Small world, man. Good morning, everyone. Welcome to your session on post-traumatic arthritis. We're going to be discussing mechanism, risk factors, and new treatments. And myself exempted, we have an excellent group of speakers today. We'll start with Adam 1040, who will be talking about the Football Players Health Study and the lessons learned, including post-traumatic arthritis, premature aging, as well as new treatment paradigms and research, followed by Prakash J Balan. He's going to be talking about mechanisms and early prediction using serum biomarkers of post-traumatic arthritis. And welcoming to our academy, Garrett Bullock, who is at Wake Forest and part of the very, very well-known Opti-Knee consensus statement to optimize knee health and try to prevent progression of post-traumatic knee arthritis. Your team, Adam is an associate professor in our department of PM&R at Harvard. He's the director of our Spalding National Running Center, as well as the director of shockwave medicine, as well as the director of running medicine. He's a former professional runner. And his research in bone stress injury mechanisms, prevention, biomechanics, and biology, as well as shockwave therapy and running medicine, are world class. Prakash hails to us from Northwestern, known to many of you for his work as a clinician scientist and director of the Nancy Knoll Strength and Endurance Lab at Shirley Ryan. And also world class researcher in biomarker analyses to take a look at who's going to or try to predict who's going to develop post-traumatic arthritis and develop the optimal and appropriate exercise regimen for folks with musculoskeletal disease. And Garrett Bullock is an instructor in orthopedic surgery at Wake Forest. He's been there two years, having been at Oxford before that. He's a former professional baseball player, physical therapist, and quantitative epidemiologist, as well as a prior Clarendon scholar at the University of Oxford. And his research focus is risk and risk mitigation, lifespan impact of exercise in sports, and looking at big data and using that for analyses in sports. My name is Joanne Borgstein. I'm also from Spalding at Harvard, associate professor there and chief of our division of sports medicine and regenerative medicine for our health care network, Mass General Brigham. And we really welcome everyone here today. Thank you for attending. I think you're going to really enjoy the information. Thank you. I'm sorry, I forgot one thing. Please silence your cell phones. Please complete your evaluation forms afterwards. And please visit the pavilion when you have a chance sometime today. Sorry, I forgot that. Thanks for the reminder, Joanne. That would have been embarrassing. All right. Thank you. Good morning, everyone. And thank you for joining us for this session. Is everyone able to hear me OK? All right, so we're going to talk a little bit on post-traumatic osteoarthritis following an ACL injury. And these are really findings that come from our work with Football Player Health Study, which is an ongoing study to better understand ways to optimize the health of former NFL players. So first, I'm going to just describe some of what we know about post-traumatic osteoarthritis of the knee in association with ACL injury, talk a little bit about what we've learned through our ongoing work in American-style football players, and then discuss where we're heading. I mean, we are seeing a lot of arthritis in younger and younger individuals related to sport. And we really need to be innovative, because we've really learned that a lot of the things that we would offer older individuals may not be sustainable in younger populations. So we really need to think creatively. So first off, defining what is osteoarthritis. I mean, this is a condition that is characterized by pain and impaired function. And one of the strongest risk factors for osteoarthritis is age. I mean, we all know that. But in younger populations, post-traumatic osteoarthritis may account for a portion of the disease that we see. And we know that ACL injury is a very strong preceding risk factor for development of this condition. So what do we know about post-traumatic osteoarthritis of the knee following ACL injuries? Well, one thing we know is that an ACL injury is one of the most common debilitating injuries that we see in sport. We also know that it got a lot of visibility with the Women's World Cup, not so much the players that were there, but the players that weren't there. And we know that ACL injuries, a large portion of these, progress on to post-traumatic osteoarthritis, upwards of 90% in that decade following the injury. We also know that post-traumatic osteoarthritis has a very high burden on our health care system. So it's a very expensive condition to treat. So we've got to figure out how to take care of this guy. And we're hoping that by learning how to take care of a population of those with traumatic injuries, we can apply this to larger populations. So we've looked at data. And the Football Player Health Study is the largest ongoing study in former NFL athletes. Right now, we've enrolled, I believe, over 4,200 individuals. And this was an earlier interim analysis on a questionnaire that we call Q1. So we looked at individuals. And again, you're post-retirement at this point. In 3,660 individuals, we saw 21% had sustained an ACL injury requiring surgery during their NFL playing years. Almost half have had a surgery in their knee. So then you start to ask the question, well, why would you have surgery on your knee? Was it a cartilage defect? Was it a meniscus tear? Was it an ACL injury? So all of those events could predispose to development of post-traumatic osteoarthritis. And we're talking about the knee in this talk. But we also need to recognize that these former players are having surgeries on multiple joints, which are setting them up likely to develop osteoarthritis and other joints later in life. Well, what have we learned about what happens after an ACL injury in these former players? Well, one, we've learned that this is a really strong risk factor for having a subsequent joint replacement. And again, this is a cohort that's in their early 50s, on average. So you've got individuals in their early 50s that are getting knee replacements early, have a very high association with arthritis. And I would say in this cohort, we're actively working through these data. We're seeing about half of former players have reported that they have some form of arthritis. That's a high disease burden. Now, I mean, are we just concerned about the knee? I would argue no. We're concerned about the health of these players. We're concerned about their activity level that they're going to be able to sustain if they have untreated arthritis. And here we see a 52% increased risk of having a myocardial infarction if you've had an ACL injury. Well, that kind of makes sense, right? If you're limping around on a bad knee, you reduce your physical activity. That's going to have effect on your vascular health. So you're going to have cardiovascular manifestations of the disease. And we're talking about neurotrauma in this population. That's clearly important. But vascular health is also brain health, right? So we really need to think about this and how this is really impacting multiple organ systems for these individuals. And we even see an associated increased risk for sleep apnea, which makes sense. You gain weight because you're not physically active. So this is really kind of the big picture and one of the things that really gets me excited about working with this population of former NFL players is the things that we know from sports medicine, exercises medicine, and we really need to keep people moving and treat their pain. We also need to think about, well, what are we seeing? What's the end result of arthritis? Well, people get joint replacements. So we've looked across our population. And this was some work that Dr. Borgstein and I published on. And we're seeing, compared to NHANES data, there's anywhere from a six-fold to 14-fold increased risk for having a total joint replacement by age category. So these individuals are having total joint replacements at younger ages. And it's unclear that that's necessarily leading to improved function for themselves long term. We've also looked at what is the limited evidence for joint replacement status in former athlete populations. I think this is really an area that's underexplored. We're actually seeing that arthroplasty, if we look at rugby, soccer, football, we actually see a high rate of individuals that have had total joint replacements. So this graph might be difficult to read, but anywhere from 8% to 12% prevalence in these populations. And these are happening in individuals that are, on average, in their 50s or early 60s. And we counsel our patients that you want to avoid a total joint replacement and keep your native knee for as long as possible. So this is really concerning that we see this. And in the former NFL players, it appears they're getting this at a younger age than other populations. We also believe there is a large