted from tumor cells in just a few drops of blood to detect cancer.

In a study published in Nature Biomedical Engineering, Yong Zeng, PhD, assistant professor of chemistry at the University of Kansas, along with his colleagues demonstrated the chip’s potential using plasma samples from ovarian cancer patients. Collaborators include Mei He, PhD, assistant professor of Chemical and Petroleum Engineering at KU and Andrew Godwin, PhD, deputy director at KU Cancer Center. The team’s breakthrough tool was highlighted in the National Institutes of Health (NIH) Director’s Blog.

Microfluidic lab-on-a-chip technology is an important tool in precision medicine, an approach that takes an individual’s genes, environment and lifestyle into account for disease treatment and prevention. A lab-on-a-chip can analyze various biomarkers, which are actively released by tumor cells into blood. Tiny vesicles, such as exosomes, accumulate in the blood and in other bodily fluids and they can provide early insights into a person’s health.

Ranging in size from a few millimeters to a few centimeters and imprinted with microscopic channels, the chips can analyze very small quantities of blood and are a cost-effective, less-invasive alternative to traditional tumor biopsies.

According to Dr. Zeng, most existing methods to engineer a lab-on-a-chip at the small (nano) scale are two-dimensional. Inspired by the nanomaterial self-assembly, a process commonly seen in nature, Dr. Zeng’s research group invented a new 3D nanoengineering method to make chips that more closely mimic the environment - the human body - from which the biopsy is taken.

Caption: Close-up view of lab-on-a-chip
Close-up view of lab-on-a-chip

"We have developed a chip with truly 3D nanostructured microfluidic mixing and sensing elements based on a herringbone pattern. The 3D nanoengineering of the herringbone structure substantially improves the surface-target interactions,” Dr. Zeng said. “The result is a more sensitive chip that can detect exosomes and other biomarkers that would have otherwise gone undetected.”

Moreover, the chip’s design does not require expensive or labor-intensive nanofabrication instruments for production. The main challenge for development of lab-on-a-chip devices is the design and fabrication of devices on the nanoscale, which are functional and cost-effective.

“The fabrication strategy we developed allows for low-cost, fast, large-scale production of 3D nanostructured patterns, which can be challenging for nanofabrication techniques such as electron beam lithography,” Dr. Zeng said. “We are the first to build a microfluidic herringbone chip using this lithography-free 3D nanoengineering strategy.”

Dr. Zeng collaborates closely with molecular biology and tumor biomarker expert Dr. Godwin.

“Our collaborative studies continue to bear fruit and advance an area crucial in cancer research and patient care, namely innovative tools for early detection,” Dr. Godwin said.

Dr. Godwin added that this area of study is especially important for cancers such as ovarian cancer, because most women are diagnosed at an advanced stage.

“The challenges in clinical implementation of precision medicine pose growing demand on better biomarkers and tests to diagnose disease early, assess disease status, predict treatment outcome, optimize therapy and overcome drug resistance and relapse,” Dr. Zeng said. “Together, we are striving to create tools that will help advance the field of precision medicine.”

This research is supported by grants from National Institutes of Health (NIH), including a joint R21 (CA1806846) and a R33 (CA214333) grant between Drs. Zeng and Godwin and the KU Cancer Center’s Biospecimen Repository Core Facility funded in part by the National Cancer Institute Cancer Center Support Grant (P30 CA168524).

Detecting Undetectable Cancers

Steven Soper, PhD, and Andrew Godwin, PhD, The University of Kansas Cancer Center deputy director, as they discuss how cancers can be detected earlier using precision medicine tools.

Speaker 1: Welcome to BenchToBedside, a weekly series of live conversations about recent advances in cancer, from the research bench to treatment at the patient's bedside. And now, your host and the Director of the University at Kansas Cancer Center, Dr. Roy Jensen.

Roy Jensen: Hello, I'm Dr. Roy Jensen and with me today are Doctors Andrew Godwin, Deputy Director of KU Cancer Center and Steve Soper, a KU Cancer Center researcher and University of Kansas School of Engineering Foundation Distinguished Professor. Today we're talking about precision medicine and the tools used to detect cancer. So, Dr. Godwin, tell us about precision medicine. What is it? How is it different from the other term you hear used, personalized medicine?

