All right. Good evening, everybody. I just want to thank you all of those, all of you guys for attending tonight. My name is Shannon Strader and I'm this year's RFC research representative. I'm also the creator and moderator for the AAP and ART Orthobiologics and RegenMed series. The goal for the webinars is to provide comprehensive education for physicians in training and physiatrists interested in regenerative rehabilitation while reducing stigma, misinformation, and encouraging responsible advancements for the regenerative field. ART is offering certificates for those who attend eight webinars this year. If you do not get those certificates, you may email me to inquire about it. If during the session you have a question, please write it in the chat box and we will answer as many as time permits at the end of the session. It gives me great pleasure in introducing our brilliant speaker, Dr. Jay Ballin. Dr. Prakash Jay Ballin is the director of clinical musculoskeletal research at Shirley Ryan Ability Lab and is the assistant professor of Northwestern School of Medicine in Chicago, Illinois. He received his medical degree from King's College London and PhD from University of Missouri and pathobiologics where his research focused on tissue engineering of cartilage and biological markers of joint disease. He is board certified in physical medicine and rehabilitation with a subspecialty in sports medicine. Having completed residency training at the University of Pittsburgh and fellowship training in sports medicine at Northwestern University, he has received multiple grants and research awards for his lab work, which focuses on using biological markers to develop novel individualized rehabilitation and exercise strategies for individuals with knee osteoarthritis. Dr. Jay is a KL2 awardee from Northwestern University and is investigating cartilage response to stress in the healthy and diseased state. He hopes this work will eventually change the way we diagnose and manage early knee OA in the future. All of his accomplishments were recently recognized as he was chosen as a 40 under 40 Chicago scientist. Thank you so much for giving a lecture tonight. Thank you so much, Shannon. And I really thank all of you guys for getting on so late tonight. I have no doubt that in the future, Shannon will be giving one of these talks as a clinician scientist in the future. So my talk today is really focused on knee osteoarthritis, which is the predominant patient population that I manage, as well as research that I undertake. So the outline of the talk today will be talking about the biology of knee osteoarthritis, biomarkers for diagnosis and treatment, biology and exercise, stressing the system, and then potentially the future, which is targeting the right patient at the right time in their disease process. So I want to start with a clinical scenario that many of you, some of your medical students or many of your residents or attendings see in your clinic. So this is a 67 year old former runner who presents with a seven to eight month history of medial-sided knee pain. And then our classic evaluation of this patient is to examine them and perform radiographs and then diagnose them with osteoarthritis of their knee. The challenge from a research perspective that I often am faced with, and it's something that I've really dedicated my career to looking at, is trying to see, trying to make, trying to look at osteoarthritis in a different way. So trying to think of it from a physiatrist standpoint. So could we have diagnosed this earlier? How do we decide the best treatment for this patient? How do we counsel her on the best level of physical activity she should recommend? So the best level of loading and what sort of rehabilitation regimen should we prescribe for this particular patient? So our common treatment regimen is essentially to firstly manage the pain. So we'll prescribe our patients anti-inflammatories or acetaminophen to manage their pain. We'll talk about our classic physiatry prescriptions, which is exercise, as well as rehabilitation, such as physical therapy, and also advocate for weight loss in these patients. We'll also talk about injections and the current injections that are covered by insurance are viscose supplementation or steroids, which are not ideal. And this really leads all the way to total joint arthroplasty. And our goal as non-operative practitioners is to really optimize the left side of the screen to delay or prevent the need for total joint replacement. If there's one thing you take away from this talk today, it's really to say that osteoarthritis is not just wear and tear of the joint. And that's the classic thing that I learned as a medical student, but it's much more complex than that. It's really abnormal biological processes within the joint that feed into abnormal biomechanics. So what I mean by that is we know that in unhealthy joints or an osteoarthritic joint, there's abnormal biomechanics, which potentiates inflammation and degradation within the joints, which leads to abnormal biology, which internally leads to abnormal biomechanics. And there's this vicious cycle of osteoarthritis. And when we're managing these treatments with our non-operative treatments, we're actually targeting some of these processes. So we'll prescribe patients medications such as anti-inflammatories to limit that inflammatory cascade. And we'll also prescribe them certain medications which may limit, and these are being developed in the future, but may actually limit some of that cartilage degradative processes. So MMPs are those cartilage degradative enzymes, and many pharmaceutical companies are now developing medications which targets the activity of those MMPs. We also prescribe activity for our patients and weight loss. And what I'll talk about today is how these treatments have both a biological and a biomechanical effect on the osteoarthritic knee joint. And that's important to remember. It's also important to remember that the joint is an organ. So when we think about osteoarthritis, we often focus on the cartilage, particularly when we're talking about regenerative medicine type procedures. But we know that the joint is an organ. That means it consists of cells with different function, and they actually are encapsulated within a membrane. And so what we know is that the native knee joint has many different components. We have the synovium, which is bilayered, produces things like hyaluronic acid, which sits on the surface of the joint, and also is important in developing some of the constituents of the synovial fluid. We have the subchondral bone, which is a supportive structure to the cartilage on top of it, and crosstalks with the cartilage on top of it. And we'll talk about it later, that when the subchondral bone is unhealthy, that in turn can lead to damage to the cartilage. And the synovial fluid itself is very important to the health of articular cartilage. Studies have shown that synovial fluid that is more acidic tends to be more common in individuals with osteoarthritis, as opposed to healthy controls. Finally, we know that articular cartilage is avascular, alymphatic, and aneural. And this is the big problem in osteoarthritis. Avascular, alymphatic, meaning that it has very limited healing potential, and aneural means that when the cartilage is initially damaged, it's very difficult to actually, for the patient to actually be able to tell that their cartilage is thinning or damaged, because there's no nerve supply to that, to the cartilage. They only really feel the pain when there's damage or stress that's placed on the bone underneath. In a healthy knee joint, we know that there's an optimal balance between catabolic and anabolic processes. What happens in osteoarthritis, we know that there's damage to the articular cartilage and other parts of the knee joints, such as the patient bears weight of the time, there's damages to different parts of the joints, and there's the release of cartilage degradative enzymes and inflammatory mediators into the synovial fluid, potentiating that damage, leading to bone-on-bone motion, which leads to joint pain. And that balance within the healthy knee joint gets tipped to an unhealthy knee joint, where there's catabolic processes as opposed to anabolic processes. So taking that forward, and I've given you a quick summation of some of the pathophysiology of OA, I now want to take it further