burden of chronic pain in this population. So this is one of the other reasons we're really delving into arthritis and trying to think about novel pain paradigms. We're seeing 2 thirds of individuals in this population report having pain that's really interfering. And over a quarter are actually being recommended prescription of pain medications for chronic management of pain. And we all know that we're dealing with an opioid crisis in this country. And there are other medications that can be considered. But if we could be a little more precise about actually treating the underlying disease as opposed to the symptoms, perhaps we would be more successful at helping this population. So we have to think about what are our traditional management strategies. And I would say they're not working well. If they were, we'd be putting ourselves out of business. And that would be great. We'd move on to doing something else to help our patients. But we look at things such as steroid and anesthetics. And we're recognizing that these really have chondrotoxicity, tenotoxicity, myotoxicity. Some studies suggesting that there is an acceleration of arthritis radiographically over a short time with the use of these medications. And again, a lot of times this leads former players with an NFL career to consider surgery. And that really can have some variable outcomes. So again, plenty of articles and meta-analyses suggesting that we may not be seeing the same safety with our traditional treatments, or that even the use of non-steroidal anti-inflammatory medications placing people at increased risk for cardiovascular events. So there's been some really exciting updates that have come from some of the earlier work in Football Player Health Study. One is the BARE trial. So again, the idea is that if you have a mid-portion ACL tear and you're able to apply a bioscaffold, you might be able to restore normal anatomy of the knee and reduce the risk for development of arthritis. There's also been some work looking at hydrogels. So the idea is you could deliver a bioscaffold that could then lead to a consistent release of a corticosteroid so that you're not just kind of blasting the joint every three months. So these are a few advances that have come from the work in Football Player Health Study. But what we're really trying to do is really come up with a full spectrum of treatment. So taking the individual that has the acute injury and thinking about what can we do to improve their intraoperative surgical approach, what can we do post-operatively to treat early knee osteoarthritis, considering biogels and drug delivery, and then even considering gait retraining, because what we really want to try to do is prevent that spectrum to end-stage arthritis and total joint replacement to later years. So again, when we think about post-traumatic osteoarthritis, what are we treating? And I think this is the aspects that we're really trying to dig into here. I mean, if you look at this MRI of the knee, what's causing the pain in this individual? Is it joint space narrowing? Is it abnormal contact from the meniscus injury? Is it the subchondral bone edema, which has been described as almost the equivalent of walking on an insufficiency fracture if you have an unstable meniscus? Or is it all the extra-articular and periarticular pathology that occurs after developing arthritis? And so these all represent potential targets that if we can then start to do a better job phenotyping, we might be able to then come up with better treatment strategies. So one approach that Dr. Borkstein and I have been taking has been considering different combination therapies. So one combined treatment is considering ways that we might treat the knee as an organ system. I really like that concept. Someone's suggesting that if we think about joints as an organ system as opposed to just separate structures that we're treating, maybe we can have a more combined approach. So in some cases, what we've observed, and this really needs to be substantiated with greater clinical research, is that the application of intra- and periarticular platelet-rich plasma injection in combination with shockwave going after the subchondral bone and soft tissue might lead to a more comprehensive treatment strategy for those with knee osteoarthritis. And we have seen, again, this is anecdotal, some individuals that maybe they have refractory pain after platelet-rich plasma, and we go after their subchondral bone edema, and then they're like, wow, OK, now I'm feeling great. Or maybe they come to me and it really seems like it's primarily extra-articular. They're seeing some improvements, but there's still a feeling there's active synovitis and some intra-articular targets. And then they're doing really well after getting a platelet-rich plasma injection. So just to talk in brief, what is platelet-rich plasma? Well, this is autologous blood, which is spun down to take the platelet-rich layer. And the idea is that this can then be introduced to the joint with the growth factors that might modify the disease process. It has been shown to be safe and effective for knee arthritis. I know there are some recent studies that have led some to say we should take a pause. We don't really have the time to go into that, but the question, of course, comes down to what are you delivering? And I think that's one of the challenges when we think about something like PRP, because an individual, depending on the time of day that the blood's drawn or other changes even within an individual, they may have different concentration of PRP or may not be achieving the same cell counts that we want to have effect. So I really nerd out about shockwave. And what's been really interesting is that as I push myself to understand the science early on with doing a number of different reviews and looking at outcomes, there really does seem to be a role that we can think about shockwave in the management of different soft tissue injuries. And my mentor for a long time, Dr. Fredrickson, that joined us here this morning, what was really exciting was as I was delving into the literature was seeing that shockwave could be considered for treatment of bone marrow edema and could even be a strategy for treatment of stress fracture. And so if we start to think about the bone edema that we see in these athletes, there's a potential target here for knee arthritis. So when we get into how shockwave works, it's not a fancy modality. It's really actually a form of regenerative medicine, which if you look at cellular studies, suggests that it can stimulate tissue remodeling. It may also have some effects both centrally as well as peripherally on pain modulation, which is really interesting when you think about individuals that have a failed arthroplasty with knee arthritis and some of the signals that we see with centralized pain. Maybe this is something we should be considering earlier on. How can we help these individuals? So shockwave is non-invasive. It has a favorable side effect, and people can continue to be active. This cartoon demonstrates the two main forms of shockwave. The first with a very high initial positive energy phase, and that's what we would call true shockwave or focus shockwave. And then the second is radial shockwave, which tends to have a lower amplitude, both positive and negative, that's more sinusoidal. And others may refer to that as radial pressure wave. We've really gone from what needed to be done under a C-arm with general anesthesia to something that looks like a 1990s desktop computer that you can wheel in between clinic rooms to treat your patients. So again, if we think about how shockwave might work in osteoarthritis, we've got three potential targets, the cartilage, the bone, and on pain modulation. So if we think about cartilage, there's actually some studies. A lot of these come from transection models in rats, those poor rats with those ACL injuries who really need to help them out, right? So they've done some shockwave to see if you can actually prevent development of post-traumatic osteoarthritis. And there have been some interesting findings that you can elevate bone turnover, you can reduce cartilage loss, and potentially increase activity at the chondrocyte level with shockwave. There's also been some in vitro studies in humans suggesting that with knee osteoarthritis, you might be able to modify certain inflammatory modulators, such as TNF-alpha and IL-10 expression following shockwave. So next target, subchondral bone. Well, the idea is that if we can increase osteocyte activity, we might be able to start to heal these subchondral bone lesions. And if you think of the kissing contusion with an ACL injury, perhaps that's one of the targets that we just have not been treating. And so again, going to these poor rats to get these ACL injuries, you can actually maintain bone density by applying shockwave early on. So perhaps there is a way to prevent some of the regional bone density loss after these ACL injuries. And there are some changes at the cellular level about TGF-beta-1, VEGF expression, that really suggests that we may be actually activating