Andrew Godwin: Well, when we think about precision medicine, it really is the marrying of science and technology together to better understand disease, the cause of disease, and ways that we can treat disease, and disease which we're talking about today would be cancer. Personalized medicine really is when we're talking about treating a patient as an individual. What kind of therapies we're developing that will benefit that patient. Whether we can identify specific markers, something unique about the patient, the patient's tumor that we're treating, that would suggest that we can more tailor their therapy. And so, really it's the idea is that it's a bigger field when we talk about precision medicine, of really the discovery, the innovations, and then how we apply those innovations directly to patients to improve their care.

Roy Jensen: Okay. So, I want to talk a little bit about how you two got together because Dr. Soper, you're a bioanalytical chemist and a biomedical engineer. And, Dr. Godwin, of course, you have substantial expertise in cancer biology and tumor biomarkers. How do you two fit together and have a joint research program?

Steve Soper: So, as Dr. Godwin alluded to, one part of the precision medicine puzzle is the technology. So, the biomedical engineers come in with new technologies that can effectively utilize the markers that, for example, Dr. Godwin would discover as part of the protocol for managing a particular disease or not. And, these new technologies are very attractive because they allow the acquisition of markers and the analysis of these biomarkers that really couldn't be fathomed in the pre-precision medicine era. So, for example, there's tools, and a lot of the tools that we're developing are called microfluidic or lab on a chip technologies, and their little technologies like this. They're technologies that are generated by the ability to produce these in a very high fashion, at low cost to fit under the limitations imposed by insurance companies. So, we can produce these devices that will analyze the markers that Dr. Godwin will discover for a particular cancer disease, and then use those markets very effectively and even in a cost effective manner.

Andrew Godwin: And, kind of to elaborate on that is that part of what my role in working with people like Steve is really to kind of put into context what the problems are. What are the problems we're trying to solve, and using then a whole different science background to how you develop devices and other approaches to solve those problems. And so, a lot of that is really the marrying of two different kinds of fields where we might understand what the problems are, and how we need to approach that to improve the patient care. But, we are limited about the technologies that are available to us at that time. And, as you know, we've seen transformational changes in the past decade or two with just being able to sequence the human genome, and then following the human genome, be able to sequence the cancer genomes. But, those are all done because we were able to advance the technology to a level that we can start to sequence at costs that weren't prohibitive. We talked about $1 billion to start with to sequence the first human genome, and now we're talking about thousands of dollars now to sequence tumor samples that we're looking at. And, that's done basically by technology driving the field, allows us to look in more depth into tumors. What drives these tumors? What are some of the Achilles heels that we can identify that could be used therapeutically? And, that only comes from working with people who have that background to build the technologies that can advance our field.

Roy Jensen: So, I can remember back to when we were recruiting you Dr. Soper, and actually the first thought that popped into my head was, I have got to get this guy in front of Andy Godwin. And, do you guys have any idea how many joint grants you guys have submitted over the last couple of years?

Andrew Godwin: Well, submitted or funded.

Roy Jensen: I wasn't going to raise that [crosstalk 00:05:16]

Andrew Godwin: We've submitted a number of grants together. I don't even know what the count is now. We've been very successful, actually, within the past six months or so of getting some of these awards.

Roy Jensen: Well, you got to build a track record, and working together.

Andrew Godwin: We build a track record and that's exactly right because we just finished submitting a grant. It went in yesterday, as a matter of fact. And, part of what Steve and I did was, on this particular grant, where Steve is the lead principle investigator and I'm one of the other co-principal investigators, was to show that we are working together, that we're making progress, that we're developing, we're publishing, and that we're making inroads into the kind of questions we're doing. And, we're happy to announce that work that Steve and I been doing for the past probably 18 months has come to fruition with the funding of our Kansas Institute for Precision Medicine, through a mechanism of the NIH that will fund this, is called a COBRE grant or Center of Excellence Grant that will also help us advance some of the work that we're doing. And, we're quite proud of that because that was a very long and tedious and arduous task to put this grant together, which was nearly 1100 pages. And, that we were recently told that we're going to be getting that award as of today.

