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Research Showcase: My AOSSM Grant Award Experience ...
February 2024 Research Showcase
February 2024 Research Showcase
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Hello everyone. Welcome to today's AOSSM Research Showcase webinar. This new webinar series is designed to showcase previous winners of AOSSM Research Grants, their research, and our sponsors. My name is Alvin Su and I'll be serving as today's moderator for this webinar. I'm an assistant professor of orthopedic surgery, as well as an adjunct professor of biomedical engineering. I'm a sports medicine surgeon currently practicing in Nemours Children's Health in the states of Delaware and New Jersey. My clinical practice encompasses the sports procedures in the knees, such as the ACL, cartilage restoration, meniscus, and hip impingement, hip arthroscopy, as well as the shoulder labral repair stabilization and procedures in elbow and ankle. I'm also passionate about basic science and translational science research. I'm also a former winner of the AOSSM Steven P. Arnoczky Young Investigator Grant in basic science. Now allow me to tell you more about today's presenter. Today we're pleased to have Dr. Cecilia Pascual-Garrido to join us today in a webinar. Cecilia is a former winner of the AOSSM Sanofi Osteoarthritis Grant. She's also an associate professor of orthopedic surgery in Washington University in St. Louis. Her talk title today is My AOSSM Award Experience and My Journey of Becoming an Independent Principal Investigator as a very successful surgeon scientist. She will share her findings from her research, which she built a solid foundation using the AOSSM seed money support and how she developed her research into today's very successful lab. And she also has a very busy practice as an adult reconstruction surgeon in Washington University in St. Louis. Without further ado, let us welcome Dr. Cecilia Pascual-Garrido. Cecilia, please take us away. So I'm going to present my AOSSM grant award experience and my journey to become an independent principal investigator. This is the current support that I have for my lab. And my research interests changed a little bit since I won the AOSSM Sanofi Osteoarthritis Grant. At that time, I was working a lot on tissue engineering and cartilage regeneration as part of my early career. Currently, I'm focusing on epigenetics, hip osteoarthritis, hip preservation, and I received funding from ORF, NIH. I also have been awarded by the AOSSM Cabaud Memorial Award and the Hip Society Otto Frank Award. So when we proposed the AOSSM Sanofi Osteoarthritis Research Grant, our proposal was basically to evaluate a cartilage mimetic hydrogel for the treatment of focal cone renditions in a preclinical equine model. And we have established a group of outstanding scientists, including Laurie Goodrich, who is a vet clinician scientist at CSU, Stephanie Bryant, who was the one who designed the hydrogel. She's at University of Colorado in Boulder. Karin Payne, who also works at University of Colorado in Denver. And then I was, during my early careers, and I was at that point at University of Colorado. We have been doing some good work together. Before submitting the grant, we had some pilot data on using this hydrogel in a rabbit model. So basically, we have used the hydrogel and tried in an animal model in the rabbit. We basically compared hydrogel versus hydrogel and MSCs, and then the left knees were served as control. This is the surgery that we did. We basically did a parapatellar approach to the knee, dislocated the patella. And then we did a critical chondral lesion that was around 3 by 2 millimeters. And this was done using a drill that allowed us to do a cartilage defect without violating the subchondral bone. The hydrogel, when you receive it, is liquid. That's the hydrogel that you see there. So basically, it's in a liquid form. And then it's photopolymerized under blue visible light. So when we did the surgery initially in the rabbits, the inoculation of the hydrogel had to be under a red light to prevent polymerization before we need it. And then the polymerization of the hydrogel was performed using this blue light. Then the hydrogel polymerized, becomes more dense, and it stayed in the defect. And then we close the wound, and we left those animals to be ambulated, weight-bearing as tolerated. The study were basically two parts. We did an in vitro study where we assessed the chondrogenesis of MSCs in this hydrogel. And then the in vivo part was the rabbit animal model. So when we did the in vitro study, we actually had excellent results. If you will inoculate those MSCs in this hydrogel, they will develop into cartilage. And then when we did the in vivo animal model, we basically compared the right knee was always for study, so we put the hydrogel. Left knee was defect with no treatments or control. And then the other rabbits had hydrogel with MSCs versus a defect with no treatments or control. So each rabbit had its own control. And what we saw was that adding MSCs to the hydrogel did not enhance cartilage. And in some cases, we even saw worse results when we inoculated MSCs into the hydrogel. With this pilot data, we proposed this product to AOSSM Sanofi, osteoarthritic grant, where we basically did a similar model, but in a large animal model. So in this case, we used horses. So we also had an in vitro part and in vivo part. The in vitro part was basically, we had the hydrogel with WASPED. The hydrogel, we basically added TGF-beta to induce chondrogenesis. We also had chondroitin sulfate and CRBDS. And then basically, we had the MSCs, we photopolymerized, and then you basically get the cells encapsulated into this hydrogel. These were cultured for nine weeks, and then we assessed chondrogenesis. For the in vivo part, we use the stifle of the horse, so basically a knee joint of the horse. Since this is a large joint, we were able to do two defects per knee. We did bilateral, and of course, the chondral defect was significantly larger than the rabbit. This was around 1.5 centimeters or 2.15 millimeters. We definitely did