mesenchymal cell recruitment. Again, we have to be careful what we tell our patients. But there are some proposed mechanisms for how this might be biologically feasible. Then we also need to think about pain. Our patients, they care what they see on their X-ray. But the reason they're coming to us is they're in pain. And the really cool part about shockwave is this process of hyperstimulation analgesia. The individual limps in, and they walk out. And the question on why that would happen when you're applying a stimuli that is initially painful is that you may actually be overwhelming the C fibers of those target tissue, which then contributes to disrupting the pain signal. And so they've actually looked at this in the rat model and have found that this may actually be happening at the dorsal root ganglion level of modulating pain. So again, this may not just be at the soft tissue level of a gait control theory of pain or depleting substance P, which would take a little bit longer, the substance P theory, but actually at a centralized level. So we are about to embark on a really interesting study in post-traumatic osteoarthritis of the knee after an ACL reconstruction. And what football player health study is doing is supporting an interventional study where we're going to explore the role of platelet-rich plasma on the treatment of post-traumatic osteoarthritis. Now, we need to think about this, though. Why does PRP work in some individuals and not in others? Or what are the rehabilitation strategies we should be applying after these cell-based treatments? There's actually very little that's been done looking at the biomechanics of those with post-traumatic osteoarthritis. We do know that after an ACL repair, you see some changes in ground reaction forces, changes in knee flexion, torque. So these are all things that have been described in ACL injury but have not necessarily been evaluated two-plus years out in individuals with early knee osteoarthritis. So that's one of the things that we're also planning to look at while we consider whether someone's responding to true versus sham PRP. We've also tried to inform ourself with the best evidence-based strategies and nerded it up writing another review article on post-traumatic osteoarthritis in athletes, where we really wanted to understand what are the studies that suggest that imaging biomarkers might be good strategies to detect disease and changes in health, biochemical biomarkers, and then even patient-reported outcomes. So from an imaging biomarker standpoint, there is a number of things that we observed in our review. One is the plane radiographs, you really need to think about how you obtain them if you're really going to actually detect disease. And so there is a Rosenberg view that I've become familiar with through this review process, which actually can help you to pick up early knee osteoarthritis. And having a really standard way of getting those x-rays is important. MRI can be helpful, but there are a number of different strategies in terms of whether you do automated versus post-processing. And it's still unclear. There's been some really great recent work by Dr. Mautner, which may suggest that MRI is not necessarily going to be sensitive enough to detect differences at a year. And then, of course, we all nerd out about ultrasound in our academy. But the challenge is that we really don't have a ton of reference values, and we know that it's user-dependent. From blood and serum, there's a number of different markers that we're going to be looking at and have been studied after PRP administration. Changes in interleukins, TNF-alpha, MMPs, BMPs, C-reactive protein. There's a number of other oxidative stress biomarkers that we're interested in exploring. From synovial fluid markers, I'm going to defer on discussion because I have someone much more expert than me on stage. But it's a challenge. How much do you go after the synovial fluid and take on the invasive nature of sampling that to make decisions on strategies versus this being a tool for us to understand mechanistically what we're doing? From an outcome scale, the COOS has been the best studied in post-traumatic osteoarthritis of athletes. IKDC, though, is another marker that we should be thinking about, particularly in active individuals after ACL injury. SANE, PASS, and pain scales are also features that we should be considering when we're following our patients after our interventions. So what I really just kind of want to summarize this talk, the key factors I want you to think about is, first off, that there's a really high burden of post-traumatic osteoarthritis, particularly after an ACL injury. And surgery does not prevent osteoarthritis. What it does is it restores the passive restraint that prevents translation of the tibia, but it does not prevent osteoarthritis. So we need to think about how we help our patients. From the NFL study, we recognize there is a very high burden of post-traumatic osteoarthritis. There is a very high rate of early total joint arthroplasty. And this has effects on multiple domains of function. So when I think about the patients I take care of in clinic that have post-traumatic osteoarthritis, I'm thinking about all the other domains of their health. And I think that's an important thing for us to do, to be holistic in our approach. The gold standard remains radiographs to detect post-traumatic osteoarthritis. And consider adding the Rosenberg view if you're looking at this population. There are a number of gaps in knowledge. And I hope to have information to share with everyone here over the coming years about changes in biomechanics and ways that we might then be able to apply this to rehabilitation. And yes, in fact, gait retraining. And we need to think innovatively. We need to be thoughtful about the use of steroids and consider non-steroidal alternatives. And I think that platelet-rich plasma and shockwave both have some good feasibility. But we really need the research to help us to understand how effective it is so we can counsel our patients and really deliver that value-based care that we all desire. So with that all, I'll thank you for your attention. Thank you. All right. Great. Thanks so much for attending this session. And thank you to Dr. Borgstein for putting together an esteemed panel today and inviting me to be part of this group. I do not have any disclosures. The outline of what I'm going to be talking about is really PTOA more at the biological level and how it's different from non-traumatic osteoarthritis. The use of biomarkers in PTOA or what we find with biomarkers in PTOA. Some of the research we're doing in trying to develop a cartilage stress test. And then potentially using biological markers as part of a treatment plan for patients going forward. So the first part is, and I loved Adam's talk for many reasons, but he also said American style football. And as a British person, I really appreciated that. So in my real football, I just imagine, and you've all seen this type of patient in clinic hopefully, a player, I hate Liverpool, but it's a Liverpool player, Virgil van Dijk, who I'm showing up here. But he tore his ACL in a game. And one thing that we see with athletes is that most athletes will, at that level, will have an ACL reconstruction. And what we're finding is that within 10 to 20 years, sometimes within five years, they have a high development of osteoarthritis. Almost 50% of individuals are developing osteoarthritis within 10 to 20 years. And the first part is to say that PTOA is different from non-traumatic osteoarthritis. This is PTOA that develops. This is OA that develops following injury to a joint. So PTOA makes up about 12% of all osteoarthritis cases of the knee. And as I said, greater than 50% of individuals with an ACL tear will develop osteoarthritis within 10 to 20 years. And the problem that we have, and I'm really excited that Garrett's here, we have no definitive treatment currently that we know will prevent or delay the development of OA. Some people will develop OA, and about 50% will not within that time period. And we have limited predictive studies, particularly at the biological level, of who's going to develop osteoarthritis in the future. So what is different about PTOA for these patients? So Adam said it perfectly when he said we need to start thinking about the joint being an organ. And when you look in the dictionary, what is an organ? An organ is an encapsulated structure with cells which each have a different function that collectively have one function, which in the case of the knee joint is motion or movement. And so we have different parts of the knee joint, and the focus generally has always been articular cartilage. But we know that there's the synovium. It's bilayered. It produces hyaluronic acid. It produces some of those constituents of the synovial fluid. We have the subchondral bone, and there's this crosstalk between the subchondral bone and the articular cartilage above it. We have the synovial fluid. And we know that synovial fluid is a viscous material, healthy synovial fluid. But also studies have shown that individuals