Okay. Good evening. Welcome to the National Fellow Online Lecture Series. Today is Wednesday, March 22, 2023, and we have the honor of having Dr. Shane Shapiro here to speak on orthobiologics. My name is Melody Rubish. Next week, our upcoming lecture is the Kinetic Chain and Biomechanics of Sport, which we have Dr. Brian Craback, who is excellent. Be sure to tune in for that. The Fellows Online Lecture Series serves as an adjunct to your individual program's educational programming. It should provide fellows with direct access to educational experiences with experienced AMSSM members and, at times, invited guest experts in a variety of formats. This should assist in your CAQ exam preparation. I don't have you guys yet with full screen. There we go. Please mute your device, the microphone, and turn off your video. Submit any questions through the chat function. That will include your name. If you want to include your program, I'm happy to add that. I, as the moderator, will ask questions during Q&A based on the questions that you submit. After the program, please complete the evaluation, which will be sent at the end of the lecture. If Dr. Shapiro has time and you want to stay on, we can have an informal chat afterwards. I believe he's in Florida, which is Eastern Standard Time, so we'll try to be respectful of his time. Dr. Shapiro did medical school at the University of Virginia School of Medicine, residency in family medicine, and fellowship at the Mayo Clinic in Florida. That is not the University of Virginia. That was his education. He currently works at Mayo Clinic Florida as the medical director of the Regenerative Medicine Therapeutics Program. He is the chair of the AMSSM Orthobiologic Subcommittee. The last year, we kept him. He stayed on, as you guys might have heard, for the Fundamentals Pre-Conference. He is currently the president of the Biologic Association, which is a free organization to join. If any of you are interested in learning more, I'm sure he will explain how you can join and get on those emails. They're very informative. For AMSSM, our annual conference, which is taking place in Phoenix, Arizona, April 28th through May 3rd, Dr. Shapiro is very involved, and we're lucky to have him. He's speaking on the main stage in session number three, so one of our first sessions on the treatment of non-inflammatory arthritis, and specifically updates on how to treat that. He's the co-chair of the Ultrasound and Orthobiologics Pre-Conference, so you'll see him running around. I think you're also speaking at the SMART workshop. Did I see, Shane? I've got a list. Somebody needs to have something that he can just make sure he's always charging his laptop, because it seems like he'll be presenting all the time. I could not find him on Instagram, and I am not on TikTok, so I don't know, but he is on Twitter. He joined January 2009. He has an impressive 885 followers, so maybe we can push him over the 900 mark after today. His most recent tweet is, of course, a retweet from AMSSM, as it should be, and I make an appearance, so we have proof of this. His first tweet that I found was from June 14th, 2010. I'm listening to The Funeral by Band of Horses, hashtag Pandora. On that note, we'll let Dr. Shapiro take over. All right. Thanks very much, Melody. Appreciate the opportunity to be here and also to the committee as well. I'm going to share my screen, and then we will get started with what I hope will truly just be an introduction to orthobiologics. I'm sure that all of us are coming at this novel field from various different levels of expertise, and that's just fine because I don't know that there are any real experts in the field of orthobiologics. This is a new field of medicine, a new subset of both orthopedics and sports medicine, and we all have a lot to learn together, so I hope to be able to help you guys out with that. The disclosures are minimal, but it is important to understand that much of what we do in the practice of orthobiologics is the practice of medicine and may represent off-label medical practice. We're going to talk about the current state of regenerative medicine for the musculoskeletal system. I'll do my best to talk about the first-generation therapies that we have in our toolkit at the moment. Since this is the fellows conference, let's see if we can find a way to apply it to relevant board questions, though that's always a tough thing to do when you're coming at such a novel topic, and then how we talk to our patients and make decisions for our practice. You guys will all be going out in practice in the very near future, and we want you to have all the latest up-to-date strategies for how we counsel patients on orthobiologics. The first thing that I always show, and anytime I'm speaking about orthobiologics, is this term regenerative medicine, which over the last 10 to 15 years has certainly grown, but also has some in the field running away from it. True definition is really just about using the body's own innate drugstore to heal human disease. That means using cells, tissues, organs, cell-derived therapies to treat human disease. This is a branch of translational research. Much of what we're talking about is still being studied, but very fast becoming a subspecialty of medicine that almost every field of medicine has explored some branch of regenerative medicine. It should be pointed out that this is a term used quite frequently by both the NIH and the FDA, as well as other elements of the federal government. I'm certainly trying not to run away from this term because it encompasses such a broad field and helps us communicate with one another. The demand for regenerative therapies is driven by the promise of novel technology. Early successes have demonstrated this potential to revolutionize healthcare, but the majority of emerging regenerative therapies remain translational in nature and many are