more groups with less amount of samples. So we had a microfracture group, hydrogel alone, hydrogel with microfracture, and hydrogel with microfracture and MSCs. These are the results of the in vitro study. We basically, as I discussed before, the MSCs were taken from the bone marrow from the horse on the sternum, and then they were seeded in the hydrogel during nine weeks. And you can see here the increased concentration of GAGs during the culture period in all three donors. And also, we assess expression of collagen type two, where you can see also that at week nine, there's definitely more expression of collagen type two. In the in vivo results, we saw a lot of variability. So we definitely proved that the hydrogel can be delivered and photopolymerized intraoperatively in a large animal model. The other thing that we show is that the hydrogel remained in the defect and resulted in a repair tissue with good bonding. But we didn't observe hyaline cartilage repair in any of the treatment groups. So you can see here, this is a safranin o with microfracture. As expected, you see fibrocartilage. With hydrogel, also we saw fibrocartilage, good bonding on the borders, that is important. The best results, we saw it when we combined the hydrogel with microfracture. And then definitely the hydrogel with MSCs, either hydrogel MSCs alone or hydrogel MSCs and microfracture, induced fibrocartilage, but we were not able to induce any type of cartilage, hyaline cartilage. This is the group when we did the surgeries. And then of course, we spent a lot of time under the microscope scoring the lesions. We did it blind, the scoring of the lesions. And this is Lori, who is, and we did the scoring together. From my learning experience from this was, I learned how important is collaboration and having a multidisciplinary approach. As you see in the group, we had a vet, I'm an orthopedic surgeon. Stephanie is a bioengineer. And then Karin is also a good scientist, especially more focused in osteoarthritis. Methodology is key. And I think that once you learn methodology, you can apply it in different experiments that you do. Manage the budget is also very important. Of course, this was a very expensive experiment. And then looking at it retrospectively, what I have learned during all these years is that you should not be too ambitious with the project you do. I think with this project, we may have had too many groups and it maybe would have been better just to have less groups and more samples per group. Also, it's critical that you learn how to troubleshoot, especially in the lab with experiments that never go straightforward. And very important to have good mentors and a good established network of people that you can ask questions and try to work together. After finishing my grant in 2016, I moved to St. Louis. I was recruited by Wash U by the, especially the, I'm working with St. Louis HIP group, which is led by Dr. Clohessy. And as you can see here, it's a multidisciplinary group where we have people with different backgrounds, starting from pure clinicians, clinician scientists, bioengineers, epidemiologists, et cetera. So my current clinical practice, I'm a HIP surgeon and a scientist. I basically treat patients with prearthritic HIP disease or HIP at risk. And these are patients that are predicted to develop osteoarthritis if we don't do any surgical intervention. So when I came here, I thought that these were good natural models of Pre-OA. And this is basically what we treat patients with FAI-CAM. These patients have a bump at the femoral head-neck area. This bump impinges into the labrum and the cartilage, resulting in cartilage injury and progression to osteoarthritis at an early stage. You can see some hip arthroscopy where we basically see labrum tears, cartilage delamination. So we did debride those cartilage delaminations. And when, of course, we do an osteochondroplasty to remove the impingement and prevent those patients to develop osteoarthritis or not, but basically to improve symptoms. These are clear example of HIP at risk, female, 34 years old, with dysplasia. We were planning on doing a HIP-SCOPE-O on the patient when we did the hypertroscopy. There was already cartilage damage, and we ended up doing a HIP replacement. Another patient, young, 38 years old, with severe FAI-CAM. Also, you can see the amount of cartilage damage that this patient had at an early stage of life. So one of the questions that we have was, what is the real mechanism in which these patients progress to osteoarthritis at a young age? So trying to understand what's the real etiology of HIP-OA. And this was a concept that was already proposed by Dr. William Harris in Boston. He basically, after seeing so many HIPs, he came to this idea that primary arthritis of the HIP was a rare condition, and that a lot of these patients that were developing arthritis at such a young age were secondary to these bone deformities. And today we know that FAI has an etiological role in up to 50% of HIP-OA cases, and it has been demonstrated that if you have HIP-OA, you have 3.7 to 10 more times to develop osteoarthritis in a five-year span. Our group has previously shown that HIP morphology affects the pattern of acetabular cartilage wear, and patients with FAI-CAM have more frequent and more severe cartilage damage in acetabulum. So we did know that HIP morphology plays a critical role in intraarticular rearrangement and progression to osteoarthritis, but one of the questions that we are currently trying to investigate in my lab is, what is the real mechanisms in which these patients progress, in which the mechanism of disease that leads these patients to progress to osteoarthritis? And we do believe that if we understand the early mechanisms of HIP-OA through HIP-FAI, this would allow us to discover potential interventional therapies to slow down the progression of osteoarthritis. So the first thing we did was starting to use a model of using cartilage samples from our patients. So I am basically a HIP surgeon, so I do surgeries in patients with early state of disease, that is patients with FAI or dysplasia, and then I also