with osteoarthritis have more acidic synovial fluid. So we know that that changes in osteoarthritis. And then, of course, we have the articular cartilage. And the articular cartilage is avascular alymphatic, so it has poor reparative potential. And it's also aneural. So when it's damaged initially, patients don't know that it's damaged until there's subchondral bone-related issues. And so overall, we know that in the healthy joint, there's this optimal balance between catabolic and anabolic processes. But what happens in OA is that you get damage to the articular cartilage. But you also get damage to other parts of the joint, such that as the patient bears weight over time, there's synovial thickening. There's osteophyte formation, bone cyst formations, things that we might see on radiographs. But eventually, you get bone-on-bone motion that leads to pain. And some of these issues are potentiated by some of the inflammatory markers and degradative markers that actually go into the joint and are released by the synovium. And we know that those potentiate joint damage further. And so the balance when we think about the unhealthy joint is that it gets tipped more towards catabolic processes as opposed to anabolic processes. The other part that I think is really critical that we need to start thinking about OA, and Adam sort of alluded to this, is that we always classically said that OA is this wear and tear condition. And in PTOA, it's even more important to not think about OA in that realm. It's this interplay between abnormal biomechanics and abnormal biology. And so what happens is you have this abnormal biomechanical process. So when a patient puts load on their joint, there's a release or a potentiation of some of these inflammatory markers, degradative markers, degradative enzymes, such as MMPs. And those potentiate joint damage even further. And so when we're thinking about our treatment for classic, not atraumatic osteoarthritis, we're trying to limit that inflammatory process by giving our patients anti-inflammatories to decrease some of these inflammatory cytokines. But there's also biological treatments that are being developed to actually target some of those cartilage degradative enzymes or matrix metalloproteinases, as outlined here. But even other studies have shown that activity modifications, and we prescribe exercise a lot to our patients, those can actually have a biological effect as well as biomechanical effect. And similarly, when we advocate for weight loss, that has an effect in both of those realms as well. So then when we think about OA, what's different about PTOA compared to atraumatic osteoarthritis? So the first point, the classical way that many physiatrists that we see in the non-sports realm is that we have this osteoarthritis. So when we have that abnormal load, it's sort of slow, low energy load that's placed on the joint over time, but it's abnormal. And you have these joints that are incongruous, they're unstable, minorly unstable, and there's some element of dysplasia that eventually occurs. As I just pointed out, there is a biological effect that leads to osteoarthritis in these patients. But in PTOA, we know that there was a single high energy impact, and that impacted the joint in many realms. There's damage to the ligamentous injury, there's damage to the meniscus, there's also cartilage injuries, and there's also damage to the subchondral bone during that trauma as well. And so that also has a biological process as well that eventually leads to the development of OA. At a bigger picture level, other differences that we see in PTOA compared to atraumatic OA is that, as Adam alluded to, we're talking about a younger population here, not that naturally occurring OA that occurs with age. In general, most of the individuals who are developing PTOA tend to be younger, at least at initiation. The other parts that we also see is that classic OA, we see individuals develop OA of the medial compartments. But studies have actually shown that there's a higher predominance of patellofemoral OA, as well as lateral compartment OA in individuals who have developed OA post-traumatically. Other studies have shown, because of the loss of the ACL, individuals who develop PTOA actually have more tibial external rotation because that ACL is gone. And then when we think about it from the biological level, there's also studies that show that the synovial fluid viscosity also changes. So the viscosity actually becomes less viscous because there's less hyaluronic acid that's actually released from the synovium in the PTOA condition. And also there's this incredibly high inflammatory load that occurs initially, particularly within the first year after someone's had an ACL injury. So I sort of tried to put this together to sort of, at the biological level, show what's essentially occurring. So we have, this is, when you think about the joint, and particularly the cartilage and the bone underneath, and when you think about it as an osteochondral unit here. So you have articular cartilage. And then you do have this sort of gray area, which is that transition between the cartilage to the bone, which is called the zone of calcified cartilage. And then you have the bone underneath. And then, obviously, this osteochondral unit is bathed with synovial fluid that individuals have in their joints. And then there's also these healthy nutrients, that crosstalk that I talked about, that occurs between the subchondral bone underneath and the articular cartilage above it. So what happens in that trauma? So that individual has a trauma to the part of the joint. And what happens is that trauma is not just to the cartilage, but it can go down into that subchondral bone. And you can have that subchondral bone fracture, as Adam alluded to. So essentially, what can happen is that osteocytes actually get activated. And you also get the release of these inflammatory cytokines from the subchondral bone. And they crosstalk with the articular cartilage above, leading to some element of loss of the articular cartilage. And as I said, osteocytes are also activated. So they start thinking that they need to repair the situation. So they release growth factors, such as TGF beta-1, and VEGF, and others. And the problem is that they lead to neovascularization. So in this situation, that neovascularization is not good, because it leads to this uncontrolled bone remodeling. And that, in turn, leads to this growth of some of these blood vessels within the subchondral bone. And then that, over time, leads to an increase in that area of that transition between the cartilage and the bone. So this tide mark, which is the top level of the subchondral bone zone of calcified cartilage, that actually increases as well. So you get more calcified cartilage as a result. And then the other part is that at the site of injury, you have necrosis initially of the articular cartilage. But you also have apoptosis that occurs about a month later around it, so apoptosis being programmed cell death. So it's not that the cartilage is just injured in the injury. The area around the injury is also damaged as well. I think it's also important, when we think about PTOA, it's also important to talk about bone marrow lesions, as Adam alluded to. And what they found is that in individuals who have asymptomatic OA, there is a high predominance of bone marrow lesions in these individuals. And over time, studies have shown that that overlying cartilage is actually thinned in areas where there are bone marrow lesions as a whole. And there was a study that actually showed that the presence of a bone marrow lesion and the size of that bone marrow lesion actually predicted the articular cartilage loss one year post. But there's limited studies that I could find that actually relate bone marrow lesions to some of these biological markers, as I was alluding to. The other part is that that subchondral bone geometry also changes. And that, in turn, leads to abnormal loading of the joint. And we see that particularly in the context of bone marrow lesions as a whole. So when we put this together with the pathophysiology that I just described, on the left here, you'll see that you have normal load. You have that healthy crosstalk in a normal, healthy joint. In a way, in PTOA specifically, you have this high energy impact and high energy load. That, in turn, leads to unhealthy crosstalk between the subchondral bone and the articular cartilage above it. And that's potentiated not just by these inflammatory mediators and cartilage degradative enzymes, but also things such as bone marrow lesions as well that we see. And you also get this unhealthy vasculature within the subchondral bone. So now I want to take that forward. So we've sort of talked about the pathophysiology biologically for the development of PTOA. So now I want to talk about using some of these biomarker changes following ACL rupture for our patients. And I don't want to bore everyone by going back to your step one exams back in medical school. But I want you just to remember back to then that articular cartilage consists of a chondrocyte surrounded by an