and talk about the use of biological markers for the diagnosis and treatment of osteoarthritis. So the first problem with osteoarthritis management is that we really are able to diagnose it further on in the disease process. And there's many issues with many of the imaging modalities available to most clinicians in the United States and the world. For example, when we see osteoarthritis on radiographs, usually that patient is really far down the line of osteoarthritis, and there are less interventional options at that stage, often in our patients. MRIs are expensive, and we don't often use them to diagnose osteoarthritis. And many of the novel treatment or scanning protocols that are available for our patients are not really the standard of care or extremely expensive and won't be available to many of the population going forward. And finally, in the old days, we used to talk about arthroscopy for knee osteoarthritis. And my generation, definitely, there are patients that come to my clinic and say, oh my God, my orthopedic surgeon did a washout of my knee and cleared the osteoarthritis. But studies have shown that sort of treatment approach for osteoarthritis is invasive, expensive, and really only gives you an idea of the subjective assessment of that surface cartilage layer. You're not really able to tell much about the biology of the cartilage as a whole. And overall, as physiatrists, we really focus on function. And there's very limited correlation between radiographs and imaging findings and the functional status of our patient. So with that knowledge, my work really focuses on trying to be able to tell whether we can be fortune tellers for our patients. In the future, will we be able to tell them how they're going to respond to particular treatments? And using that diagnostic potential or prognostic potential, will we be able to individualize our treatment approach for our patients going forward? And in turn, will we be able to intervene more on the bottom half of the screen as opposed to the top half of the screen, which is end-stage osteoarthritis? Before I go further, I do want to quickly talk about the structure of cartilage because this is very important for osteoarthritis and important when you're thinking about regenerative medicine for osteoarthritis. So cartilage consists of a chondrocyte, which is the cell here, surrounded by an extracellular matrix. And that extracellular matrix has three major components. The primary component is water, which is very important to the native cartilage health. The other component is collagen. Collagen consists of these fibrils, which gives cartilage its tensile strength. And glycosaminoclycans, one of which is agracan, which gives cartilage its compressive strength and actually holds the water. So what we know is that in osteoarthritis, there's predominantly damage to the extracellular matrix of the cartilage. The macrophages get attracted to this area of the extracellular matrix, and they potentiate that damage by releasing matrix metalloprocyanases, which break down that extracellular matrix further. And we're actually able to measure some of those breakdown products in the bloodstream, synovial fluid, and even urine of our patients. And that's really the focus of a lot of the research that I undertake using biomarker technology. Studies have shown that some of these biological markers, if we look at the early stages of the disease process, which is the left side of the screen within the time course of someone's osteoarthritis, these biological markers show up in the biological fluids of our patients much sooner than any of our imaging modalities. And studies have shown that you are able to measure some of these in the bloodstream in their higher concentrations, but there aren't any diagnostics, there aren't any blood tests, for example, for osteoarthritis, and we'll explain why that is going forward as well. So now we've explained some of the premise for using or measuring some of these biological markers in the biological fluid of our patients. Now I want to talk about exercise, which is really the focus of my research. So the first thing we talk about when we're talking about exercise and what goes hands in hand is talking about weight loss. And this really hits home the idea that osteoarthritis is much more than wear and tear of the joint. In the old days, like I said, we often used to talk about wear and tear being what osteoarthritis is. But as I said, it's that complex interplay between biology, which is abnormal, with abnormal biomechanics. And there's more and more studies suggesting that osteoarthritis is actually a chronic inflammatory state. The reason that we think that is because there are studies that have actually shown that individuals who are obese or overweight have a higher incidence of hand osteoarthritis. And obviously the hand is not a weight-bearing joint. So it suggests that there is this chronic inflammatory state or systemic inflammation, which is leading to these individuals having a higher propensity to develop osteoarthritis of their hands. Also, when we think about belly fat, there's actually studies that shows that white adipose tissue, which is predominant in belly fat, actually releases adipokines, such as adiponectin and leptin, which are associated with chronic inflammatory disorders, such as rheumatoid arthritis, as well as insulin resistance. And they also release other inflammatory mediators as well. And these have been associated to be higher in individuals with osteoarthritis at baseline. Next, I want to talk about exercise as well. And the common recommendation that we give our patients is greater than 30 minutes of moderate intensity exercise five times per week. And that was the classic prescription that I learned as a resident for prescribing for someone with osteoarthritis. Now, the challenge with that sort of prescription for someone with osteoarthritis is that that prescription, although very good, is actually specifically for cardiac health. We don't know how that impacts someone's knee joints. So, we did a study actually looking at physical activity and radiographic progression of osteoarthritis. And this is a cohort that is available to all of us for research purposes called the Osteoarthritis Initiative. It was a multi-center study, but they're essentially following individuals with osteoarthritis at baseline, and they're eight years out. So, they're looking at natural issues that occur in these individuals with osteoarthritis. And within that cohort, there was actually a sub-cohort that actually, where they measured physical activity using accelerometers. And they also looked at baseline demographics. And what we did was actually to look at that sub-cohort, which is about 1,200 people. And what we wanted to look was at four years, were there factors associated with radiographic progression of their osteoarthritis in these individuals? So, we're not looking at symptomatic progression. This is purely radiographic progression of osteoarthritis four years down the line. So, if you imagine a patient with osteoarthritis and mild osteoarthritis at baseline, four years down the line, we wanted to see what factors were associated with them developing moderate OA at that radiograph of the four-year time point. I'm going to ask a question to you all. What factors would you think would be most related to the progression of osteoarthritis radiographically in these individuals? What do you guys think? And you can put them in the chat or if you wanted to. Oh, and I gave it away. No, no, go ahead. Anyone have any thoughts? So, I'm going to look at the chat here. Obesity, yep, weight. Anything else? Age, gender. You guys hit all of the points, which is great. So, those are the classic and classic factors associated with osteoarthritis. And so, that's great that you know that. So, the first thing to say that older age at baseline, female sex, higher BMI at baseline, and higher baseline pain were all associated with radiographic progression of osteoarthritis. What we found was not associated with osteoarthritis progression radiographically was actually physical activity either on the low end of the spectrum or the high end of the spectrum. A prior knee surgery or prior knee injury. Now, this is not within the four-year time period. This is pre-inclusion in the study. Those are not associated with radiographic progression of osteoarthritis. So, the first