not widely available. Unfortunately, because of this promise and demand, a predatory market has arisen. That's driving demand through unscientific promises that create unrealistic expectations for patients. If we go strictly to some of these conditions that we all see so frequently, we have a problem with unmet patient needs. Osteoarthritis is probably our biggest. We have an aging population. Some in our older generations are high demand. We have an obesity epidemic in this country and that has just led to a worsening problem with osteoarthritis. On the right here, you can see the upward trends of knee and hip arthroplasty utilization where around 2023, we expect to be doing 1 million knee replacements per year and probably over 500,000 hip replacements per year. Extrapolate that out to 2040 and we're over 3 million knees and 1 million hips. It's an extraordinary burden on our healthcare system. I don't need to convince you guys that arthritis is a serious disease. This is from the Osteoarthritis Research Society. These numbers have been updated. As of 2019, we're talking about 300 million people worldwide, 50 million Americans, and a stark increase over the last two to three decades. Part of the problem is that if you look at what the non-arthroplasty recommendations are for osteoarthritis, there really aren't that many. I think most of us are quite comfortable prescribing certain types of exercise and physical therapy. We know how to prescribe NSAIDs and counsel our patients on over-the-counters. Then the occasional steroid injection is the only other thing, major treatment recommended by these three major societies, the American Academy of Orthopedic Surgeons, the American College of Rheumatology, and the Osteoarthritis Research Society International. All these other things that we might commonly do in our practice when consensus panels has looked at these therapies, they can't make strong recommendations for them. That really leaves us without much of a toolkit to help our patients when they come to us for treatment with arthritis. We've labeled this the osteoarthritis treatment gap, whereby if you look on the left side of the screen, initial management for, say, someone who's in their 30s and 40s and has occasional knee pain, those recommendations of physical therapy and exercise, NSAIDs, and occasional injection, those are pretty good and they work reasonably well. Then over here on the right side of the screen, we have arthroplasty. Though growing, it is still a great treatment that works very well and enjoys a high success rate in the appropriate patient, most of which are elderly and lower demand patients. Over here in the middle in this treatment gap are patients in their middle ages who have prolonged periods of pain, knee stiffness, knee swelling, poor quality of life, and we don't have great treatment options for them to manage what can be up to two or three decades of their life, depending on when they contract this. Tendinopathy is a similar problem. Cases are increasing worldwide as well. Athletes are going to be at high risk, as are those with occupations that do repetitive loading of a tendon, and not everyone has a risk factor. You look at all these different diagnoses with tendons and then you add that to unmet patient needs with osteoarthritis, and you can see why we've landed where we've landed, and it's because we don't have great non-surgical treatment options, and in many cases, we don't have great surgical treatment options. That's where orthobiologics come in. Orthobiologics, I consider to be a subclass or subset of novel regenerative therapies. Definition is biologic substances intended to enhance the healing and alter the natural course of an orthopedic condition. The big three, as we call them, because they've got the most experience, the most safety data, and are the most available, include platelet-rich plasma, bone marrow aspirate concentrate, or BMAC, and microfragmented adipose tissue, or MFAT. We'll talk more about those. The original is platelet-rich plasma, and if you strictly want a definition, we're talking about a concentration of platelets that we create through density gradient centrifugation. Over here on the right, you see three layers of whole blood. This is the patient's own whole blood. You draw a certain volume of blood, you place it in a centrifuge, and then based on the density of the cellular pore plasma, the platelet-rich plasma, and then red blood cells, you can separate those three layers out through the centrifugation and then select the platelet-rich plasma level, which is rich in growth factors. We know from our medical school textbooks that the platelets initiate and regulate all phases of the healing cycle. This originally started in the late 90s with oral maxillofacial surgery, but very quickly found the orthopedic and sports community. Most of us who've been doing this a long time started around the turn of the century, but this newspaper article and the story surrounding the Super Bowl where the Pittsburgh Steelers played the Arizona Cardinals was really the spark to this flame because two injured Steelers had fairly significant ligamentous injuries that occurred during the AFC championship game, and we're going to keep them out of the Super Bowl expecting a six- to eight-week recovery. Both athletes were treated with platelet-rich plasma and returned to play in the Super Bowl just two weeks later. One of them won the MVP. When the New York Times got hold of that story, the next thing you know, every 85-year-old patient with a rotator cuff tear was in our office looking for platelet-rich plasma. These are those cycles of healing that I talk about. Inflammation is the earliest phase after an injury. The tendon or ligament will go through a phase of proliferation that involves different cytokines that get released from platelets, and then over time, usually weeks to