extracellular matrix. And there's three major components of the extracellular matrix. There's water that's held within proteoglycans that gives cartilage its compressive strength. And also you have collagen type 2, which gives cartilage its tensile strength. And we know in osteoarthritis there's damage to that extracellular matrix, such as the patient bears weight over time. There's also the release of these from the synovial fibroblasts, the release of some of these cartilage degradative enzymes. You get the release of some of these inflammatory mediators that potentiate that damage as well. And in my research, we measure some of those biological markers in the serum, in the blood, in the synovial fluid, in the urine even of some of our patients. And we try and look to see how that relates to their loading or their exercise. Studies that epidemiological studies using biomarkers have actually found that on the right side of the screen here, you have someone with total joint replacement. On the left is that sort of early pre-OA biomarkers, some of these biological markers you can actually see in the blood of your patients earlier on in the disease process. So the area that's the potential area where one could utilize some of these biomarkers in particular is this sort of asymptomatic phase for the development of PTOA. We know, looking at the biological literature, we know some of the stuff that's going on at the cellular level immediately after a joint injury in that acute phase when you have that apoptosis of the cartilage. And then, like I said, you have this asymptomatic phase that eventually leads to that symptomatic phase where the patient's presenting to you with joint pain. So how can we use biomarkers to evaluate that very, very early progression? So we're talking about one year post injury or ACL reconstruction. Because we know in that eight week to one year period, there is a lot of catabolism that's occurring within an ACL reconstructed joint. And so you get this balanced tip still towards a catabolism even at one year. And then the anabolic pathways are decreased as a result. So IL-1RA is a receptor antibody to IL-1 beta. So it's anti-inflammatory. And similarly, IL-10 could be inflammatory, anti-inflammatory, but it definitely decreases in that one year period. So that leads into some of the research that we're doing in trying to be fortune tellers for our patients in trying to decide who's going to develop osteoarthritis. And why that's important is that that could allow us to intervene earlier in our patients. So my lab sort of uses this idea of a stimulus response framework. It's analogous to a cardiac stress test. So for example, if you take a person with what you think may have cardiovascular disease, you get them to walk on a treadmill. You look at EKG changes to stratify risk for the development of osteoarthritis. In my research, what we do is we get people to walk on a treadmill. We look at biomarker changes in response to loading. And then that gives us some idea of how that load is impacting their joints as a whole. And so it gives us an idea of the stress response, potentially, and the inflammatory response of the cartilage or the joint to loading or exercise in patients. And a study out of Stanford actually showed this type of approach. So 30 minutes treadmill walking. And that biomarker response to that treadmill walking actually predicted cartilage thickness changes at five years post on an MRI. So the area that we're really focused on is the ACL reconstructed individuals. And we know ACL reconstruction could be beneficial from improving stability, allowing athletes to be higher level of function, and also better function overall. But what we also know is it does not prevent against the development of OA. And so can we develop a test that allows us to look at the biological state of the joint, and then, in turn, how that joint will respond to loading? So my lab has essentially developed a, on the left here is an individual. That individual is walking on a regular flat treadmill. On the right here, we've created a tilted treadmill. So we can actually individualize. The stress of each knee joint is different when you walk in this tilted paradigm. So it's not just walking where you can say, well, the biomarker changes. It could be coming from one knee joint compared to the other. Our biomechanical studies suggest in this particular case, the lower knee joint takes more of a stress. So we do know that there's potentially more of a loading profile on the left side of knee joint, in this case, than the right. And so what we look to see is biomarker responses to that. And the biomarker we measure most commonly in this realm is the one that, if you look it up, is most tested in the literature, is a biomarker called COM. So this is an extracellular matrix of cartilage. And what it does is it ties together collagen type 2 fibrils. So what happens is every time any of you in this audience take a step on your knee joint, that mechanical factor actually gets transduced. A mechanical signal gets transduced from the extracellular matrix to the chondrocyte. And COM is this marker that helps do that. So it's really important for your joints to get loading. And so in a healthy joint, COM is actually a very good thing. But we know in unhealthy joints, in an osteoarthritic joint, there's the release of COM. And so we say that increased COM is analogous to increased cartilage stress. So what we found was that when we did this sort of tilted paradigm, there was a specific increase in serum COM. So the biomarker only when you test the ACLR knee, the ACL reconstructed knee. In the healthy knee, when you test it, you don't see this biomarker response. And these individuals were two to five years post-ACL reconstruction. We also saw significant increase in inflammatory mediators that you don't see when they're rested. So there is some differences that occur with loading in these individuals. The other part that we also saw was that there was a significant correlation between some of this increase in that biomarker of cartilage stress and the angular change of the kinematics of the knee joint in our patients as well. So there is, again, that relationship between biology and biomechanics in our patient. And the other part that was really interesting is that we saw that that level of knee flexion that they had actually had pretty strong correlations to the level of inflammation that we measured in their bloodstream in response to that walking that we did on this tilted treadmill. The other part that we're also looking at is actually now to use some of those biomarkers to look at how it responds to treatments. And so one common treatment for ACL reconstructed individuals is get them to run on an anti-gravity treadmill. And these treadmills, actually, you can vary the amount of body weight that individuals place on their low extremities while they're running. And so we did a study where we actually got people to walk at 100% of their full body weight, and we compared it to 50% loading. And these were individuals with early osteoarthritis. And so what we found was that, as you would expect, is when they walk on their full body weight, there's an increase in pain. When they do it at 50% body weight, there's actually no increase in pain, which is really fascinating. The second thing that we also saw is that there was an increase in that biomarker associated with cartilage stress at 45 minutes of walking, only when you walk at your full body weight. When they did it at 50% body weight, there was actually a decrease overall. And then the other part, when we think about pathological gait parameters, there was actually some improvement in gait parameters when they walked at 50% body weight, as opposed to their full body weight. So reduction in cadence, increased stride length, and a wider base of support. So some of those pathological gait features were actually masked when they walked at 50% body weight. Finally, I want to just, as Adam talked about regenerative medicine, one other food for thought that I just want to leave you with is this idea of the synovial fluid milieu being related to the outcome of the injections that we do for our patients. So we're doing a study in individuals with early osteoarthritis, who we actually look to see what synovial fluid biomarkers are related to the outcome of an injection. So we look at their change in function, four to 12 weeks post-injection. And what we looked at is whether there was any relationship between the biomarkers and biomechanics in these individuals, that baseline that predicted who's going to respond to treatments. And so I'm working with one of my colleagues, James Cotton, at Shody Ryan Ability Lab. And so what we're looking at is pre-injection biomechanics here on the left. And we're looking at post-immediate biomechanics, and then four weeks down the line biomechanics to see if there's any relationship into that immediate biomechanical change post-injection and the outcome of the injection. And what we found, interestingly, is that there were significant relationships in the synovial fluid milieu to the outcome