thing is to say that I use this information to tell my patients that physical activity is not bad for their knee joints. That's the first thing to say. And that's very, very important to counsel your patients on that. The other part is to say is then when we're talking about an orthobiologics talk, it's also important to think about exercise and whether it has an orthobiologic effect. So, there are a number of studies that suggest that diet and weight loss do are beneficial to people's cartilage. So, there was a study from Hunter et al, which looked at a diet and exercise intervention over 18 months. And what they found with this intervention essentially may be challenging for many patients out there, but it essentially involved a 750-calorie constricted diet. And there was a significant reduction in weight, which also had a relationship to decreased joint contact forces and inflammation systemically in these patients, and also was associated with improved symptoms in these patients of their knee osteoarthritis. There's another study out of Finland, which actually looked at a progressive aquatic resistance program over 16 weeks in individuals in osteoarthritis. And what they found was individuals engaged in this regimen, and they actually found that they had improved biochemical content of the extracellular matrix of their cartilage, as well as improved symptoms and improved gait speed overall. So, there was a functional as well as a biological effect in these patients. And finally, when we look at physical activity as a whole, there's a study, the same group out of Finland also looked at 12 months of physical activity monitoring, and they found that the individuals at the highest level of physical activity, so the highest tertile of physical activity, actually had regional increases in their extracellular matrix constituents with improved global function and cardiovascular fitness. So, loading the knee joints in a healthy way could actually impact the health of someone's cartilage. So, it doesn't mean that exercise doesn't have a biological effect, it in fact does. So, using some of this information, where does my lab sort of look at this? So, my career goal is really to look at osteoarthritis in a different way. So, when we think about that patient at the beginning with their symptoms, we examine them, we perform radiographs, whether they have knee or hip OA, my goal is to take a biological sample from that patient in response to exercise, generate a biological or biomarker profile for that specific patient, and the hope is then to review the biology of their disease in the context of their function, and then prescribe an appropriate type intensity of duration of physical activity for that patient that is most healthy with their knee joint. So, I apologize. I'm hungry! I'm hungry! I'm hungry! I'll be back. I'm hungry! So, sorry, my son is hungry, he's probably here. I apologize, I'll be back, I'll be back. All right, so, you'll be all right. Sorry, it's throwing me off my game. I'm moving on. So, type intensity of duration of physical activity, and what we want to do is to then retest their biological profile to look at their pathology and the progression of their pathology going forward. So, the first thing is to say is, can these biological markers correlate to functional abilities, and can we use them to prescribe physical activity for our patients? So, my lab uses this context of trying to develop a cartilage stress test, so, similar to a cardiac stress test. So, in a cardiac stress test, you get someone to walk on a treadmill, and you look at, you essentially get them to walk on a treadmill, you look at EKG changes, and you try and stratify risk for the development of coronary artery disease in these patients based on EKG changes that may occur. So, similar to that, we get individuals to walk on a treadmill, and the biomechanical stimulus being walking or loading their knee joints, and then we measure biomarkers of cartilage stress in response to that exercise, and we tried, and studies have shown that this has both diagnostic and or prognostic value in our patients. The unique capacity of this methodology is that it does, we are able to measure in real time the cartilage stress response, and it allows dynamic assessments where we're able to outline individuals who've compromised cartilage earlier on in the disease process. Prior studies have shown that 30 minutes of treadmill walking, in this type of approach where we measure the serum biomarker response to that, actually is able to predict cartilage thickness at five years down the line on an MRI. Our first study in this realm actually looked at looked at interval walking in our patients. So, when we think about walking on a treadmill, classically we get individuals, we tell individuals to go and exercise 30 to 45 minutes, and the patients usually think that involves walking continuous on a treadmill for 45 minutes. But what we wanted to try was to see whether an interval walking approach, where they walk for the same duration of walking with two rest breaks of an hour intermittent within that, actually had a biological as well as a biomechanical advantage compared to that continuous walking approach. What we found was that at 30 minutes of continuous walking, there's a significant increase in knee joint contact forces, and there was a walking time effect. That means the longer that they walk, the bigger the difference that you saw in the two types of stresses that are placed on the knee joint. Next, what we wanted to look at was a biomarker of cartilage stress. And so what we looked at was a biomarker called COMP, which is in the extracellular matrix of cartilage. And what COMP essentially does is that it actually holds together collagen type II fibrils. So every time you take a step, what it does is it transduces that mechanical signal from the extracellular matrix of the cartilage to the chondrocyte. And as we'll talk about later, we know that the chondrocytes are mechanosensitive. So they need some level of loading to maintain their health and COMP transduces that signal. So the higher amounts of COMP that there are in the bloodstream of our patients, that means essentially that there's higher amounts of cartilage stress. So what we looked at was we measured COMP when individuals walk continuously as opposed to walking in an interval walking approach. And what we found was when they walked continuously on the treadmill, there's a significant increase in COMP at 45 minutes walking continuously, as opposed to the interval walking approach where there was a negligible increase in that marker of cartilage stress. So this suggested that the interval walking approach, you get the same level of cardiac benefits, but it might actually be beneficial to your knee joints as a whole because there wasn't as much stress is placed on the joints. And there also wasn't as much of that biological response in terms of osteoarthritis. Next thing we wanted to do was to then apply it to individuals with osteoarthritis in a specific sport. And we were approached by a group out of England who was actually interested in looking at the health benefits of golf in individuals in knee osteoarthritis. So what we wanna see was could golf on prescription actually be beneficial for individuals with knee osteoarthritis, both in terms of their cardiac benefits, but then also in terms of the cartilage benefits on these individuals. So we know that aerobic exercise is strongly advocated for individuals in knee osteoarthritis, but the problem with getting individuals in knee osteoarthritis active is that there's a lot of fear avoidance. Individuals are worried about worsening their disease as a whole. So golf, which is played by over 17 million people above the age of 50 could actually be a beneficial exercise for individuals with osteoarthritis. And what we wanted to look at was whether golf in type of prescribed approach could be beneficial. What I mean by that is, is that could individuals with osteoarthritis who walk the course, as opposed to you use a golf cart, when you're prescribing in that type of realm, is that beneficial? And the important thing to remember is that these individuals who approached us were actually trying to show the health benefits of the sport in the United States. But the challenge in the United States, so the mass majority of rounds of golf played in the United States were actually