do patients with advanced osteoarthritis. So the idea was that if we could take cartilage samples from patients with FAI and patients with advanced osteoarthritis, we could then compare the phenotype, histological phenotype, and also the pathways that these patients were expressing. So you can see here in the video how we actually have a model where we retrieve these cartilage samples in patients with FAI at the head, neck area. And then basically what we do in this study, basically what we did initially was to show that if you will see these lesions on the microscope, you can see here that the phenotype is the same in patients with early state of disease and late state of disease. So during early state of disease, you see already an osteoarthritic phenotype in the cartilage at the head, neck area. And if you would compare to osteoarthritis, it's exactly the same. So poor structure, lower cell counts, etc. So although you don't see it microscopically, if you would see that tissue under the microscope, you can see that there's already an osteoarthritic phenotype. And on top of that, what we did was assess inflammation, and we were able to show that the amount of inflammation that these patients present at the head, neck area in patients with FAI is as severe as in those patients with advanced osteoarthritis. So proposing that the reason why these patients are progressing to osteoarthritis is because there's a focal local of inflammation that continues to be chronic and ends up altering the joint, and then that joint fails and progress to osteoarthritis. What we did next was basically to compare transcripts from cartilage at the impediment zone from patients with FAI-cum and late state of disease. So we used the same kind of methodology, patients with early FAI and patients with late FAI. And then basically what we did was we performed a RNA sequence, and we performed transcriptome analysis. And this is what we found very interesting for the first time, that the heat map was able to confirm that we have two clear clusters of disease. And basically, we confirmed that early and late state of disease are different molecular entities. And you can see here in this heat map, the pathways that are activated are downregulated in early FAI, are highly expressed in late FAI. And contrary, those pathways that are really high expressed in early state of disease are basically downregulated in late FAI. In order to understand the connection between genes and identify key molecular players, we perform protein interaction analysis. And this basically allow us to identify have genes that have a critical role probably in the progression of osteoarthritis. So among them, we identify the PPR gamma. The PPR gamma has been shown to have a critical role, especially in the knee, in the progression of osteoarthritis in the knee. So as the osteoarthritis progress, you start to lose expression of PPR gamma. Then these are models where it's a wild type versus a knockout. So you can see that if you do a DMM model in the mice, you can see that there's some degeneration. But if you are not expressing PPR gamma, this degeneration is way more severe. This is another model, large animal model, where basically they treated these animals with PPR gamma receptor agonist. And you can see that if you maintain the expression of PPR gamma, it will have a protective role in preventing untreated osteoarthritis. So basically we started expressing, tried to investigate the PPAR gamma during progression of HIP OA disease. And what you can see here is using the same model. So basically patients with FAI, patients with advanced arthritis, and then we also always have a control from allografts that we obtain, fresh allografts from donors. You can see non-disease, there's a high expression of PPAR gamma in the nucleus. This is a molecule that is expressed in the nucleus of the cell. And then during early state of disease, you start to lose expression of PPAR gamma and almost non-expression in advanced state of disease. So you can see here, represented here. And then of course we confirmed that with Western blood. So you can see in early state, you start to lose expression and in late state of disease, there's no expression of PPAR gamma. So basically we showed that Bp or gamma was gradually suppressed during OA progression in HIPFAI. And then the question that we had was, why is PPAR gamma being suppressed during progression of HIP OA? And we looked into epigenetics, basically methylation stainless in the DNA that will suppress genes to be expressed. So our hypothesis was that the chronic inflammation that we show produce stainless in the DNA methylation, so a dysregulation of the molecules that are in charge of methylating the promoter area or CpG islands. So what happened is you have a dysregulation of the DMT that are DNA methylation transfer enzymes. These methylate the CpG island of PPAR gamma, and then you lose expression of this gene. So we had to prove that. So in order to do that, we did what is called MSP. So MSP allows you to see the amount of methylation you can have in a promoter area. So we basically use CpG for PPAR gamma or promoter area. You can see that as the disease progressed, there's a higher methylation in that CpG area. So something's going on that there's a hypermethylation in this area, and then you lose expression of the Bp or gamma. So we investigated the enzymes that are in charge of methylating, and there are basically three isoforms, the 1, the 3A, and the 3B. And the 1 and the 3A, you don't have an expression when cartilage is normal, but if you have late state of disease or osteoarthritis, there are high expression of DM1 and DM3A. Contrary, DM3B has basically almost good expression in cartilage, and then you lose expression of DM3B. That's why we say that it's a dysregulation, because during progression of osteoarthritis, what you see is that there's an increased expression of the 1 and the 3A, and then you lose expression of the 3B. So basically, this is a summary. So during progression of disease, you lose expression of PPAR gamma and DMT3B. As you can see here, no expression in the