of the injection. So we found a negative correlation between these two biomarkers, which are associated with cartilage breakdown, and the outcome of the injection. So the more they had in their synovial fluid of these collagen-based breakdown factors, the less response they had to injection. So putting that all together, I've sort of given you so much we could talk about with PTOA. But I just want to end by just saying the goal of my research and I think Adam alluded to this, is that we need to strategize an individualized treatment approach for our patients that takes into account not just the imaging or the physical exam, but takes into account some of the biology, some of the biomechanics, and also some of the psychosocial factors that our patients go through every day. And as I said, individualizing our patient approach, that's something we spout a lot in physiatry, but I really think it's no different when we think about PTOA as well. I'd like to thank my lab and take any questions at the end. Thank you. OK. Well, I want to thank everyone for allowing me to be here today. It's especially great to be a physical therapist at a PM&R conference. We're synergizing our rehabilitation and non-operative strategies. So, so far, the panels you've heard up here have been fantastic, and we've really focused on really two pieces. Number one is really the mechanisms of injury within to develop post-traumatic osteoarthritis, particular to the knee. This could be a major event, such as an ACL tear, followed by ACL surgery, or even more importantly, the microtraumas over time of, say, tackling within the football study. We've also seen that I've also looked at the biomarker strategy and how this can look at in terms of prediction of PTOA, but also the trajectory of different patients in creating individualized strategies. Now I'm going to take you into a little bit of different focus now. I wear two different hats within my job, really from a physical therapy perspective, but also as an epidemiologist. And the focus of my talk is really on prevention of PTOA across the spectrum. And when you look at rehabilitation, and particularly prevention, there's really a whole process that originally focused by Van Mechelen and then updated from Caroline Fitch called the TRIP model. And so far, we've really focused on the etiology and mechanisms of injury. But we're now going to look at really in terms of establishing the burden from a physical and mental perspective, and then also how to develop preventative measures from a primary, secondary, and into tertiary perspective. I would also like to highlight before discussing these topics is that I am only a piece of what I'm going to present today. This was driven by Jackie Whitaker and Adam Colviner from University of British Columbia and La Trobe University of Australia. And then also more in the behind the scenes of Kay Crossley of La Trobe, Iwa Ruse from University of Southern Denmark, and Carolyn Ennery from the University of Calgary. The Opti-Knee Consensus, which is a consensus on rehabilitation and prevention of knee post-traumatic osteoarthritis, is really a multi-year process. We started this in 2019 at the Osteoarthritis Research Society International, ORSI, in Toronto, where our first steering committee was engaged. And from there, we developed guiding questions, multiple expert stakeholder groups from patients to clinicians to parents to coaches to athletes. And then we did a seven systematic reviews for evidence synthesis. And then we went into the generating recommendations, revising, and then rating and scoring these. Here's just a brief overview of all the systematic reviews and meta-analysis that you'll see here. And we're only going to focus on two particularly. Number one of the mental and physical burden of knee injuries and then development of PTOA, and then also into the rehabilitation and prevention of PTOA. When we think about the mental and physical burden, and even into the cost and work limitations of knee injuries and the development of PTOA, we focused on this from the systematic review of over 50 articles. And we focused on two different pieces, the development and trajectory of mental and physical quality of life, and then comparing knee injured patients and athletes to healthy match controls. And when we look at the physical components of health-related quality of life, we see two interesting pieces. Number one, after knee injury, that we see a bump in their physical components of health-related quality of life, starting at six months, but ending at five years post-injury and or surgery. And we really think this is about having the proper rehabilitation and returning to sport, physical activity, or physical function. But after the five-year mark, and we get into the 5, 10, 15, 20, and 25 years, we see a slow degradation of their physical function, physical quality of life over time. And this is really because of the development of PTOA within these different populations. Now, when we compare this development and trajectory over compared to same match controls of non-injured athletes or patients, when we include all studies, we see that there's no difference in their development and trajectory of physical health-related quality of life. However, when we exclude the high risk of bias studies, which were really based off inability to quantify exposure, and also in terms of their selection bias of patients, we see that there is knee patients that did not have knee injuries had almost a two-point improved physical components quality of life, which meets the minimal clinical important difference within this thing. So to sum up, we see an initial increase in physical quality of life, a slow degradation due to PTOA, and that healthy non-injured knee patients show an improved physical components over this same lifetime strategy. Now, when we look at the mental components of health-related quality of life, we see a different story. We see basically a stabilization of their mental health-related quality of life across the lifespan post-injury, from two years to 10 years to 15 to 25. And when we compare this in terms of healthy knee controls, we also see that there's no difference between injured and non-injured knee patients. And when we exclude these high risk of bias studies, we see the same thing, that there's really no difference. So now that we've established the burden from a mental and physical components across the lifespan, we're really going to go more into the prevention strategies within knee injury and PTOA. And there's really three pieces to this. There's primary, trying to prevent knee injuries from ever happening, secondary, trying to prevent PTOA particularly, which will be the main focus, and then tertiary, which is after development of PTOA, how do we keep you at some functional level? But first, we are going to talk a little bit about primary prevention. As my grandmother used to tell me, an ounce of prevention equals a pound of cure. If we could help develop and prevent knee injuries from ever occurring, we can never have a lot less worry about PTOA development. Now, I should state that we can't prevent all injuries, but we can reduce the public health impact of this. And this has been really well described and evaluated for lower extremity injuries through multiple different cohorts, from Carolyn Emery's iSprint in Canada to Haglund's Swipe in Knee Control out of the University of Lincoln in Sweden, from Verhagen's School-Based Physical Activity Prevention, and then Kay Crossley's Prep to Play out of Australia. And this is really focused on neuromuscular warm-up and exercises, focusing from range of motion to full functional movement patterns, change in direction, and basic strengths. And this lasts from 10 to 15 minutes, two to three times a week, depending on the program. However, as I just stated, that we can't prevent every single knee injury. There's still an exposure of risk in terms of any physical activity or sport participation. And really, as this talk has been eloquently described so far, it's really about trying to mitigate the risk of development of PTOA after that major injury. And so when we look at the Opting Knee Consensus Statement, when we talk about prevention, there's really a few main focuses. Number one, it's really trying to modify the risk factors for this disease. And number two, it's trying to reduce the progression. And when we talk about rehabilitation, we're really talking about exercise therapy and other interventions that expands beyond just one type of medical provider, but really it's the intervention themselves that we're giving them across the spectrum in interdisciplinary care. And rehabilitation is really the health strategy for the tools to give to our patients to gain independence. Now, before that we go right into the actual prevention and rehabilitation strategies, I do want to give a little bit of a side quest or sidebar to discuss about PTOA. When patients come to us for care for osteoarthritis, particularly post-traumatic osteoarthritis, they don't really focus on their knee joint so much. It's really much more about the symptoms, about