played with a golf cart. And there was a study out of the golfing community, which actually looked at golfers who play golf. And what they found was that individuals who play golf are actually more likely to be overweight or obese than the general population. So what we wanted to look at was using golf and we use golf as opposed to a lower dose versus higher dose walking, could prescribing golf as an exercise intervention with different doses as we look at here, could that actually be beneficial with individuals on their knee joints? So what we did essentially was we got individuals to walk the course for 18 holes. And we compared that to individuals who use the same individuals who did the same round of golf, but they use the golf carts. And we did the same outcome measures in terms of taking blood from them at periodic intervals, measuring their pain and the perceived exertion at different time points while they're walking the golf course. What we found was as you'd expect that there was a larger number of steps when they walk the golf course, as opposed to using the golf carts, which is the blue here. And there was a higher amounts of perceived exertion in that as well. When we looked at pain and joint pain and inflammation, we found that they walk the course there was a significant increase in inflammation as well as increase in pain as opposed to when they use the golf carts. IL-1RA, which is a receptor antibody to IL-1 beta, so anti-inflammatory was actually increased when they use the golf cart as opposed to using walk the course, which means that there may have been potentially an anti-inflammatory effect in those individuals who use the golf carts as opposed to walking the course. And finally, when we looked at that biomarker of cartilage turbinova, which is calm, there's a significant increase at all time points when they walk the course. However, when they use the golf cart, there was only a significant increase at the last time point. We also looked at beta endorphin levels, which are very important for feelings of wellbeing associated with exercise. And what we found was when they walk the course, there's almost a 10% increase in beta endorphin levels as opposed to using the golf cart. So that's also important when we think about the beneficial effects of exercise. And though that's not related to this talk today, it is important also what's not related is which had the better golf scores. And what we found was when they walk the course, they overall had a better golf score as well. Next, I wanna talk about stressing the system. So we've talked about exercise in terms of physical activity and loading the knee joint and how that impacts someone's knee joints. And then we talked about using a golf cart or using this type of approach when evaluating the beneficial effects of a potential sport. But next I wanna talk about stressing the system. And our current evaluation of knee osteoarthritis is that patients present with symptoms. And like our patient at the beginning, we examine them and perform radiographs. And the challenge when I'm evaluating this patient and trying to decide what's the best prescription for this patient is that I really have no information on the metabolic state of the joint. And in turn, how that joint is going to respond to loading. So our lab is now focused on trying to develop a test where we're able to tell the biological state of someone's joints and in turn, how that joint will respond to loading. So on the left here, you have a treadmill. So it's a standard treadmill where someone walks on a flat treadmill. And on the middle here, we have a treadmill with a medial lateral tilt, which we have fabricated in our laboratory. And on the right is an individual with knee osteoarthritis. And what we do is essentially we get patients to walk on this treadmill and we get them to walk flat. And we look at the biomarker response to that. And what we can do with this type of approach is that we can individualize the stress that's placed on each knee joint. So each knee joint, as opposed to walking flat, is that there's different type of loading or different type of stresses that's placed on knee joint going forward. What we found is that in the lower knee joint, there's a significant increase in the joint angle in terms of a various angulation of that knee joint in the knee frontal plane. And so that means that one specific knee joint is getting more of a stress than the other knee joints. So what we did was then to measure the biomarker, biological effect of this type of approach in our patients. And what we found was we took healthy controls without osteoarthritis and we compared them to individuals with osteoarthritis. And what we found was that when we walk with this sort of tilted paradigm, there's a significant increase in that biomarker of cartilage stress in both in individuals who are healthy controls and individuals with osteoarthritis. But based on the biomarker response, we were actually able to differentiate individuals with osteoarthritis as opposed to normal controls. And we also found that with another marker of cartilage degradation, MMP13, there's a significant increase in individuals with osteoarthritis in this type of cartilage stress test as opposed to normal healthy controls. And then there was a significant correlation between both of these biomarkers in these individuals, which is interesting to see. What we found was that the biomarker response that we see in these patients is significantly higher using our methodology compared to other methodologies in trying to differentiate individuals in knee osteoarthritis from normal knees, and then trying to decide how that specific exercise is impacting their knee joints. When we looked then at some of those risk factors for the development and progression of osteoarthritis, we found that there were differences in this cartilage stress paradigm based on some of those risk factors. So individuals who are older, individuals who are female sex, and individuals with higher BMI actually had a higher biomarker response to this tilted paradigm, as opposed to individuals who did not have those factors or a younger age or a male. And also when we looked at radiographic grade of knee osteoarthritis, we found that individuals with moderate osteoarthritis as opposed to mild osteoarthritis actually has significantly greater biomarker response using this tilt paradigm that we weren't able to see when they walk on the flat treadmill. Interestingly, in the bottom right here, you'll see that people with the most severe osteoarthritis actually had less of a response. And what we think that is maybe due to is that they have less cartilage in their knee joints and therefore don't have as much of a robust biomarker response to that. So this cartilage stress test was able to differentiate individuals with knee osteoarthritis as opposed to normal cartilage and normal controls. And we're now looking to develop, look at biomechanistic pathways as well as other biomarker relationships using this type of cartilage stress paradigm in our patients. Next, we wanted to apply that to a specific rehab regimen that's commonly used for individuals with particularly ACL tears, but also with osteoarthritis. And this is the anti-gravity treadmill. And many of your physical therapy, physical therapists in your institutions may have access to this type of treadmill. So the way that this treadmill works is that you're able to vary the amount of body weight that's placed on the low extremities using the positive pressure that's placed within a vacuum while someone's walking. And what that vacuum does is that you vary the amount of positive pressure and you're able to raise the low extremities up. And you're actually able to vary the amount of body weight that someone places on their low extremities. So what we wanted to look at is that in these individuals with osteoarthritis, when we walk at 100% body weight, as opposed to 50% body weight, would there be a significant difference in terms of both the biological as well as the biomechanical response in our patients with osteoarthritis? Really looking to see whether this type of approach is beneficial for our patients. So what we hypothesize is that compared to 100% body weighted walking, 50% body weighted walking would be associated with a significant decrease in this biomarker of cartilage stress, but also significant decrease in pain. So