Roy Jensen: But, you didn't have anything else to do, right-

Andrew Godwin: No, that was just the-

Roy Jensen: ... other than write the-

Andrew Godwin: ... that was just one of many, but I think between Steve and ourself, we've got two small business grants that are going forward. We probably have submitted about a dozen grants together since since you've came to KU, and you want to talk a little bit about your large program grant?

Steve Soper: So, I also have a center grant, it's a biotechnology resource center. And, one of our major charges is to develop new tools for enabling precision medicine. And, the way we're doing this, these tools are directed towards looking at a new class of biomarkers called liquid biopsy markers, and it's very interesting. It's an extremely fertile area. There's a huge amount of power in these liquid biopsies, and the major thing is that in at some point in time it may forego the need for doing a solid tissue biopsy, which is a surgical process. This is just a simple blood draw that can be used to pull out relevant biomarkers that can be used to manage a person's cancer disease, and a lot of different cancer diseases, both the solid tumors and the liquid tumors, the leukemias as well. And, this is what this is. It's basically a chip to isolate tumor cells out of blood samples. So, the tumor cells in circulation and blood had been known for a number of years. But, the problem was the technology really wasn't there to grab those markers out of blood because the tumor cells are very few in any blood samples. So, with the envisions of these new technologies comes the ability to analyze and pull out these tumor cells and it's a really simple, minimally invasive, that's what they call it, approach for guiding therapy, seeing how patients responding to therapy, using these simple blood tests. And, the nice thing about this is that there's other liquid biopsy markers as well besides the circulating tumor cells. And, one of these is called these nanoscale vesicles. They're small little bubbles, if you will, that are loaded with biomarkers that Dr. Godwin has been working on. We've actually developed a new technology to pull those markers out of blood. And, what's really attractive is that they might have a big impact in early detection of cancer. This is what's very attractive, and his knowledge in the biology of these nanoscale vesicles, that's what they're called, nanotechnology. And, our ability with bringing the technology to the forefront to kind of help him with his studies is going to get this technology, and plus the markers that they use to the bedside in a very expeditious fashion. The one other thing that I'll mention about this is that Andy and I are also involved in translating this technology. Okay. So, it's really nice to do this in your laboratory and publish a nice paper that gets out to the general public. Really nice. But, really what you want to do is to put these technologies and the markers they're geared for in the commercial sector. That is built businesses that can actually distribute this in a much more expeditious and efficient process than Andy or I could do. So, we're working very hard on translating these technologies into the commercial sector by starting businesses. And, actually that's a source of funding. A couple of grants that Andy and I have we're focused with a partner in the business side to get this technology and the markers into the public sector.

Roy Jensen: So, Dr. Soper, speaking of cutting edge tools, you brought an interesting device to us today that we have displayed on the coffee table here. Would you tell us a little bit about that?

Steve Soper: Yeah, sure. Absolutely. So, this little chip will isolate circulating tumor cells. It will pull them out of blood samples and ignore the red blood cells and the white blood cells. Okay, that's fine. But then, what are you going to do with them after you've enriched them? And, the device that you're looking at here includes this chip and then other chips that have been added to what we call this motherboard. The same thing that's in your computer. And, what this'll do is after it enriches or pulls those tumor cells out of circulation, it'll actually identify them exactly as tumor cells. And also, we can harvest out or pull out the genetic material to look for mutations that might be in those tumor cells to help us make decisions of what kind of therapy that particular patient should be receiving. So, that's the precision medicine part of it, is actually enriching these biomarkers out of liquid samples, blood. And then, doing molecular characterization of those cells to help guide therapy, i.e. precision medicine.