months, we're talking about a maturation phase where a tendon or a ligament becomes strong enough to do its basic functions again and also stops hurting. What happens, especially in tendinopathy, is the injured tendon becomes stuck in an arrested phase of healing where it does not pass through the proliferation and maturation phases. For that reason, it can take years to sometimes resolve, if at all, and of course, continued degeneration can lead to frank tears. The idea behind platelet-rich plasma was to jumpstart the healing process again, essentially a start over where we were reinitiating an injury, sometimes using a needling technique or a tenotomy, and then adding the highly concentrated platelet-rich plasma and the growth factors that get released as a result to try and jumpstart the three phases of healing again. Now, you can look at all of these in vitro studies, and these are the main cytokines and growth factors that have been attributed to the therapeutic effect of platelet-rich plasma. This makes for a really nice graph here or figure and also helps us talk to one another about why we think platelet-rich plasma works, but the truth of the matter is we shouldn't be paying attention to this stuff at all because it's really all just theory. Every one of these cytokines and growth factors has been shown to be released by the platelets, and even in some in vivo animal models, we can find some therapeutic mechanism of action that utilizes these cytokines. Unfortunately, none of this has ever been proven in human tissues, so when we talk about regenerating a tendon or possibly treating osteoarthritis with PRP, we don't know that any of these growth factors are actually involved in that therapeutic cascade. So, it's a real problem for orthobiologics and one that has slowed us down in terms of progress because much of the research in the orthopedic and sports medicine space has hung its hat on this as the therapeutic mechanism of action. It's really never been proven. So, platelet-rich plasma usually administered under ultrasound guidance, so definitely be practicing your ultrasound injection techniques. We're usually numbing up the tissue around the area of pathology and not so much putting lidocaine into the tendinopathic portion of the tendon. As I mentioned, there is a needle tenotomy in many cases with this, and then we inject the platelets into the torn portion of the tendon. There is an abundance of literature showing some structural resolution of tendons after they've been treated with PRP, but there's an equal abundance of literature showing no structural improvement after PRP, and so we still have a lot of heterogeneity in our scientific findings. Very early trials struggled, probably because of low numbers, low subject numbers, to demonstrate a therapeutic effect of PRP when it comes to treating tendinopathy. As we started getting more and more studies with more and more participants, high-quality meta-analyses have been able to demonstrate superiority of platelet-rich plasma over almost every comparator. If you compare PRP to, say, corticosteroid or saline placebo injection, local anesthetic placebo, some therapeutic treatments like dry needling, physical therapy, or extracorporeal shockwave therapy, we're able to see through meta-analyses that there is a meaningful clinically important difference supported over controls in almost every one of those cases. There's some early evidence that PRP might help rotator cuffs heal this is both as an adjunct to surgery and with PRP alone. We're not talking about full thickness rotator cuff tears because you really can't keep the liquid PRP in the torn rotator cuff long enough for it to really matter. But for partial thickness tears randomized controlled trials and meta analyses are looking pretty good. And then also as an adjunct to surgery we now have meta analyses, showing decreased rates of incomplete healing decrease pain levels in the post operative period and improved functional outcomes so you will see a lot of orthopedic surgeons. As you guys go out into practice you'll see a lot of orthopedic surgeons offering PRP as an adjunct to surgery right now. I'm not sure it should be considered anything near the standard of care, just yet, but it is very commonplace in practice based on the latest literature. So what about that arthritic problem that I talked about well in this particular situation PRP really shines, we have somewhere at this point between 30 and 40 randomized controlled trials, not all of them are positive. There are certainly some randomized control trials that do not show an effect, a beneficial effect of PRP to treat knee arthritis. But when you look at the sum total of these well well conducted randomized control trials, you get to numbers that are in the thousands and meta analyses show the effect of platelet concentrates go beyond the mere placebo effect, and that PRP injections provide better results than almost any other injectable option. If you compare the longevity, the PRP outpaces, both corticosteroid and hyaluronic acid also so might find them just equal to those other injectables in the short term. However, in the long term, they outperform. However, the improvement remains partial. And what that means is we're not curing anybody's arthritis with PRP. This is simply medical management this is treatment, and like, like any treatment. It will require repeat treatment over the years, depending on how patients do with their symptoms and their quality of life. At least one of those meta analyses and there have been several now has been accompanied by calls in pretty high level journals in the orthopedic community that the time has come for platelet rich plasma to be part of the toolkit, when it comes to the non management of knee arthritis, and recent publication by the American Orthopedic Society for sports medicine has shown that between 60 and 