the first thing to say is that when you look at these patients, when they walk at 100% fully loaded walking on the left here as opposed to 50% loaded walking, what you'll notice is that that 100% loading walking, which is their normal walking that they do with osteoarthritis, is that they have a very narrow base of support compared to the 50% loaded. And when we did some of our biomechanical testing, they actually get more of a normal gait pattern as opposed to pathologic gait pattern with a 50% body weighted walking, as opposed to the 100% body weighted walking. So this is essentially what we do. We get patients to walk 45 minutes on a treadmill with a rest break of an hour. And so what we found was that when these individuals walked at 50% body weighted walking, there was a significant decrease in their pain at all time points pretty much compared to 100% body weighted walking. So when we're thinking about prescribing an exercise for our patients, we of course want them to make sure that it doesn't cause them pain so they're able to do it. But what we also found was that when they walk for 45 minutes with this 50% body weight, there's also a significant reduction in that biomarker of cartilage stress. So there's less stress that's probably being placed on their cartilage as opposed to the 100% body weighted walking. And that's important for us to be able to counsel our patients. The other interesting thing, although we need to tee this out a little further, is that when they do the 50% body weighted walking, there was a trend towards an increase with an anti-degradative marker during that rest period, which we didn't see with the 100% body weighted walking. I'm not saying that this type of approach has an anti-degradative effect, but it certainly suggests that it may have a more of a protective effect in our individuals with osteoarthritis as part of a rehabilitation program that includes walking exercise. So using this anti-gravity treadmill decreased pain, decreased marker of cartilage stress, allowed our patients to achieve their exercise targets for the day. But what I want to say is that this is probably analogous to offloaded walking. So something like pull therapy could be very similar to this and we're actually undertaking a clinical trial of this compared to pull therapy in our patients going forward. So what's the future? So for the last two periods, I really wanna talk about some of the studies we have ongoing in our laboratory right now, as well as what we see as the potential future management of osteoarthritis. So the first is that we're using some of this technology in other realms of physiatry. So the first is to look at individuals with cerebral palsy. We have a high development of joint disease and osteoarthritis, particularly of the hip and of the knee joint. And one of my research assistants, Chad Hanawaka is now a medical student at Northwestern. He's been investigating the relationship of some of these biomarkers to functional grade of CP, as well as joint pain in these individuals. And what he found, as you would expect, is that the older some of these individuals CP get or are, the more joint pain and the less function that they have as a whole, as well as less strength that they have in their quadriceps and hamstrings, as you'll see on the top left here. But what he also found was that there was a significant correlation, actually negative correlation with some of these biological markers and functional abilities and pain in these individuals. And what we think that is due to is really showing some of the mechanosensitive nature of some of these biological markers. We know that many of these patients with GMFCS grade three, they're less functional and less mobile. And so aren't putting as much weight on their joints. And so the relationship of some of these biological markers to their function is different from an individual with osteoarthritis that we see predominantly in the population. But it does suggest that some of these biological markers do have some relationship to function, even in individuals with CP. The other thing that we also looked at that one of our fellows that worked with me, Ali Heuselhorst, has been working on is actually looking at the concept of cartilage atrophy. And I think this is really, really important when we think about regenerative medicine type approaches. So when we think about osteoarthritis, we think about that we're trying to get back to that normal cartilage, particularly with a regenerative medicine approach. And on the left here is an individual with osteoarthritis and they have thin tissue, rodent articular surface, and patchy prostrate gland and staining of their articular cartilage. But in individuals with cartilage atrophy where the cartilage is underloaded, and I mentioned that cartilage is mechanosensitive. So if you actually take someone into space or you take a spinal cord injury patient when they're not loading their joints, they actually have been shown to develop cartilage atrophy. So they have thin tissue and they also have reduced protoglycan staining. And studies have actually shown that if you then reload these individuals' joints, you're actually able to regrow cartilage to some extent. So what we did was to actually look at individuals with acute spinal cord injury, and we did baseline MRIs on their knees, and then we compared them to six weeks down the line. And these were either paraplegics or quadriplegics. And what we found was that, sorry, we took synovial fluid from these individuals, we took blood as well, and we also took these MRIs, as I mentioned. And what we found so far is actually really interesting. So we actually have a few patients that have been through the protocol so far, and I wanted to show this MRI. So this is an individual with a spinal cord injury, and on the left here is their baseline MRI. So this was actually an individual with a spinal cord injury who had osteoarthritis at baseline. My radiology collaborator actually read his MRI and looked at cartilage thickness on his MRI, and she actually looked at the lateral femoral condyle and was actually able to show that there was a partial thickness defect on his lateral femoral condyle, and this individual was not bearing weight on his joint. And this defect had actually changed into full thickness chondral defect six weeks down the line, suggesting potential cartilage atrophy. Now, we have a lot more patients who've been through, six patients have been through this protocol so far, and we're undertaking a biomarker analysis of these individuals as well, but I think cartilage atrophy is also another important concept for many of you to also think about as well when we think about osteoarthritis. Finally, I wanna talk about targeting interventions to the right patient at the right time. So when we think about targeting our treatment for our patients, we often think, and whether that's orthobiologic or whether that's exercise, it's really important to think about targeting our treatment to that patient at the most beneficial time to their disease process. So we're doing some studies looking at firstly psychosocial factors and association with outcome, but we're also looking at peripheral factors on the knee joints as opposed to central factors and seeing how that impacts the outcomes of our injection. So basically we're looking at ultrasound assessments of our patients and using ultrasound and looking at subjective analysis as well as objective analysis of ultrasound images and seeing whether those have a relationship to outcome of our procedures, but also looking at synovial fluid assessment of our patients and seeing whether that has any relationship to the outcome. So one thing that's not been clearly ascertained is whether the synovial fluid milieu in terms of some of these biological markers have any relationship to the outcome of some of our orthobiologic or classic interventional procedures for knee osteoarthritis and also to specific gait parameters. And I mentioned at the beginning that osteoarthritis is a biomechanical as well as a biological disease process, but are there certain biomechanical parameters that are able to predict the outcome of someone's injection or procedure? And that's something we're also looking at as well. So the first thing to look at is some of those central things that I mentioned. And we've done some studies looking at psychosocial factors, which is