reduced function, increased pain, and inability to perform the activities or hobbies or sports that they're working for. Within our consensus, we really focus more on the clinical signs and symptoms of symptom OA and then help define structural knee OA, which is the actual disease of the joint itself. Loss of cartilage, chondric lesions, et cetera here. So when we talk about secondary prevention, this really begins with good rehabilitation after knee injury. This could be non-operative or operative for any type of major knee injury. This is beyond the scope of this talk here, but there is a lot of discussions on operative versus non-operative ACLR reconstruction and how that actually can affect knee OA for a different talk. But when we talk about rehabilitation and returning to activity or sport, we really need to focus much more on meeting different goals in terms of physical function and strength and power and not certain time-based strategies. So this starts with gaining range of motion and strength and quad activation. In the early stages is we protect the graft, moving to single leg stance and gait, which has already been described eloquently before in the other talks. Moving to full functional movement patterns, everyday life, and then going into bilateral unilateral strength training, followed by neuromuscular training, and then finally return to sport. And when we're talking about prevention of PTOA is that it's really about three different pieces of the puzzle from a patient-centered perspective. Number one is education, self-management, and then the whole thread throughout of this is really from a person-centered care perspective. Now, when I meet with patients that come into the clinic to work with any of their PTOA or osteoarthritis generally, one of the biggest pet peeves I hear is that they always talk about, oh, I have bone on bone. Or my friend said, I have bone on bone on my knee, and that's why I have knee osteoarthritis. I think this is a description that we need to move away from, which has been hinted within the other conversations here, is that osteoarthritis, particular PTOA, is much more than just, quote unquote, wear and tear or bone on bone. I think this also really gives them this type of thought process and wording really moves away from them being able to help affect or own their own self-management strategies. And number two is really when you look at the literature within, and then particularly with this consensus statement, exercise is the best medicine for the baseline of trying to help them within their PTOA prevention and then tertiary prevention. And one of the first things that I was taught and hearing within my clinical rotations long ago in physical therapy school was that one of the best things I heard was motion is lotion. And when you think about exercise or movement, it helps us maintain a healthy weight. It keeps us in exercise. It helps joint synomial fluid movement and also have strength to protect the joint throughout the lifespan. And number three is really finding strategies together between the clinician and the patient to keep your knee healthy long after you have discharged them from your care, keeping your weight down, which we've already talked about throughout this talk of talks of systematic inflammation and also in terms of the downward sequela of that, exercise, and then also in terms of thigh strength as well, which is keeping stability and also in terms of changing and altering and maintaining healthy biomechanics through gait, running, and also other exercise movements. When we discuss about self-management strategies is that there's really a couple of different things. And this is really moving beyond after they've released from our care. Number one is maintaining exercise habits. And this should be at an individualized strategy. When we're focusing on this, it's about trying to find the right exercises for the right patient at the right time. Someone that's a 16-year-old or 18-year-old soccer player is going to be much different than, say, a 55 to 65-year-old that plays tennis or a weekend warrior versus an 80-year-old that's getting into a different strategy for function and all that. Number two is that we need to have strategies for when rehabilitation for the patients have bad days. This is one of the first things I always talk about with my patients is that rehabilitation and then also recovery across the lifespan is not just a linear process. Not every day is going to be perfectly improving. It's that there will be days where your knee hurts or you don't feel as good or it feels stiff. And we really need to educate them as that this is OK. But then also, what are the strategies that they can do with themselves to stay within the progression that they're trying to get to? From a recovery standpoint, are there any type of modalities or type of compression from ice? Or how are we going to think about recovery? Loading during that knee flare or not having as good a day with your knee, but also reloading after you've coming out of that bad day or bad week with your knee. And then finally, reintegration as we move from rehabilitation to functional lifespan activities. How do we want to think about that process of return to sport or return to functional activity? And then finally, it's really about one thing that I really love doing with my patients is checkoffs for function and strength. When they leave my care, I always give my patients two, maybe three exercises, movements, or strength patterns that they use to help make sure that they're still on the right path remaining a certain level of function. This could be a single leg deadlift. This could be a single leg walk down from the stairs or climbing stairs or some type of movement like that. Or even with some patients, having equal reps on the leg extension machine for quad strength. And then finally, which has been a thread throughout this talk, is really from a person-centered care perspective. It's really making this about the patient-centered of their goals, what do they want to return to, and what's going to work for them. There's many times when I have patients that are, particularly adolescents, is that they might have different goals than what their parents are talking about. There's many, for example, if we have a soccer player or a basketball player or a football player, the parent might be saying, I really want them to return to the football team for next year. And then after you get into their talks with a teenager, they might be like, I actually don't really want to play football anymore. So I think it's really important to understand what are your patient's goals and help aligning this in an individualized strategy. And then also, what are we working for? In terms of this is really about, as PTOA is from the lifespan perspective, we need to think about this long after they go away from our care. Maintenance strategies, what is the maintenance exercise program you want them to maintain? How do we want to maintain that? That's going to look very differently for a 17-year-old versus a 45-year-old versus an 80-year-old. Different check-ins, sometimes this might be screening for their teams, this might be a strength and conditioning session, or it might be an actual full physical examination that happens annually or biannually. So finally, I want to sum up. Number one is that PTOA is really two different pieces. And if we think about from a patient-centered perspective, it's all about their symptoms and trying to relieve their symptoms. But we also have to consider the joint and disease burden and process over time to effectively manage and treat PTOA. And then finally, when we think about from a prevention standpoint, it's really about education, self-management, and the threat of person-centered, individualized strategies. And this is not just for our time of rehabilitation or within our care, but effectively having them be able to manage their prevention from a primary, secondary, tertiary perspective across the lifespan. And I think I hit that on the right time. And this is my contact information if you want to ever email me or whatever. So. Thank you. All right, team. We now have time for a Q&A. And I want to remind folks this session is being recorded. So please come up to the microphone here to ask your questions. I'll lead us off with a cute little ball here. Garrett, you had a picture at the end of what looked like a female contour from birth to cane. And in the middle section was high heels. Can you comment about how you advise folks, male, female, whatever gender, on high heels and their effect on the knee mechanics? Yes, so maybe that's better. Hear me good? OK. That high heels definitely. I think that that is actually, I've had patients from return to functional activities, like when are we going to use heels if they need to for their style or for their work life? And that- They can't hear you. Ah, is that better? Yeah. Yeah. Okay. And so, really a transition period, if we're going from a knee injury, say ACL surgery, of when are we going to use heels and how long are we going to use heels, and make sure that we have a sufficient calf flexibility, but also ankle dorsiflexion from a joint perspective. Oh, and Prakash? There is a study in, not in PTOA, but specifically in OA, where they actually looked at, so the knee adduction moment is something we talk about in physiatry a lot, and it is a marker of medial joint stress, and they actually found that a heel above 1.5 inches significantly increases the knee adduction moment, so there's more medial, so I don't tell patients that, but I do think that that would be too much, but I do think that heels are actually not great. And what is the average heel height on a cowboy boot? No, no. Anyone know? Not from Texas. 