Andrew Godwin: And, kind of to elaborate on that is that I was involved in the first basically platform that was ever approved by the FDA to look at circulating tumor cells, and that's referred to as cell search platform. It was originally with Johnson and Johnson, it's been sold again. But, what's important about Steve's approach is, we were very limited about what we could do. We could only really enumerate, meaning we're getting just counting the total number of circulating tumor cells you had in a patient sample, and using that as a prognostic indicator of the likelihood that patient would go on to progress in disease, or have a better benefit. And, it's a little bit what we call now looking at the idea of minimal residual disease, which is really where the liquid biopsy has the greatest impact potentially in the in the field right now. And, that's looking at as a patient finishes their initial therapy, surgery, chemotherapy is that imaging has a real limitation about the ability that it can detect rare tumor cells left behind after all the surgery and treatment. And so, when we talk about minimal residual disease, we're looking at new technologies to look deeper and deeper into blood, into urine, into other bodily fluids as evidence whether there are any tumor related cells there still. What technology like this allows us to do is not only count them, which is what we've done in the past, but do really the molecular characterization, looking deeper. What is unique about those tumor cells we're pulling out that might be the bad actors that are coming back and allowing the disease to come back earlier in a patient. But, really what we're trying to do and look at as we're gone from kind of step one, counting cells, and saying that if you have a certain number of cells that that's a bad prognosis, to now being able to, not only count, capture, now look at those specific markers in there. Even doing sequencing of the genome out of some of these captured cells, that it really advanced our understanding about what cells are remaining in the blood and whether those are the ones that are going to recur early, and how we might be able to alter the treatment much earlier in the course before waiting for symptoms, before waiting for imaging approaches, which have limitations, that we can actually do this much quicker and earlier in the course to help basically intervene at a time when we still have a chance to have a successful therapy.

Roy Jensen: Okay. Go ahead, Steve.

Steve Soper: So, while we're painting a very positive picture of these liquid biopsies, there is some challenges, and the challenge is when you do a solid tissue biopsy, you're pulling out millions of cancer cells, and it really accommodates a lot of the existing processing strategies in place to characterize the genome. The challenge with the liquid biopsies is in one mil of blood that you may pull from a patient, there may be only one to ten cancer cells. So now, the dichotomy is to take those few cells and do the same type of analysis that you can get with the same quality of information that you can get from a solid tissue biopsy. And, that's where this new technologies that we're developing comes into play too, is how to take that small amount of material and generate clinically viable information.

Roy Jensen: So, if you're just joining us, we're talking with doctors, Andrew Godwin and Steve Soper about precision medicine tools that can improve the way we detect cancer. If you have any questions, you can post them in the comment section. Please be sure to use the hashtag BenchToBedside. So, how else can these types of devices be used besides diagnosis and monitoring of disease?

Andrew Godwin: Well, I mean as I said before, the most important thing I'm looking at is looking at whether we can detect any residual disease. And, that's number one. I think that is going to have the greatest impact. And, as we've talked about before, early detection is really essential in many cancers, especially cancers I study like ovarian cancer, where the vast majority of women, when symptoms arise, the disease is already spread past the the ovary and now throughout the peritoneal cavity. Being able to find those diseases early, we know that they can be treated with current therapies, and now evolving therapies that we're getting much better response rates, and we can get to a point where we can almost cure those diseases. And so, with certain cancers you want to find them as early as possible. The other thing is, Steve mentioned before, we want to track disease burden. We want to understand that the therapy is working as it's supposed to with a device or approach that is going to be cheaper than imaging routinely where we might be doing monthly blood draws to look for evidence. And we do that now. Right now, for example, in certain leukemias where we'll look for a marker called BCR-ABL. We'll test that as an indication of whether that patient's in remission, whether we can detect that that specific biomarker in the blood. We do that routinely every day in my clinical lab and those are ways that we can give feedback to the physician that they can share with the patient to talk about the fact that they're in remission, or that if we start to see the disease come back, that marker will also come up because that's a very important marker associated with the specific kind of leukemia. So, these are really kinds of methods that we want to apply that will help the physician better interpret the state of the patient's disease that they're treating, so that they can make changes on the fly, really. Looking at the fact that if these therapies aren't working, what's the next one we can do? And, a lot of the analysis we're trying to do is identify also the Achilles heels of these tumors that are arising. So again, as Steve mentioned before, when you take a biopsy from a patient of a solid tumor, for example, there are many different types of cells in there and that refers to heterogeneity. So, not all cancer cells, even within the same tumor are the same. By doing liquid based biopsies, we can actually track and look at the different kinds and populations of tumors. Some might be responding to the therapy and those go away, but then you'll have another subpopulation that arises during the treatment. We want to understand why they're arising, why are they resistant to the therapy we're giving, and then be able to basically treat and change the treatments to be tailored, back to personalized medicine, to that patient's given disease as it as it comes back.

Roy Jensen: Okay. So, I think a lot of people assume that the lab on the chip concept is some future state, and you're saying that you're actually taking these devices and using them to help manage patients today in the clinic.