well documented in the literature, but also looking at whether patients' expectations of a procedure actually has a relationship to their outcome. And some of my lab has actually looked at this and we looked to see whether the expectations had any relationship to change in pain following an injection. And these were steroid injections. And what we found was that there was a significant improvement in pain and disability in these individuals post-injection, but there also was a correlation between the level of their expectations of a procedure and the outcome. And I don't know of many particularly orthobiologic type procedures that have looked at that. And that may be an area to also look at as some of the psychosocial factors as well as expectations of outcome in terms of orthobiologic procedures. And that may be an area of opportunity. Also, when we think about orthobiologics and when we think, I've mentioned a lot of things about exercise, but there's many things in orthobiologics which aren't answered in terms of osteoarthritis and the appropriate age, stage of age. But particularly for me, what I'm very interested in looking at is the post-injection protocol. We've talked about loading the knee joint and how that impacts cartilage. And what is the most appropriate loading of a knee joint? We've talked about delaying loading on a knee joint potentially being detrimental to the cartilage, but immediate loading may not be beneficial either. And that's something to think about going forward in our individuals in knee osteoarthritis. The other part is that many orthobiologic treatments really focus on cartilage, but there are many other parts of the knee joints as well that we talked about at the beginning. And many orthobiologic type studies really focus their treatment on growth factors impacting the cartilage released specifically with PRP. But what we wanna look at is how do some of these orthobiologics impact the subchondra bone as well as the synovium? And that's definitely something that we're interested in looking going forward. And I also wanna give you some food for thought. So much of my research during my PhD was looking at tissue engineering. And I talked about some of the peripheral parts of the knee joint. So the milieu, the synovial fluid milieu actually impacting the outcome of our procedures. And why I say that is that we know that that environment in osteoarthritis is unhealthy within the knee joint. And maybe there's a level of unhealthiness, a level of inflammation beyond which someone's not gonna see a beneficial effect to whatever procedure we do. And that could be a procedure that could be exercise. And those are things to potentially look at going forward in our patients. Similar to that, there are many studies also suggesting some of these orthobiologics, you know, we wanna make sure that the cartilage that we're recreating or regrowing actually has the native mechanical biochemical properties. And those are still studies that need to be addressed. That's still something that needs to be addressed in many of our studies, looking at orthobiologics. And really just telling you that those are things to look out for as you evaluate orthobiologic type studies. Some of my research in my PhD actually looked at the concept of tissue engineering, individualized tissue engineering products for individuals with osteoarthritis, specifically osteochondral constructs. In the future, maybe that we get a patient and we do an MRI of their knee joints, we 3D print a specific osteochondral construct for that individual's osteoarthritis. We go into their knee joint, we take a biopsy of their cartilage from a healthy part of their knee joint. We expand those cells in culture, we see them in a scaffold, and then we implant it as a functional device in the knee joints of our patients. And some of the studies that are ongoing in the literature that we've also performed actually looked at the development of osteochondral constructs in individuals with osteoarthritis. So there are a lot of studies looking at injecting cartilage into the, or injecting cells into the knee joints. And what they found was that when you see these cells into a scaffold as a cartilage layer, and you then put it into a defect, that cartilage can get sheared away just by the number of the forces that are placed on them in the knee joints. However, when you place a bony substrate material onto the bottom part of that cartilage layer, that in turn, that bone substrate material can act as an anchor, actually integrating that cartilage and bone layer into the native knee joint as a whole. And that's probably the future potentially of cartilage regrowth in individuals in knee osteoarthritis, particularly from a surgical perspective. And we did a study actually looking at that in a rabbit model of osteoarthritis. So in the top left here, you see that there's an empty control. So this person has an osteochondral defect that wasn't filled in. And then we took an osteochondral construct. So this has a cartilage layer with allograft bone being the bony substrate material. And what you'll see is that there's very minimal growth of that cartilage layer into the native cartilage. And partly that's because the bone layer underneath didn't really incorporate into the native bone. Whereas when we looked at the tantalum metal, which is what's used in many total joint replacements, that incorporated very, very well into the native bone and led to the best amount of cartilage regrowth on top of that. And similarly, bioactive glass, which is what my PhD focused on, when we looked at that, that incorporated relatively well, and there was a relatively good growth of the cartilage layer on top of that. So when we're thinking about our orthobiological principles or orthobiological approaches to knee osteoarthritis, what I want you to take home from this is to also think about the subchondral bone, because if that's not healthy, then your cartilage layer on top is probably not gonna be healthy either. Finally, I wanna talk about genetics. And this is a question I often get from many of my patients. And it's trying to decide why do certain people respond to orthobiologics? Or why do certain people respond, cartilage respond to exercise? And part of it may be that genetics play a role. And we know that chromosomes consist, the ends of chromosomes consist of telomeres. And as we age and as they divide these chromosomes, or these cells divide, the ends of these chromosomes actually shorten. And what we know is that young cells have very long telomeres, greater than nine kilobase pairs. But for every division, there's a loss of about 100 to 200 base pairs. And when the erosion occurs beyond six kilobase pairs, there's something that's called chondrocyte senescence that occurs. This means that those cells are not going to respond to whatever growth factors you actually expose them to. And so after puberty, you lose the enzyme telomerase, which actually helps to lengthen some of those chondrocytes. So chondrocyte senescence, which is something that we're actually looking at in my lab, is could be some of the, could actually lead to, or could actually be a reason for some of the noise that we see in terms of different outcomes, in terms of our regenerative medicine type procedures. And that's something we also want to look at in terms of outcome of osteoarthritis management. Finally, what I want to talk about is the future. And so when we're thinking about osteoarthritis future, the future of osteoarthritis management, we want to make sure that we're evaluating our patients, of course, examining them, imaging them if needed, but also potentially in the future, we'll be thinking about biomarkers, as well as the genetic status of their particular, of their particular osteoarthritic process, as well as some of the psychosocial factors, which are at play in terms of the outcome of the treatment of our patients. And I think ultimately as physiatrists, and particularly many of you who are junior on the phone, I think the beauty of the way that we manage osteoarthritis as physiatrists is that we really try and treat patients as an individual. And if there's, I really want you to take that home from the talk today, is that osteoarthritis is much more than wear and tear, and it's really trying to individualize our treatment approach based on biology, biomechanics of our patients going forward. And I truly