70% of their members offer PRP as part of their routine medical practice, and 70% of those physicians are increasing their use of PRP. Unfortunately, not all PRP is equal, and there are somewhere between 40 and 50 platelet concentrating systems on the market and the reason for that is it's very easy for companies to get approval. predicate device and so if you have a centrifuge, and a kit that can separate platelets from whole blood. You can demonstrate your substantial equivalence to the FDA and then they will clear that device under the 510 K system. And what that has led to over the past 20 years or so is a multiplication of multiple different systems, and every one of these systems will have variability from patient to patient, and even within the same patient and so this has led to a huge problem when it has come to platelet rich plasma clinical trials because we cannot standardize the preparation very well, and we cannot standardize the product that these systems will put out. So when you're treating patients in a trial. Most patients are being treated with a different therapeutic agent PRP as a procedure can be very standardized but PRP as the product is very hard to standardize, and that is what has led to a lot of the variability and outcomes across orthopedics and sports medicine. One of those preparation differences that you may have heard about is Lucas site, rich platelet rich plasma versus Lucas site, or and this refers to taking out some of the white blood cells before before when you're making the platelet rich plasma before you do the injection. There had been some early studies with meta analyses that showed Lucas site poor PRP may have been better for joints and Lucas site rich PRP may have been better for tendons. There's a little bit of theoretical sense based on what I told you before, whereby, with tendinopathy we're trying to jumpstart the healing again by actually promoting inflammation. When, with respect to osteoarthritis we want to do the exact opposite because osteoarthritis is usually too much inflammation in the joint. Now the study in the American Journal of Sports Medicine. Someone has debunked that and if you looked at weekly injections in nearly 200 patients, they really all did well and there was no significant differences between Lucas site rich or Lucas site for, and just anecdotally in my practice I see about the same thing until we're able to standardize the output of PRP, we really should not be advocating for therapeutic mechanisms of action that we don't entirely understand. Platelet rich plasma and then about 10 years or so ago, number of us tried to pivot to a product that is made very similarly to platelet rich plasma and that's bone marrow aspirate concentrate be Mac as we call it very similar to PRP is manufactured by density gradient centrifugation so again we're separating a liquid fractionation into three different layers. The difference between PRP and be Mac is when you're aspirating from the bone marrow as opposed to venipuncture whole blood, you're getting a different originally felt to be rich with stem cells that was sort of the theoretical origins of the be Mac product, but in reality what we've learned later on some 10 years later is there's really not that much in the way of stem cells within the bone marrow or at least you can't harvest enough of them. And so it is much more likely that something in the mixture of the Mac the bone marrow. It also has cytokines and chemists of kinds like PRP may have a different therapeutic profile, possibly more anti inflammatory possibly more immunomodulatory all of that is still yet to be proven, but we have started trialing these more cellular therapies in clinical trials. The first series was largely related to be Mac for early stage hip necrosis a vascular necrosis is a debilitating condition of young people, many of whom have been exposed to high dose steroids, and it can lead to collapse of the joint of the hip joint requiring hip replacement at a very young age so anything that we can do to arrest the collapse before that happens is incredibly valuable and so be Mac has been used for this for over 20 years, and the, the outcomes are really quite good in terms of how we do this and how we apply it into an area of a basket and process. So on the right you see how we harvest bone marrow, I usually do this from both sides, patients can be awake or asleep. There's a number of different techniques out there that you can harvest bone marrow. have been tested scientifically in the literature, and, and then you just take your bone marrow you filter it and you centrifuge it down much in the same way as you make PRP, and what comes out as a very concentrated cellular product that like the PRP can be injected into an area of therapeutic need. So here's the ABM that I that I mentioned. This is a study out of Mayo Clinic in Rochester patients did very very well with this and continue to do well this study is now five or six years old and patients are essentially cured, and can avoid hip replacement that's really profound. So it only made sense that we would try this for that problem that afflicts 50 million Americans osteoarthritis and so this is a study that we launched back in 2011, and tried to compare this to placebo control, using patients as their own placebo control so one arthritic knee gets BMAC and one arthritic knee gets saline. We did pre and post MRI imaging and we did a full product characterization with flows cytometry, all of this under the watchful eye of the FDA. And what we found was a little bit surprising because our patients did very very well, all the way out to 12 years old so many of my patients I've continued to see at year two and year five and, and some of them are still doing great, with very limited pain but unfortunately the placebo need did quite well. We struggled to explain that at the time but what we now