Andrew Godwin: There are devices that have received, like I said, FDA approval for certain ones. Some of the things that Steve and I are working on will require us to basically do this in large clinical trial settings to determine, which we're working on right now. We have many, many studies underway to look at these in controlled clinical trial settings to understand how they're superior, potentially superior, to our current ways that we monitor disease. And, Steve can talk a lot about some of the projects that we've been working on and applications to that. But, it really is that you have to show that these are head and shoulders above what we currently use to monitor patients so that, again, everything comes down to there's a cost associated with any kind of testing you do. There's a cost associated with any treatment you give. And, our goal is always to give the drug to the patient who is most likely to benefit from that drug. Because all drugs are expensive and all drugs, for the most part, have a toxic profile. So, we want to be able to tailor that kind of therapy. But, at the same time, we're using this as a method, kind of a measuring bar. Are we improving? Are we improving where you're changing the course of the therapy? Are we changing the course of the disease? Are we improving the outcomes of those patients? Because that's the only way we will be able to convince payers that these are reimbursable tests that we should be using universally in the lab.

Roy Jensen: So, it seems like we often apply new technology to liquid tumors first, and then there's a lag period of time before this applies to solid tumors. Could you tell us projects that either one of you are working on in regards to solid tumors that we may see in the clinic or the laboratory relatively soon.

Steve Soper: Sure. We have a couple going on. One is in non-small cell lung cancer. The challenge with non-small cell lung cancer is is that the solid tissue biopsies are very expensive, and you always want to continuously monitor the patient to see how he or she is responding to therapy as Dr. Godwin alluded to. So, the blood based test is a very attractive way to obviate the need for these solid tissue biopsies, reduce the cost to the patient. The insurance companies will like that, and it allows you the opportunity to do frequent testing to make sure that that patient, as Andy alluded to, almost in real time responding to therapy, and make therapy changes to make sure that the patient has a good clinical outcome for whatever chemotherapy is embarked upon for that patient. So, that's one area. I have to get back to the liquid tumors, to the leukemias, because we got a couple major projects going on there with people at Children's Mercy Hospital, locally, and then also the KU Cancer Center. One is in acute lymphoblastic leukemia, and the challenge there is this is a very large patient population. Pediatric patients typically get acute lymphoblastic leukemia. And, to monitor recurrence for these patients, they're doing solid biopsies on bone marrow, which is a very painful process. We can obviate the need for that by using these blood based tests instead of these solid bone marrow biopsies, which is extremely attractive for patients. The other one is in multiple myeloma as well, which is also using a bone marrow biopsy. Obviate the need for that by using a blood based test. So, those are two good examples of the advantage of using liquid biopsies for monitoring minimum residual disease and recurrence from minimum residual disease.