believe that's the future of osteoarthritis management. I want to thank many of my collaborators going forward and also to thank my lab and many of the residents, some of which may be on the call, I think are on the call, and medical students who've worked with me. And I want to thank Shannon and AAP and ART3 for inviting me for this talk today. I'm sorry about the interlude with my son who was asking for dinner. I promise you my wife gave him dinner just as we were talking, so I apologize for that. But thank you for your patience on that. I'll take any questions. Thank you so much. That was so interesting. I think oftentimes we learn OA as black and white, and it's so complex. And I love the philosophy of RegenMed. It's not necessarily just PRP and regenerating cartilage, but the whole environment and everything needs to be thought of. So it was wonderful. Yeah, so any questions? Brooks. Go ahead, Brooks. Hey, how's it going? That was a great talk. Thanks a lot. Thank you. I have never heard of comp, but I do think it's really interesting that the more advanced osteoarthritis sees a decrease. And I'm wondering if you guys have ever tried sort of an independent validation of what might be going on. For example, what comes to mind if the vasculature is just so poor and maybe comp isn't getting into the circulation, or if you've done even some simple gradients between synovial fluid and plasma of comp or some other biomarkers to kind of get a sense throughout the progression of osteoarthritis severity. That's a fantastic question. Brooks, you want me to ask you, are you a researcher yourself or are you a- I'm an MD PhD student now. So I'm doing my PhD. I was going to say that's a scientist level question. So not that a med student wouldn't be able to answer, but that's a great question. So the first thing is to say that we, there are studies that have actually looked at comp and how it gets into the bloodstream. And what it's thought of is that there is a, it does get into the lymphatics and then into the bloodstream that way. So there definitely is certainly a decreased vascularity of the knee joint in individuals in the osteoarthritis that may impact it a little bit. It is definitely one of the weaknesses of this type of cartilage stress test approach is that we're not able to firstly say that the comp is coming from the bloodstream, coming from the individual knee joint. That's why in our studies, we always limit, we always exclude patients with osteoarthritis in other joints, or at least pain in other joints. We take long view x-rays to exclude patients with hip osteoarthritis. And the point of trying to develop the stress test is that we're trying to individualize the stress of that particular joint. To your point about the validation studies of plasma versus synovial fluid, yes, we have done that and we have seen some, there is a correlation between the two and there are other labs that have done that, but it is the challenge. And so definitely when you're gonna go through this, when you apply for grant funding, et cetera, you get a lot of feedback and some of the feedback that I've received from grant funding agencies is that they want more of a robust biomarker approach rather than just looking at comp. Can you tell more? So we are definitely doing more exploratory biomarkers and trying to look for other biomarkers rather than comp. It's just the most studied in this realm, but there definitely are certainly other biological markers which may be beneficial, sorry, may have some relationship to some of these biomechanical parameters I mentioned. But fantastic question and great point. Awesome, thanks a lot. That's really interesting. Thank you. I had a question. I have a question on whether there've been any studies on whether PRP or bone marrow have seen any growths in cancer. Given that your last slide was talking about telomerase, I know that that's one thing that cancer has plenty of. So have any of these biologics caused an increase in malignancy or any side effects with people that have cancer? Really, God, you guys are killing me with great questions. Not killing me, impressing me with great questions. Great question, Anne. So that is obviously a concern. I mean, I don't think that that is something to think about. What you always wanna do when you think, and I wanna go back to my slides here, which it's kind of the premise of, let me see if I have it here. Oh, please, the one before this. I have too many clicks here. Okay, this one. So this is the really key slide here to what you're asking about, right? So when you're thinking about tissue engineering, this is sort of a basic slide that someone's doing, going into a PhD of tissue engineering would think about, right? So you wanna make sure, and it's this one that you're talking about, that your cell source is immunocompatible, it's active and controllable. You don't wanna put a cell into a joint that it's uncontrollable. And I didn't put it in there, but there was a study out of Pittsburgh when I was a resident, which was a case study actually where some of, and it was for a disc degeneration, intervertebral disc degeneration, and some of the stem cells essentially leached out in this rabbit model of disc degeneration. And it looked like there was an opacity on the X-ray. Now they could obviously sacrifice those animals because it was an animal model and it was actually an osteophyte. So as far as I'm aware, I don't believe that there are studies which suggest that there is uncontrollable growth of some of these stem cells. And I don't do, to be honest with you, a lot of stem cell type procedures, but I think it's very important to think about when we're doing stem cell procedures. I'm not saying that there's anything wrong with stem cells for knee osteoarthritis, but thinking about, is that cartilage? It may look like cartilage, but does it behave like native cartilage? Does it have the same biochemical, biomechanical properties? And does it, and also, what's also happened in some studies is that PRP, for example, has led to the growth of osteophytes because you're not just leading to regrowth of cartilage. You can also lead to regrowth of bone. And when unhealthy bone tries to regrow, it doesn't grow as healthy bone. It grows as osteophytes. So you also have to remember that as well. So that's why it's always done under image guidance, most of these procedures, but these are things that we haven't quite cleared up in the field of regenerative medicine for osteoarthritis, but those are things to think about as well. I think your question is a really, really good one and a great thing to think about. And my goal, particularly at the end part of this talk, is not to tell you that one way or the other, whether it's beneficial or not, is to give you food for thought. So that when you're a resident, I don't know if you're a resident or a student, are you a student, resident, student? Okay, student, when you are a resident, you can think about this type of approach of like, okay, I might do a regenerative medicine procedure, but it's choosing the right patient at the right time within their disease process. And it's not a one size fits all approach. That's what I want you to take away from this talk today. But great question. Wonderful, thank you so much. You're welcome. Any other questions anyone has? I had another. Sure, Brooks. Yeah, go ahead. I'm just curious if, you know, you saw some improvements in pain and your biomarkers when you, during the exercise trials, where you take half the weight off of the patients. Does that take away some of the cardiometabolic benefits of exercise? Really great question again. So actually we did measure, I didn't show that, but we did do heart rate monitoring on these patients. Now the level of vigorous activity that they get is more, but the level of moderate intensity activity was the same. And so there was no significant difference between the two. That would be obviously the concern. We're actually planning to do a clinical trial where we would essentially get, we're not gonna do this 50%, but probably do something, we would probably do the minimum amount of body weight support that leads to 50% reduction in a patient's pain. And the patient just does that three times per week for 12 weeks. And we're just trying to do it as part of a clinical trial. And that's really the next phase of what we're trying to do. But so far we've not seen any