know, many years later is that the injection of a non harmful substance into the knee something like saline is always going to produce short term relief as well. So we would perhaps take an arthritic knee in a, in a younger healthy active patient these are middle aged patients that we are mostly treating, and then they get to go back to their life because one or both of their knees is feeling better they're going to be more active they're going to start doing that exercise again they're going to rely less on and says, and overall people do quite well. Unfortunately, not well enough to demonstrate that we could regrow cartilage in the knee, this is that quantitative T to MRI mapping that we did and we did not see any statistical significant regrowth and cartilage so many of our patients are coming for stem cell therapies as they will call them and many of us will call them stem cell therapies. I'll mention the accuracy of that in a little bit, but we should be discouraging our patients from from thinking that this is somehow a cure for osteoarthritis because it's not. At the same time, there's been a second be mapped randomized control trial up against hyaluronic acid, not placebo, and the result the group in Italy, who studies and utilizes a lot of orthobiologic agents, they, they conduct very rigorous clinical trials and they were unable to demonstrate significant clinical difference as well. That might lead you to think adipose tissue could be better and there are ways as I mentioned micro fragmented adipose tissue there's ways that you can concentrate adipose harvested from liposuction in much the same way we've we've done with bone marrow and that's another one of these fancy new treatments that patients will come in and ask us about. To date, it's still early. There have not been many placebo controlled trials to look at micro fragmented adipose tissue. However, can Mountner has done a very nice retrospective review of his patients treated with either M fat or B Mac, and found the outcomes to be good at 12 months with no significant difference between between either of those and so I think that has led many of us, myself and the authors here am SSM members included, looking for ways to counsel our patients and making sure that we don't try to encourage orthobiologics over the standard of care or even orthobiologics or one orthobiologic over another. Let's talk about some of the perinatal products that are out there. I think there was more rampant use of this, three, four or five years ago, some of that has been reined in due to some regulatory enforcement by the FDA. We call them perinatal products because most of them are sourced from either some form of dehydrated amniotic tissue or umbilical cord blood, all of them were marketed for a period of time under the premise that they contain stem cells. It's complicated but certainly none of the dehydrated non living tissues created from amnion could possibly have stem cells in them that's just not scientifically possible. And then when it comes to umbilical cord blood. No license that has ever been given by the FDA to use this in an orthopedic indication. And if you don't expand cord blood in a lab, so the so called culture expansion, you're talking about the same number of cells that you would have in BMAC or perhaps MFAT anyway so the safety and the legality does not warrant using these products in our patients at the current time. The FDA has gone to great lengths to clarify this that no stem cell product or exosome product as those were sometimes being marketed have ever been approved for treatment of any orthopedic condition like arthritis or tendinitis and so there's this controversy over what is a mesenchymal stem cell, what is a stem cell, how much stem nest do they have and there are scientists and and very large scientific societies that have devoted their entire careers to studying these various populations of cells that all have this unclear potential unclear biological function and I think many professional organizations are still on the hunt for what it is that a stem cell can actually do across multiple organ systems, not just in orthopedics and sports medicine. So this hasn't stopped. Less well meaning individuals, hopefully not AMS system members out there for selling stem cell and regenerative interventions, a lot of research by our bioethics colleagues, looking into this marketing cell therapies as you can see on the left side orthopedics and sports. Those are the top three and cover more than 60% of all the businesses that are out there marketing, a number of unlicensed therapies that that have not been approved. So we see this in our practice and if you guys are working in this space also you know that patients will come in with their arthritis and their tendinitis and they'll ask you about stem cell treatments so my group surveyed 533 patients and we asked why, why is it that you're looking for a stem cell therapy for your particular condition. And what we learned was really interesting. The number one cause that people walk through the door, especially for arthritis is to to regrow cartilage that's what they think the stem cells can do and, of course, as I, as I showed you that's that's not the case yet. They may have a medical contraindications some people will say nothing else worked or they were recommended by a friend and family so they there's all these reasons why why patients come in, looking for these treatments but not all of them are valid reasons to have an orthobiologic therapy so we've labeled this stem cell tourism, and most of the patients that are stem cell tourists will have contacted multiple providers, a lot of times, just asking how much something costs. In many cases patients don't understand the therapeutic mechanism of a cell therapy and that's because we don't entirely understand the therapeutic mechanism of action. So that makes it