nucleus, versus in the DMT1 and DM3A are not expressed during normal cartilage, but you start to express a lot in advanced osteoarthritis. So basically, we proved the other thing we wanted to show was that it was the 1 and the 3A that were binding in the CpG promoter area. So basically, we did that with an assay. It's called TIP assay. That allows you to see what molecule is binding into the CPD promoter area, and we show that it was the DMT3A. So DMT3A is in charge of mediating the CpG promoter area, and then you lose expression of PPAR gamma. So this is a hypothesis we have. During early stage of FAI, that's a chronic inflammation. The inflammation produces a dysregulation of the DMT3, especially an increased expression of DMT3A. This methylates the CPD island, and then you lose expression of PPAR gamma. So clearly, what we are doing is trying to understand why PPAR gamma is so important for the cartilage on the stasis, especially in the hip, and we are looking into two things. One is the synovium. We are basically looking into microphage polarization. We do believe that losing PPAR gamma results into a polarization of macrophage to an M1 state which is pro-inflammatory, and then directly we are investigating the role of PPAR gamma in mTOR pathway, as it has been suggested that it can affect chondrocyte catabolism. On top of this, we have developed a model of hip FAI in a small animal model, and basically this was the award that we received from AOSSM, and basically what we did was we used immature rabbits, and we basically started injuring a specific zone of the fasces, of the hip fasces, and if you do an injury in this area, what will happen is you will develop a bone bridge, and there will be an overgrowth on the top resulting in a kind of FAI-cum-deformity. So this was the model that we did. We induced the surgery and the epiphysis of the femoral head, and then we had two stages. The first one was to confirm the deformity, and then currently we have finished the 16 weeks that basically confirms that these animals are developing osteoarthritis, so these are kind of the X-rays. You can see at 16 weeks how these animals are developing osteoarthritis. We joined space narrowing and sclerosis, and then you have the deformity, and also here at 16 weeks, the osteoarthritis. We confirmed the deformity using SSM. This is a collaboration that we have done also with Rush, with Marcus Beamer Group, and Stephen Mell, so you can see here that the deformities where we were expecting is located in the anterolateral aspect of the head-neck area, and then these are the macroscopic lesions. You can see at four weeks, you start seeing that cartilage damage similar to what we see in patients with FAI-cam, and at 16 weeks, also almost osteoarthritis in that area. The same with the femoral head, specifically at 16 weeks, you can see that there's osteoarthritis. We also confirmed this using Safranin o, so you can see here at 16 weeks, at the wave-bearing zone, you lose Safranin, suggesting, of course, loss of proteoglycans, and then also we have done immunofluorescent to confirm the loss of expression of collagen type 2 and increased expression of collagen type 10, comparing, especially we saw these changing at 16 weeks. You can see the injury, the loss of expression of collagen type 2 and increased expression of collagen type 10, and then on four and 16 weeks, we also assess expression of MMP-13, and we see the most differences at 16 weeks. We also have proved this by PCR, so similar results with loss of expression of collagen type 2, increased expression of collagen type 10 and MMP-13, and we also do micro-CT just to confirm changes in the subchondral bone area, showing that there's osteoarthritis. So the future plan is we continue now with this proposal that has been also funded by ORF, which is basically trying to understand the role of PPAR gamma and cartilaginous autophagy and macrophage polarization on the synovium in collaboration with Dr. Mas from University of Michigan. We are also trying to understand better if our model is really reproducing the FAI that we do believe it does from our preliminary data, and then what we are trying to do is FEA and nano-indentation with our rabbit model, and then we are preparing another one submission to develop an interventional therapy in our FAI model with nanoparticles with either siRNA or DMT3B. So in conclusion, Hip-FAI is a pre-OA Hip disease. Early and late stage of Hip-OA disease are molecular distinct entities that we show through RNA sequence and pathway analysis. PPAR gamma plays a key role linking RNA and DNA methylation to OA progression, so basically showing that there's hypermethylation at the CpG promoter area, and this down-regulates expression of PPAR gamma. There's a deregulation of the DMTs, specifically we see a suppression of the 3B and a high expression of 1 and 3A, and our translational model has proved to be a biological pre-OA and an OA Hip disease model, and we are currently working on pathomechanical validation of this model. So finally, I'm going to finish this talk of the things that are important to do research. I think that it's important to have adequate research training throughout your whole career, especially during residency and fellowship, and also, always I teach my residents and fellows and post-docs that an impressive number of peer-reviewed articles is not a proof that an individual has made important contributions, nor is guarantee of grant funding, so trying to communicate that the important thing is to do good science. It's not about how many papers, but how meaningful those papers are going to be, and then as clinician science, we also have to think that whatever we are doing, it is going to have a meaningful clinical application because the ultimate goal is to improve patient care. Early engagement, as I said before, is very important for research, even better if you can start in medical school. Multidisciplinary collaborative approach is critical. You cannot do science by yourself. You need PhDs, you need bioengineers, you need epidemiologists, et cetera, and of course, you have to be in an adequate