limitation in terms of cardiac or change in cardiac benefits of the exercise, for sure. But that's a very important to think about. In the golf study, interestingly, as you would expect, we did. So when they use the golf carts, we did see a significant reduction, but they still easily attain physical activity guidelines for the day easily. So it's still really beneficial to them, but that's something else to think about when we think about individualized exercise prescription is that we still wanna make sure they get the cardiac benefit from that. Cool, thanks. Thanks. Well, I have one question, if that's okay. Sure, Shannon, yeah. So I know, I think it was in JAMA, they recently came out with a PRP study. Yes, yeah. Not to focus on PRP because I'm not a much believer, but they did bring up a good point that it's hard to standardize PRP and orthobiologics, regen, everything. Like you mentioned case-by-case and focusing on the patient, what time, their age, how far are they and the disease co-morbidities. So we're seeing the future and regen med orthobiologics with clinical trials. Do you think there's a way to standardize where it like promotes research, I guess, promotes positive results and so on? Promotes positive results instead of saying, oh, there's nothing here, but maybe. Yeah, and that study definitely, I think it created a bit of controversy within our field. I saw a lot of stuff on, not that I'm a Twitter fiend, but I did see some comments on Twitter about it. You probably did too, right? Like people were like a little, because the study, I mean, the study is, it was one of the few randomized clinical trials that are out there, but maybe the PRP product was not the most optimal. And I think that was the argument that people were saying in terms of the concentration of the platelets. I think what I would say is that I think it is, there's a lot, I think trying to make sure that we are doing things scientifically is the best way to do it. So I brought up a lot of things about factors that have, I think it potentially does have a benefit in a certain subset of patients with osteoarthritis, but not every patient with osteoarthritis. There are labs that are looking at, I talked about that synovial fluid milieu, and they're looking to see if the synovial fluid milieu has any relationships. We're looking at it more for, because we don't do a ton of PRP at our practice, but we're looking for like hyaluronic acid and steroid injections. But similarly for PRP, I could imagine that that environment that you're injecting the PRP to, testing that environment pre-injection may be a good way to say whether the injection is going to help them at all. And that could be the future, as well as some of the patient specific factors. We talked about the age, the severity of their OA radiographically. Those are going to be things to also consider as we go forward in terms of individualizing your regenerative medicine approach. And I think, I mean, that's the challenge with doing randomized clinical trials, because usually it's very hard to get a very, very small population, like a specific age, other factors, a specific level of OA, and then it doesn't have that bang for the buck. And that's why I think maybe some of the studies are not showing the clinical benefits. Similar with many of the hyaluronic acid studies in the past, because I think hyaluronic acid does have a benefit in certain patients. But when you take all comers with OA, it never shows the benefits. And so that's why, like I said, in this presentation, I really want you to think about individualizing that approach and thinking about that might be beneficial in certain patients, but not in all. Having said that, I have patients who come in who are like 85 years old, who are really convinced that PRP is going to help them. And I'm almost talking them out of it, because I know 85 year olds with bone and bone OA, that's, it's not going to help them. They're very active, but that's also another thing. And then I think the other part that we don't talk about much in physiatry is the expectations, right? Like if a patient expects something to work and more than we're doing a study on physical therapy and expectations of physical therapy and whether that has relation to outcome, expectations definitely play a role. And I think the challenge for you as you go into your future career is trying to figure out what's the cause of the noise? What's the cause of difference in outcome? And that's what I'd love to see is like, trying to prognosticate for patients going forward. That's where the future, I think of regenerative medicine, particularly in orthopedic type or orthobiologic type procedures could be really fruitful. All right. Thank you so much. Can I ask one question before we end? Yeah. No, go ahead. Oh, Dr. Franz, how are you doing? It's not really fair. You could just ask me. Hi, Shannon. It's nice to see you. Yeah. It's been a long time. Dr. J. Ballin, I enjoyed the talk and I thought I had asked the question just to let you know that I was here, but also, you know, it strikes me that if you think in other areas of gene therapy, regenerative medicines and neurology, you know, one of the one that came up was, of course, with that Alzheimer's treatment from Biogen that lowered amongst its outcome that got that approval was it lowered the beta amyloid levels in brains as a biomarker. And it strikes me that the stress test that you proposed could also be used as maybe a way to like get reaffirmation that if you offer one patient PRP and they, you know, they may or may not respond. And I know that there's often a delayed outcome in terms of improving cartilage thickness, if you're going to get it at all, which is maybe a controversial thing, but the way you could leverage that sort of rapid ability to kind of interrogate a biological response and essentially stratify people into groups of people you might expect to be responders or non-responders based on that. I think that you were sort of alluding to that, but is that one of the ways that you might actually be able to, you know, use precision medicine in your practice or what direction? Yeah, I might've missed it with the stress test, but I thought that was maybe a really neat way to distress the system and also get a readout for therapies. Exactly, exactly, Colin. You know, I think what we're specifically looking at is trying to see, eventually is to try and prognosticate how someone may do with a specific treatment based on their response to our stress test. And that could be utilization for novel therapeutics to see whether someone's going to respond to that. Obviously that's a clinical trial, that's long ways down the line, but right now we're really just, I'm just trying to look at, we are testing people with ACL injuries right now because they're on the milder spectrum of OA to see if they have less of a response compared to the OA. So right now it's just to show that we're able to differentiate individuals, but the future could be using it as part of a therapeutic approach or prognostication of individuals with OA. It's a great point. And thanks for joining today. No problem. I appreciate it. I'm doing it from home too, but I turn cartoons on downstairs. I keep my kid out of my office. Oh my, yes, my kid, my son, I promise you you got dinner. I just want everyone to know that. It was refreshing to see somebody else than just researchers. I know. It does remind me, especially with your accent, that BBC reporter. Oh yes, exactly. Exactly. It is very much like that. Very much like that. I was like trying to gently push him the other way. That's exactly what that BBC reporter did as well. It was, yeah, no, he was fine. He was fine. Any other questions? Thanks so much, Shannon. It was great to see you and thanks for all you're doing for the AAP and everything. I'm really proud of you and seeing how you've had all the stuff that you're doing. So thanks again for the opportunity to talk today. I learned so much. I always am so grateful to learn from you guys. Thank you. Thanks, Shannon. Thanks, Candace. Take care. Hopefully see you all in New Orleans. Have a great night. Thanks. Thank you. Thank you for everyone else. Thank you. All right, bye-bye.

exercise

regenerative medicine

osteoarthritis

reducing stigma

early diagnosis

personalized treatment

biological markers

interval walking

golf as exercise

individualized tissue engineering