incredibly difficult to counsel patients. How do you consent, a patient for procedure. If you can't explain to them how that procedure is supposed to work. So I'm going to conclude here with what am SSM has tried to do about what we call responsible translation of regenerative therapies and sports medicine so orthobiologics and sports medicine, how do we use them, how do we counsel our patients, and we have a census paper that we've written and published in the Clinical Journal of Sports Medicine highlights of that paper and a different figure were published in the British Journal of Sports Medicine and it would take me too long to read you all the pieces but the idea is that it's complex, and we're trying to treat our patients unmet needs we're trying to help the patients that need improvement in the quality of life, but there's all sorts of practice considerations that go into manufacturing orthobiologics or delivering orthobiologics, the terminology and standardization is still an issue as I mentioned, informed consent is very difficult. We don't necessarily have all the science and therapeutic mechanisms of action worked out, and so that's why we just have a lot more work to do. So, what does that mean? Well, in my opinion, the current crop of first-generation orthobiologics treatments, they're good, but they may not necessarily be great, and they leave much to be desired, with the exception of things like the avascular necrosis that I showed you. There's no clear evidence that we're regenerating cartilage. Nevertheless, it's still reasonable to use orthobiologics to treat pain. Certainly, an option for those patients that are stuck in that treatment gap, and if we're going to do that, informed consent, patient education, and managing expectations is very important. This figure was in the AMSSM issue of the BJSM, and talks about our tiered approach to how we go about counseling patients regarding their orthobiologic options, and really, in an area where you don't have all the answers, combining very valuable factors, such as a clinician's expertise, but also the patient's values and the patient's preference, goes a long way in helping patients decide what their best treatment options are. I think it's very important when you go out into practice to make sure that the patients understand everything that you've discussed. It may be worthwhile, in addition to just a signature on a consent form, actually getting additional signatures that the patients understand you've told them these treatments are not going to regrow cartilage in their knee. We're not going to be curing arthritis, because we've looked at this. Many patients still can't quite understand the science, even when we do our best to explain it to them. So, I'll finish, since this is supposed to be somewhat board prep, I'll finish with this, which I somewhat adapted from a board question I had a number of years ago, but you got a 55-year-old avid pickleball player, comes to sports medicine clinic, eight weeks of right lateral elbow pain, so we're past the acute phase into the kind of subacute chronic phase, tenderness along the lateral epicondyle and common extensor tendon, so this is lateral epicondylitis, and we have patients already tried some ibuprofen and worn one of those elbow compression braces and had five weeks of physical therapy, and they come in and say, doc, what should I do next? So, more physical therapy, certainly sounds reasonable, prescription-strength NSAIDs, I'm not sure that we should really be doing that after eight weeks of symptoms, two platelet-rich plasma injections, many of us will offer patients platelet-rich plasma, sure, and extracorporal shockwave therapy that's growing in use also for tendonopathies, and there's a lot of good research behind it, but the answer, I believe, actually is none of the above, and the reason for that and the board pearl for you guys is that, in my experience, the CAQ test and the boards really don't like making novel therapies that don't have enough evidence base or don't have enough recommendation strength, strength of recommendation yet, that can't be the right answer, and so if you're seeing PRP on a standardized test right now, it's likely that that is not the correct answer. So, I will stop there, and I see we've got some good questions in the chat, and I'm going to let our moderator, Melody, fire away at that. Thank you all for attending, and thank you for your attention. That was a great, great lecture. Thank you so much for putting that together. It looks like a lot of the questions are pretty specific. People are wondering how to apply this to patients, and Andy put a link to the AMSSM position statement on principles for the responsible use of regenerative medicine and sports medicine, and Dr. Shapira, I know that you were involved with that, so that's a good one to put in if you guys want to take a look at that and follow the link. One of the questions that I think we should start with is your post-procedure protocol, tendon versus joint, when do you restart PT, offloading for a period of time, how long you tell them to hold out of activity. Could you just go through a little bit of what you recommend, and while you're doing that, could you also mention if you talk about multiple injections with patients? Yeah, and I think the first thing to recognize when we're talking about all orthobiologics is that I showed you a lot of those level one trials that are investigating products. We don't have enough level one trials. We don't have enough level one evidence, and in most cases, we don't have strength of evidence when it comes to the post-injection and post-treatment protocols. That's number one. Number two is that many of our patients have extraordinary life circumstances like weddings and cruises or vacations to Disney, pickleball tournaments, golf tournaments, things like that. Because this isn't an ACL