environment that supports your vision of becoming a clinician scientist. This is our group. These are all the funds that I received to do research, and these are all my postdoc and technicians in my lab. Thank you very much. So, Dr. Pascual, can you share some of your experiences and perspectives on how the AOSSM, like seed funding, helped you to get early success in your research career, and finally, you were able to kind of transition that into a higher-level funding and ultimately become a kind of independent researcher? For example, the AOSSM Sanofi grant that you had really a great success on. Yeah, definitely, so, you know, when I won the AOSSM Sanofi Osteoarthritis grant, I was in an early career, and the project that I was doing at that time was basically in tissue engineering, and these days, I'm not doing that line of research anymore, but I definitely, that grant impacted tremendously my career. I definitely became a better scientist. I started a long-term relation with collaborators that I'm still working with, and most importantly, I established a good foundation in my career as a clinician scientist. I learned to have good rigorous methodology, how to travel should, and I work a lot with per-clinical animal models. When we did that project, we were working in a horse model, so large animal model, and these days, I'm still using some animal models to do the line of research I'm doing these days. Okay, so that means that that seed funding from the AOSSM to provide important kind of foundation, let's say a good stepping stone for you to be able to generate some meaningful early results, and then also that's the start point of a lot of collaboration that you started and still maintaining these days, and you would say that those are part of the keys that you were able to get higher-level funding till nowadays, right? Yeah, absolutely. I think that you definitely have to have a strong foundation on how to do science, and collaboration and knowing and networking with good scientists is key. Okay, and so if there are like future early career researchers like you yourself early in career to want to be a surgeon scientist that want to devote themselves into meaningful translational research, if they want to try to apply for these AOSSM seed fundings as their starting point, and what advice do you have for them and what recommendations do you have for them to be successful going through this route? Yeah, I think that that's a very important question, and I think one of the success for me was to have a great team. I think that is very critical that you put together a group of people that are really committed to help you achieve the goal of the grant. That's in regards of the environment you want to have, and then I always, when I try to work with mentees and residents, I always tell them like when you start doing research, it's always very important to keep it simple and don't be too ambitious. You know, so when I even did that grant, looking at now retrospectively, I think I was a little bit ambitious, and I can tell you a clear example about that, because it was a large animal model. It was an expensive model, and we didn't have enough animals. So what we did was we did too many groups with small amount of samples because we were too ambitious, correct? So we were trying to compare all the possible scenarios, but looking at retrospectively, it may have been better to do less groups and more samples in each group. So that's a clear example in how to try learning from my own mistakes of not to be too ambitious with what you are proposing, even when you do, you know, extramural funding, if you are too ambitious, they are going to shut you down. So it's very important to keep it simple. And then the other thing is to learn how to overcome trouble because there's going to be points where you're going to be frustrated, things are not going on, and then how to overcome those trouble, that is basically troubleshoot. So that's a lot of what you need to have to run also a successful lab, know how to troubleshoot. And one of the things is to be in an environment where you can ask colleagues, you know, you've been doing this experiment, what we are doing wrong. So I think that's very important. And then the other thing. Yes, please go on. And then the other thing I always tell my mentees are because we are clinician scientists, every idea that you have, you have to be thinking about impacting patient care because our final goal is to translate our findings into, you know, into improving patients' lives. And we have that capacity that probably somebody that is a PhD solo may not have that capacity. So always think that is this going to be able to be translated later to clinical practice? OK, those are really precious advice for especially early stage career researchers and clinician scientists. I totally believe that. And thank you so much for sharing that. But I want to follow up a little bit on the practical side of putting in a grant application, especially for the seed fundings. So based on what you told us, I believe based on the experience and also the experience not just being a scientist, but also reviewing grants in your career, would you say that to be a more attractive applicant as a applicant to the ALSM seed grants or even a sequence in other institutions or organizations, it is important, number one, to make sure what you're doing, especially if your role is a surgeon scientist, is make sure what you are trying to pursue can be translated to patient care in the future. And number two, make sure your goal and aims are achievable with the scale of the grant will allow so that you're not looking at probably pie in the sky type of thing. And they'll actually decrease the chance of being accepted for a seed grant. Would you say that's kind of... Absolutely, absolutely. I think that that's definitely a take-home message. Yeah. OK, thank you. And then you mentioned a little bit about the change of your research trajectory. So early in your career, you were very successful in a cartilage defect repair. And later on, as you start the next phase of your career, you can transition into