Andrew Godwin: And I will say, I can talk about five to six examples that we're currently doing in collaboration with Steve and some of my other collaborators at the University of Kansas. And, those involve, one is ongoing right now, which is a study looking at another molecule within the blood which is called circulating or cell free DNA. And, Dr. Soper has a platform that we're testing right now to see that if it can enrich for the types of DNA, small fragments, that we will be using, using a next generation sequencing platform to evaluate for mutations in the blood as a surrogate to having the tissue available. And, that's a study that we're doing that was led by Priyanka Sharma who is one of our breast oncologist here, and that was funded by a pharma group. And, we're having as many as 300 samples. We were able to collect longitudinally over 43 patients on that study, and we're tracking disease burden by looking at the mutation frequency, using the circulating DNA in the blood of breast cancer patients. And then, we can actually track when if our drug, which is a targeted drug, is hitting the target and we're seeing the loss of those tumor cells and therefore the mutations we're tracking, or that we're seeing those mutations come up again as an indication that we have the tumor basically a recurring. We have two studies that are focused on what Steve was talking about, which is called extracellular vesicles, or the extra, what we call, exosomes frequently, and what those end up being is we're now using and creating a device that can help with a diagnosis of children with bone lesions. And, in this case, we're studying Ewing sarcoma, which is mainly a pediatric sarcoma that we're studying children from anywhere from one year of age up to 18 into their adolescent years. And, this is another liquid based test where we're looking at those exosomes that carry a specific marker that we can, not only capture the exosomes, but then measure that specific marker. That marker is unique to Ewing sarcoma. So, if we can find that it helps us diagnose what that bone lesion would be. And so, we're comparing that to the children that have rhabdosarcoma and osteosarcoma. We have another project that is an adult's which is looking at another sarcoma referred to as gastrointestinal stromal tumor. And, we've identified markers that are very specific to that disease, and we've now been able to show that if we, again, capture those exosomes, measure those specific markers in those exosomes, that we can first of all diagnose patients to have gist, but we can also determine if they're responding earlier to their approved therapy, which is called imatnib mesylate, or Gleevec. But, more importantly we have markers that would suggest before we even give that patient that drug, whether they're going to respond to it or not. And, that's some of the basic research we've done. Now, translating it onto platforms like this, the microfluidic platform where we can capture these extracellular vesicles or exosomes, and then interrogate those all on the same chip. And, allows us for, again, a liquid based diagnostic that will tell us, not only if the patient has disease, what type of disease it is, and whether they're likely to respond to the predicted therapy, or the frontline therapy, they're going to be able to get. But, it all goes back to, ultimately, why I got into this field. Part of my research is I wanted to attack cancer in patients before there are symptoms, and so that you can provide a cost effective test when you go into see your family physician. We currently for women that have suspicion of ovarian cancer, they'll get something, a blood test called CA 125. It's a protein that's in the blood that they measure. Prostate cancer patients, men that are later, as a screening tool, we look for PSA. So, liquid based tests have been out there. But, what we're trying to do is look at molecules that are different than people have looked at, that will be more specific for a cancer, that come up earlier in the disease course, and that are exquisitely sensitive and specific so that we can accurately detect, not only that they have cancer, but tell what type of cancer it is. Because finding cancer early is really the ultimate goal that we always want to strive for because that's the best area to basically help prevent the disease, and help treat it before it actually becomes a major issue.

Roy Jensen: So, I want to ask you a question around the topic of tumor heterogeneity. And, how does this technology deal with that problem, and specifically, one of the major problems in clinical oncology is the development of resistance, and how can you potentially utilize this technology to predict in advance, or catch very early, when you begin to see a chemo resistance to the current therapy regiment?

Andrew Godwin: Well, I can tell you for our studies in gastrointestinal stromal tumor is that the tumors can get around the original therapy, which is very good. It's one of the first really effective targeted therapies, Gleevec or imatnib mesylate. But, what we can now see is that they, as the tumor gets around that therapy and evolves, we can pick up new mutations that are coming out and we can do that in real time. It doesn't require going in again and figuring out, do they have a tumor showing up? Can we find it with imaging? Is it getting bigger? We're actually looking at the individual markers that are suggesting that the original clone has gone away, but we're seeing that resistant clone come up. And, that resistant clone, a lot of times, gives us hints about that they might be more susceptible to another therapy. And, that's really where you're looking at it. Because, as you are well aware of, the biggest problem we have in oncology is that we'll develop an extraordinarily specific drug, has great effects, and then the tumor evolves. And, the way that tumor evolves can be very quickly. It could be over months to years, but that we need to capture that evolution early in the course so that we can make those clinical decisions. In using these kinds of liquid based biopsies, we can ask those questions early. What are the new tumors that are arising? Why are these tumor cells getting around the therapies that we know are effective? That we see rapid decline in tumor size, we see improvement in the patient's health, but it's coming back. Why is it back? And, before waiting till we have a large tumor mass that many times, when it metastasizes, we can't biopsy it anymore. We're just treating it now as a diffuse disease. This allows us to look at, not only one metastatic lesion, but multiple ones. We might not know which metastatic lesion has those set of markers, but we can see the diversity of the marker showing up that represents the heterogeneity that as a tumor evolves, those metastatic tumor cells might be three different diseases, 10 different diseases. You never know. And so, those are what we try to look at. As the bio markers change, you will see multiple different clones that are coming out and those are representative of that.

Roy Jensen: Well, thank you so much Doctors Soper and Godwin. That's all for today. To learn more about KU Cancer Centers for Research, visit the Cancer Research and Education Section of kucancercenter.org. We appreciate you joining us and we invite you to tune in next Wednesday at 10:00 AM for BenchToBedside. Thanks for watching.

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