reconstruction where you know some of these things are destined to fail if you don't go about the post-protocol period the right way, I try not to be very dogmatic. The one thing I do with every patient is discuss that we consider these treatments, or at least I consider these treatments drugs, and it's a drug that we are trying to provoke a therapeutic response, and if you don't give the product an opportunity to provoke that therapeutic response, it is less likely that you will get that response. Likewise, we know that tendons do not heal in one day, in one week, or even really in one month, and so we really do need to partner with our patients on the post-rehab protocols. I make them very individualized. If there is a patient who has lateral epicondylitis and has already had 12 weeks of physical therapy, I'm not necessarily going to send that patient back to physical therapy after I give them PRP. I really think that from an exercise perspective, we've probably maxed out there, but I don't want to send them back to sport either, and so I talk about a gradual return to sport. I will often brace patients. If, say, it's an elbow, I'm bracing their wrist. I don't want them doing wrist extension and wrist flexion repetitively over the next couple of weeks, and so for me, it's a two- to three-week period of relative rest. What that means is going to differ from patient to patient. There may be some splinting involved during that two- to three-week period, and then I want to gradually have them go back to regular activity and gradually go back to sport, and if there is a deficiency that I think could benefit from physical therapy, I'm absolutely going to encourage physical therapy, so that's a long-winded non-answer, but it is based on the lack of evidence to support any specific therapeutic regimens. And there was a question about tips on choosing PRP preparations. So many systems you mentioned are out on the market, and tips on when to perform tenotomy with PRP versus PRP in minimal infiltration. Yeah, that's a great question, so I'm going to start with the easiest one. I think when we have tendinopathy, the evidence would still support using tenotomy, and that comes, in my opinion, from well-designed trials of tenotomy before PRP existed. So we know that in a tendinopathic tendon, for the conditions like lateral epicondylitis or maybe like the rotator cuff that has shown some benefit of PRP, I'm doing a light tenotomy with that. Now, if my ultrasound or my MRI shows high-grade tearing, then I'm absolutely not doing tenotomy. And so if you look at some of these tendons are actually quite thin, and if you have a 75% tear, my needle is not going to be completing that tear. And in those situations, I'm trying to keep the platelet rich plasma localized to the torn portions and then maybe dotted around the unhealthy areas of the tendon, but I'm certainly not doing tenotomy there. So that's the second part of that question. The first part of the question is much harder to answer. I don't think we've demonstrated superiority yet of any one particular platelet manufacturing system. I would encourage fellows and interested practitioners to go to the literature and look at the positive versus the negative trials. It definitely, especially in more recent, the last two years, the more negative trials have tended to use lower platelet count outputs. And so if you start with a larger volume of blood and then you're concentrating well, you will most likely have a higher dose of platelets. And if you start with a smaller volume of blood and you do less of a concentration, you will have a lower dose of platelets. Again, think of this as a drug and a drug dose, and we have not proven yet that one is superior to the other, but we're definitely looking at that. And myself and some colleagues in the AMSSM are currently doing statistical analysis in those studies to try and combine them in a meta-analysis and see if we can tease out dosing requirements. But it's a little bit unproven, but many of us anecdotally think more is better, at least to a point. Speaking of drugs, could you discuss a little bit how you explain to patients your use of anti-inflammatories or non-use of them and steroids and what your timeline is to try to avoid the use of that pre and post? Yeah. And so, you know, normally when we're going towards an orthobiologic product, it's because the standard of care hasn't worked. Most patients have already trialed NSAIDs. Many patients have already had a steroid injection for certain conditions. So I definitely don't want the patients utilizing those therapies in the sort of periprocedural period when it comes to an orthobiologic. For one, we don't really know how they interact very well. In most cases, when it's been studied, there are a couple studies out there looking at NSAIDs around PRP and have shown it to not be detrimental to the function of the platelets. But in reality, we just don't know how they interact. If the NSAID was working, the patient wouldn't need platelet-rich plasma. If the cortisone shot was working, the patient probably wouldn't need PRP. And so I try to avoid them. And of course, if the PRP is effective and if in that two to three week post-procedural period, the patients are doing what we ask them to do, in most cases, my patients don't need any other adjunct therapy. There is, of course, some discomfort at times when you're dealing with tendons, not so much joints. I find the PRP in a joint to be very well tolerated and patients really shouldn't need rescue medication in attendance sometimes. And so we'll look at a short course of a light narcotic, trying getting them to use Tylenol if we can, trying to avoid the NSAID. But we're not torturing patients either. So you have to have a little bit of flexibility. And there was a question about ultrasound. Do you look at it before you do the procedure? Does that change