the epigenetics of pre-arthritic hip and also the future prevention of that. What kind of drove that transition? And then why, what kind of attracted you so much about a pre-arthritic hip? Yeah. Yeah. So I think this transition was a natural transition for me, second to my practice. So during the last 10 years, I have been treating patients with pre-arthritic hip disease. So I'm a hip surgeon and I see patients with early FAI, patients with dysplasia, so patients with pre-arthritic hip disease. And then I have the other spectrum of patients. We have patients already with advanced arthritis that need a hip replacement. So looking at that scenario, I think that for us that we are clinician scientists, it's extremely important to investigate the problems that you see in clinical care, because our ultimate goal is to improve patient care. So my idea of the clinician scientist is to have a bed, so we see a problem, we take it to the vent, and then we bring it back to the bed. So that's very unique to us as clinician scientists. So having this patient population, I thought that it was a unique opportunity that I couldn't miss out. Would you say that early in your career, those experience doing cartilage works actually was great kind of help, and again, build a foundation for you to pursue this more focused kind of hip studies at the moment now? Yeah, absolutely. And when I was actually doing research on cartilage restoration and tissue engineering, I was doing a lot of treatment for cartilage defects. I was more focused in the knee. So I was always parallel. It's very important that what you investigate, you are also seeing that problem clinically. And that's the whole beauty of being a clinician scientist, that we see the problem, so we know where we have to go and what we need to investigate. So I think that that's key. You have to really investigate what you see in clinic. Okay. So in this kind of discussion, and you mentioned that you have to really be seeing patients and doing surgeries, right? So instead of being a so-called podium surgeon, a surgeon scientist, you need to have real clinical experience and skills in the patients so you can constantly translate your research back and forth in between the bedside and the bench side. So in that regard, orthopedic surgeons are typically very busy in the United States and probably worldwide as well. So how do you balance your time and effort, or even more importantly, your energy in between the two roles? Why you need to balance that and keep running a very kind of productive clinical practice and surgical practice while you need to run a lab that also generates meaningful results? So how do you run this parallelly and manage your life without burning out? Yeah, yeah. I would say it's the hardest thing to do, to have a good balance. I always said that, you know, I've been being a clinician scientist almost for seven years. You have to be in the right environment because you have to be in an environment that they really value what you do as a scientist and also as a surgeon. So I definitely, when I moved to Washington University here in St. Louis, it was key for my career because it is a great place to develop as a clinician scientist. In regards of how, other than the environment, I think that I learned to prioritize, be consistent, and I also try to have a very efficient schedule. I also have learned when I'm the most productive and creative. So I try to take advantage of those hours to spend for more intellectual work that is critical for us. So I think that one of the things that happens when you become, you know, after five years or six years in practice, you have a high, at least I have a high volume practice. And if we are really not prioritizing that intellectual time, it's very hard to come with an idea. So I know when from the day, what are my most, my best time to work on intellectual work, which is normally very early in the morning. And I try to be consistent on using those hours for intellectual work. And then the other thing is I have established a very high performance team, both clinically and in the lab. Although it took me many years, I finally have achieved that. So if you have a high performance team on both ends, clinically and in the lab, that will probably allow you to be a very high performance person. In regards of the one things I've learned from the team, I'm working with a team is I normally do bi-weekly meetings with my team, both my clinical staff and also my people in the lab. And I'm always open to feedback and it's very important, the feedback, because I think that that allow us to keep performing everybody at a very high level. So it sounds like that there are several key components. If you allow me to try to summarize in there. So number one is definitely prioritize all the things in your daily, weekly, or even monthly, yearly schedule and use the best part of your day or the best part of your week to focus on the thing that demands your mental work the most, right? And for a lot of us, actually, it would probably be in the morning, even though it's not for all of us. And the secondly is to find an environment that will support this kind of endeavor in research as a surgeon. And obviously, it seems like Washington University in St. Louis is one of those premier places. And the third is to build a team, probably your working family, so you have good support in clinical and celery stuff and also in surgery. And even in surgery, when you need cover from your partners, then people will be willing to help each other. And does that mean that you have to really treat your team well? Actually, we should all do that, but especially if you want to run a multi-role surgeon and scientist, then it's more like building a working family and more so than just a team only. Would that be a reasonable description for what we are aiming for? Yeah, absolutely. You need to learn how to be a leader. So it takes time. It takes time. And there are certain things you can do to become a leader, a better leader. But absolutely, it's a learning experience. But I think the communication is key with the clinical staff and