1.5. All right, so nothing above that. Nothing above a cowboy boot. Yeah. How's that? Good science here today. Centimeter, not inches. Was that a sentence? Inches. I said inches. Inches. Yeah. But a cowboy boot is- Would anyone else have any questions? Come on up to the mic, please. So at a practical level, so let's say we have a patient whose earlier arthritis, am I hearing we have them exercise at a level that is not painful? So we're thinking that that is contributing to the inflammation. So aquatic walking, I mean, things like that, where you're talking about decreased weight bearing. I mean, how can we actually use some of these things while we're waiting for all the research to come through? Thank you for the question. I don't know if I have an actual specific answer to that. A lot of that sort of period, as I was showing in the timeline, from one year out to five years out, the exact exercise that one should do during that period is unclear. We're doing a randomized clinical trial right now where we're comparing anti-gravity treadmill walking versus pool walking because it's more generalizable to the population. And we're trying to see not just does it improve pain, but what is the mechanism by which it might be doing that? Is there a change in muscular activation? So we're doing some EMG. Is there a change in biomarkers? And is there a change in the joint stress as well? So hopefully I'll have more of an answer at that clinical trial about a year in. And so far, anecdotally, patients really like it. At least that's what I'm hearing from my research system. But I think that that strategy could be a really good thing. The problem is what they do in their everyday life, I don't have as much control over. So that's still not exactly clear. But that's something that we're trying to study and get that. So I'm sorry I don't have a specific answer as yet to that. I'll extend that question a little bit, Garrett and Adam, if you'd like to answer. You know, it's a tricky dance. We're here to reduce pain. We inject this and shock that and try to get people feeling better. But they still may be 28 years old and want to do the Boston Marathon. And what should be our stance on that? What's the ethics of that, knowing what we know? What's our end point? And, you know, how do we advise folks on how to return to activity? Yeah, I think that's a great point, is that what I advise is really, and I talked about this a little bit in the talk, about trying to understand when your knee flares or when you're having, is trying to maintain or try to maintain through that period. I always argue that, you know, one of the things is if you're going through that post-acute phase is having physical activity through biking or water jogging or water walking or the anti-gravity treadmill. But then also at the same time, we really need to focus on a lot of the work that's come out of Brian Petra, Simona, UNC, is that having that gait pattern get optimally very quickly can really affect how the turnover of bone and how that actually affects PTOA in the long run. And what they've seen is that actually with the step, when they're on the involved side of trying to get that to be the correct amount of ground reaction force, that they actually light, they're under loading that strategy over time. Yeah, so along those lines, you know, if I have a, so if I have a runner, I mean, at the end of the day, they're going to do the sport they love to do. And the question is, how can we allow them to reach their goals and to mitigate disease progression? So, you know, again, we didn't really get into the whole load management piece. I mean, we do understand that there's a whole green, yellow, red zone, which can be applied for tendinopathy of keeping people's pain below five and ideally zero to two out of 10 for long-term management and rehabilitation. With arthritis, I mean, in general, synovitis is bad, right? Joint effusion is bad. I mean, some type of activity that's changing the mechanics of the knee over the time they're doing it, that's bad. So those would be like, for me, pretty clear times to say, look, your body is telling you, you're not ready to do this level of activity. There certainly is some evidence for gait retraining that we can at least target, try to improve the symmetry of how people move. We can try to reduce the loads through their joints. I mean, the former director of Spalding National Running Center was very into barefoot running. I don't take that absolute approach, but you can actually reduce rates of loading. You can change the distribution of forces through the hips and the knees to transition more loads through the foot and ankle complex by changing foot strike. But at the very least, looking at people's kinetics and kinematics and then trying to actually then use pain as a guide for the type of gait retraining you might do. It might be cadence, it might be trunk lean. There's so many different strategies. And I think at the end of the day, to an earlier question, until the research comes out, no, we have actionable items here. You got to go to physical therapy. You got to focus on lifestyle. You got to treat other conditions that might be affecting their pain. If you can't sleep, that's a problem. If you have heart disease, you should treat that along the way. You know, we should be thinking about the cognitive health of these individuals because if they're pain catastrophizing every day, well, that's also not going to exactly allow them to rehabilitate effectively or follow our treatment recommendations. It's just how much of this can we be really aggressive with, especially when there are things that are out of pocket like shockwave or platelet-rich plasma. And that's where I think the science would be really helpful for us to have more definitive answers, but at the same time to recognize those are more benign outside of the cost. We do have strategies. Talking about shockwave therapy, I wonder how much force is necessary. You know, there are these new massagers out there that a lot of people are grabbing. There's vibration techniques. There's TENS. You know, are you getting some force to make a difference, or do you really need a significant amount of force to get that decrease in the inflammation there? Right. So, again, from the standpoint of shockwave, I'm happy to nerd it out on this one. I mean, you know, what's the difference between a massage gun and a device that costs over $20,000? I mean, one has at least been looked at by the FDA, and the other is being marketed for, you know, giving yourself a massage. So I think really what we have to think about is I think you can take an all-of-the-above strategy. My general approach is to help patients understand the biological plausibility of what we're doing with shockwave and to think about, like, a massage gun might be very appropriate for treating myofascial pain. I think we have time for one more question. So this question is related to early management of ACL tears, knowing that often ACL repairs are several weeks after the injury, and you might have someone coming into your clinic with that large hemarthrosis, and you might be the first one to see them. Considering ACL tears are typically associated with hemarthrosis and the heme products from RBCs can cause chemical and oxidative damage to both cartilage and synovial tissue, do you guys have any thoughts on early aspiration of the hemarthrosis in an attempt to try to delay any post-traumatic knee osteoarthritis? It's a really great question. I mean, certainly that is, as you alluded to, I think the hemarthrosis is a big component of that abnormal inflammatory process, as well as some of that neovascularization that I also described, as well. So I think the early aspiration, personally, I think it's a really good strategy to consider if someone has a big hemarthrosis, I would certainly go forward with that. So yeah, I totally agree. Is that something you would do, as well? Yes. Well, I want to thank everyone on the panel. I think it's been wonderful this morning. I appreciate your effort. I also want to thank everyone who attended, both here and virtually. And please fill out the evaluations kindly and honestly, so we can plan for next year. Thank you, and have a good day.

post-traumatic arthritis

non-traumatic osteoarthritis

joint components

abnormal biomechanics

inflammation

biomarkers

synovial fluid viscosity

bone marrow lesions

cartilage stress test

individualized treatment

multidisciplinary approach