what you recommend for leukocyte-poor versus leukocyte-rich or other orthobiologics? And then how do you monitor it after the procedure? Yeah. So certainly for joints, I'm not really using ultrasound to do anything other than see my effusion and guide my needle. But absolutely, when it comes to tendinopathy, the ultrasound, as most of you guys know, is such a powerful tool. I do collect several pre-procedural pictures of areas of tendinopathy that I want to focus on. I capture the needle in those areas. I think it's very good positive feedback for the patient that we're treating the unhealthy areas of tendon. And then when patients come back, I am re-imaging that particular tendon with ultrasound. But I counsel patients beforehand, at the time of procedure, that the evidence does not support structural change in all patients. And so Mayo in Rochester, John Finoff and others, Jay Smith did a great job of showing this a number of years ago across a wide swath of tendinopathies, that many patients who got a whole lot better, their ultrasound images did not improve, and many patients whose ultrasound images improved still had symptoms. So we haven't entirely worked that out just yet. And as long as you're being honest with the patient, I think it's a very good tool to use to help you guide treatment. Thank you. Somebody asked about the, what are some emerging avenues in orthobiologic research? What do you think there's more work to do like standardizing therapies, potential therapy augmentation, exosomes? Yeah, that's a great question. And my hobby horse is all about dosing and therapeutic mechanism of action. So every one of these procedures that I described for you has been allowed to sort of perpetuate in orthopedic and sports medicine practice, because they're considered procedures. And as we know from ourselves and our surgical colleagues, a lot of people will do a lot of different procedures differently. And if you don't have standardization, it becomes harder to study. And so the next set of studies that really need to be conducted need to go back to the lab so we can say, what is the appropriate therapeutic dose of PRP? How often should we give that dose? Same thing for BMAC. What is actually in BMAC? What is the therapeutic cytokine that helps relieve knee pain in osteoarthritis or promote bony regeneration and avascular necrosis? These are things that we don't know. And it's affecting our ability to validate these therapies in other areas of medicine, get FDA approval, get insurance coverage. Those are all things that we lack in orthobiologics right now. And it's because the translation of the therapies into routine practice has proceeded more like a procedure than an actual drug product. Okay, I have one last question. Just a quick question about your preferred local anesthetic and its concentration, diluted versus standard, since you mentioned trying to avoid too much anesthetic, but also needing to infiltrate the needle track. Yeah, right. So first of all, for joints, that's super easy, because you can anesthetize everything outside the joint that you want. Get that lateral retinaculum in the capsule nice and numb. I use 1% lidocaine without epinephrine, raise a very nice skin wheel, and then just layer that on the outside, the superficial and subcutaneous tissues, and try not to touch the joint with lidocaine. And you really don't need it. Once that area is numb, and you aspirate the effusion and put PRP in there, 95% or greater of patients will not have pain related to that procedure. There are about 5% of people that will get a little bit of a flare. And whether that comes from residual white blood cells that are in the PRP or not, I don't think we really know. But that can usually be managed in the same way that you would get a steroid flare in the same 5% of patients. When it comes to tendons, that's a little bit harder, because tendons do hurt when you're doing a tenotomy. And even if you're not doing a tenotomy, PRP inside an area of torn tendon tends to be quite painful. So I still use lidocaine 1% without epinephrine. I just try and stay away from my therapeutic target. And what I try to do is get the healthier portions of the tendon nice and numb. If I'm doing a rotator cuff, we're going to anesthetize the deltoid. I'll slip a little bit of lidocaine into the bursa. And then just constant communication with the patient while we're doing the procedure. How well are they tolerating it? If it's not hurting them at all, I don't use any lidocaine at all. If they've got discomfort, I'm going to try and layer the lidocaine in. And you can see the lidocaine move under ultrasound guidance. You can see where it goes. And if you just keep it away your tear and your tendinopathy, then there's essentially more room for the PRP. That's how I tend to do it. And it's worked reasonably well for me. Thank you. So I think that was great. For those of you still on, if you can go into the chat, Andy posted a short feedback survey, which is really helpful for the subcommittee that puts these together. We always want to make sure we're meeting the needs of our membership. And if something is really helpful, we want to try to do more like that. And of course, Dr. Shapiro always gives a great talk. And that was really wonderful of an overview, but also specific things for people to use when they're in their own practices. And Robbie just posted about a helpful paper regarding local anesthetics and platelet function, which it has a link in the chat. Eliza, so you can watch it. Okay. I think we can call that unless there's anything else you'd like to say, Dr. Shapiro. No, thank you again for having me.

3rd Edition, CASE 13

3rd Edition

Elbow and Forearm

orthobiologics

regenerative medicine

osteoarthritis

tendinopathy

platelet-rich plasma

bone marrow aspirate concentrate

microfragmented adipose tissue

stem cell treatments

AMSSM