with the people in the lab. I'm always trying to be available. But I also, what I have done in the past is with my schedule, I have what is called open office hours. So that's basically two hours a week where I basically open my office to all my mentees. So it's kind of the time that we can go through questions that they may have. So that has improved tremendously my efficiency instead of constantly emailing back and forth and trying to find a time. It's like, OK, Fridays, normally these two hours are open office. Right. Well, it sounds like some university professors, they try to do that, too. Even though to some of them, it will be their headache time. They have to answer millions of questions from their students. But it sounds like that you kind of value the in-person interaction so that it's more efficient and you can actually catch and kind of send out more messages than just writing emails. And like you said, it's even more efficient. You can get things discussed well without misunderstanding, probably in five, 10 minutes versus one hour writing an email. Would that be a curl? Absolutely. Absolutely. You're way better meeting open office. I do two hours every other week rather than probably trying to be 30 emails where normally, you know, the things lost. And it's very important, you know, the face to face. So a lot of people would say that or from the institutional view, a lot of health care system, even academic places, they may think that the most valuable part of the surgeon's time is probably to see patients and do surgery. Yeah. And so we all know that surgeon scientists can contribute to in a very unique way that combining both worlds of being a surgeon, clinician, and a scientist, like you said, translation of the science in between the two sides. And what would you highlight as the most valuable merit of a surgeon scientist in today's kind of health care environment? And why are surgeon scientists kind of indispensable and they cannot just be replaced by or viewed by their surgical volume, but also their research will mean so much since we have researchers for a long time, we have surgeons for a long time. Then what is the unique thing about surgeon scientists that we want to highlight for our community and society to know about? Oh, yeah. Clinician scientists are super valuable for a system. And one of the things is that we have something that nobody has. That is basically we can do science and we can see the problem. So that normally generates great questions that need to be answered in the lab. And that cannot be done by somebody who is constantly in the lab. And that cannot be done by somebody who only does surgeries. And the only way to advance science is through translational research and, of course, clinical research as well. But if you see in the history of medicine, the things that have really impacted, you know, tremendously in patients' life are discoveries like insulin. Well, we go to orthopedics, the highly cross-linked polyethylene that we use in arthroplasty that was discovered by Dr. William Harris, who was an incredible surgeon, hip surgeon, is an incredible surgeon. He's now retired, but he's still doing that. And if you read the story about him, it's what he was seeing is basically he was seeing the problem because these patients were having osteolysis and everybody was thinking that it was a cement. And then when he started, you know, going to the lab and he started seeing, you know, that the macrophages were basically starting to be super active to the polyethylene. So once they did a high cross-link, they didn't see this anymore. So that's a clear example of the tremendous impact that that has had in orthopedics, because today we don't see anymore where after arthroplasty. So it's the only way we can advance science, having people that are seeing the problem. So I always teach my residents and my mentees to, when we are in clinic, you know, to see things that nobody has seen before. It's not like, oh, this always happens. Well, it is happening because of a reason. Like let's put the clear FAI. So for example, femoral acetabular impingement that people think is the cartilage delamination that produces osteoarthritis. That's not what is producing osteoarthritis. It's like we have studied in the lab. It's basically the focal local inflammation. You have a chronic inflammation inside the joint at the zone of impingement that is basically altering the homeostasis of the joint. So those are the things that we need to do. So the one thing I would say is like with a system that we have these days, of course, it generates a lot of revenue doing surgeries. And, you know, we both do surgeries. We do a lot of surgeries. I may not have the volume of full clinicians, but I still do several hundred cases a year. I think that in a department, you cannot have everybody being a clinician scientist. Of course, you have to choose, you know, who are the people that are going to be clinician scientists. Maybe normally it's very few. Like here at WashU, we may be 10% clinician scientists. You cannot have a lot of people doing clinician scientists, but those people that you see that have the potential to be great clinician scientists, you should support them. So if I want to put it in a nutshell, meaning that surgeon scientists, since we are doing clinical practice, we have that unique environment to have these inspirations by seeing our patients every day and doing surgery every day. And with the training background in science and research, they were able to ask questions in a way that can be answered in science, scientific research, and then we were able to go both sides. So that's the value of the surgeon scientist. All right. I have one more question for you. So you've been a member of the AOSSM for more than 10 years now. Actually, I think I'd probably be the same way too. But I want to ask you about this. Can you share your experience with AOSSM and why being a member of the AOSSM is such a valuable and precious kind of experience and assessed on your side and how that has helped in your career? Oh, yeah. I love AOSSM. I think AOSSM, I have been a member probably 10 or 15 years. And AOSSM promotes emerging research, innovation, and excellent educational programs. I have been able to participate actively in numerous committees and also in the annual meeting. And there is no other society I enjoy the most. I have met colleagues, leaders, and friends. And I think that we all share the same value that is basically to advance science to keep people moving and active. So that's something very important to me because I think that movement makes people happy. And this is what we do at AOSSM. We use good science, good educational programs, innovation, and we help people continue their life being active and mobile and happy. Oh, thanks. And one last question, if I may. So what's coming up next? What's up on the horizon coming in the next few months, few years in terms of research and social clinical practice that you're excited about and you want to share with the community? Yeah. Yeah. So I will just say like in the next two years. So in regards of the science, we are very excited. We are preparing our first R01 submission probably will be in October. And I think this is the culmination of many years of research with all these institutions that have supported me, ORF, AOSSM, NIH. And I feel proud about it. It takes a long time to be ready to submit an R01. And I think we also lately we have established great collaboration with biocomputational lab where we are basically going to try to show for the first time the combination of mechanical loading and biological response to that mechanical loading in hip FAI. So we have developed a model of FAI, a small animal model of FAI. So right now with that model is the time to start doing interventional therapies and also understand really how is the cartilage responding in terms of biological response to that mechanical loading. So we are very excited about it. If you became successful, then maybe in the future you'll take all the business of the joint replacement surgeons, right? A lot of arthritis. No, no. I actually think that osteoarthritis will be more prevention than treatment. So the thing I do a lot of arthroplasty, you know, so the arthroplasty, you know, gives you the patient such a great outcome that it's a great surgery. And even now, you know, it's all outpatient, patients are working the same day. So I truly believe that the area where we could definitely make a difference is more in the pre-arthritic hip for early diagnosis, you know, try to have ways to diagnose earlier when those patients start to be pre-arthritic and when we have to intervene earlier. Because I do think that sometimes we are intervening late and those joints are, you know, they are, the fate is to fail. So I think that the reason is because we are not capturing those patients early enough. So I believe more in prevention than treatment of osteoarthritis, actually. Yeah. I think there's a future trend for a lot of things in orthopedic surgery, doing medicine as well as the preventative measures, other than just trying to salvage it in the very end. Yeah. When I was in training, I was always told that hip replacement has been one of the most successful procedures ever developed in orthopedic surgery because the dramatic change in life quality after that. And maybe in the future, people will say, you know, the hip arthritis prevention based on your work and others will be one of the most important kind of advancement in orthopedic and translational science. Yeah. Thank you. So is there anything else you want to share with the future researchers, surgeon scientists, or clinician scientists, or just the AOSSM community? Yeah, I think that we can basically close it saying that being a clinician scientist is a privilege. I love to do it. And I think that we can make an impact not only treating our patients, but leaving something behind that could be used for a lot of people, not only the people I treat. So we have to encourage people to continue being clinician scientists. Not everybody is made to be a clinician scientist, but if that's your dream, you should pursue it because it's going to be very impactful for the society. Okay. Thank you so much. It's so great to have you today. All right.
Video Summary
Dr. Cecilia Pasqual-Carrito, an associate professor of orthopedic surgery at Washington University in St. Louis, recently presented her findings from her research during a webinar hosted by the American Orthopedic Society for Sports Medicine (AOSSM). Dr. Pasqual-Carrito discussed her journey as a clinician scientist and the impact of receiving the AOSSM Sanofi Ostrich Arthritis Grant. She initially focused on tissue engineering and cartilage regeneration, but her research interests shifted to epigenetics and hip osteoarthritis. Dr. Pasqual-Carrito explained her study on evaluating a cartilage mimetic hydrogel for the treatment of cartilage injuries in a preclinical equine model. She discussed the results of the in vitro and in vivo studies, which showed promising potential for the hydrogel, but did not lead to cartilage repair. Dr. Pasqual-Carrito then shared her current research on pre-arthritic hip disease, specifically femoral acetabular impingement (FAI). She highlighted the importance of understanding the mechanisms that lead to hip osteoarthritis and the role of epigenetics, such as DNA methylation, in suppressing gene expression. She also discussed her ongoing research using a rabbit model of FAI to investigate the role of mechanical loading and biological response in hip cartilage. Dr. Pasqual-Carrito emphasized the value of being a clinician scientist and the unique perspective and contributions they can make to advancing knowledge and improving patient care. She encouraged future researchers and clinician scientists to prioritize their work, collaborate with multidisciplinary teams, and stay focused on the clinical application of their research.
Keywords
Dr. Cecilia Pasqual-Carrito
orthopedic surgery
epigenetics
hip osteoarthritis
cartilage mimetic hydrogel
pre-arthritic hip disease
femoral acetabular impingement
mechanical loading
clinical application
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