Thank you very much for being here, guys. Okay, Rachel, come on up. All right, well, thank you, Dr. Cole and Dr. Dragoo, and it's an honor for me to be up here and helping contribute to this course and its development. We're very excited that you're all here, and we appreciate you taking time out of your clinical schedules, out of your family, and out of your life to be here for the next couple days. And we, of course, appreciate the support of AOSSM and the ON Network, and this is a very exciting time in orthopedics, and so thank you, and again, it's my honor to be up here. We'll start today's talk with an introduction about orthobiologics, kind of looking at it from 30,000 feet, what are they, what do they mean, and then we'll get into a lot of the nitty gritty with our excellent panel of faculty members. I have no disclosures relevant to any of this. So biologics, these are, it's the hottest topic in orthopedic surgery, and it's really the hottest topic in medicine right now. If you look in the news, if you look in media, if you look in PubMed and look anywhere, you're gonna see things on biologics and stem cells and PRP, not just for orthopedic applications, but for many applications within the entire field of medicine. So this is a very exciting time, and with that comes a lot of discovery and research. What can orthobiologics treat? Well, in our world, they treat injuries or pathologies to tendons, ligament, bone, articular cartilage, and meniscus. And some of the more common applications in our practices include tendinopathies, osteoarthritis, and focal cartilage defects, but these are just three of many areas of application for orthobiologics. As an example, the role of biologics in the development of chondrosis or osteoarthritis is all of these things, disease modification, trying to prevent cartilage damage, trying to augment the nonsurgical treatment of arthritis, using biologics as an adjunct to surgical interventions, or using biologics as the surgical intervention. And we wanna prevent that injury that we see on our top, which is a classic ACL mechanism, from becoming an arthritic knee at the age of 30 to 40. And that's where orthobiologics may have a huge role. We need something for that tweener, and this is a slide I borrowed from Andreas Gamal. This patient right here is young, but too far for cartilage restoration or joint preservation, and likely too young for arthroplasty. So we need something, some intervention for that in-between patient or the tweener. And again, this is where orthobiologics has a significant role in our practice. What is the problem? The general problem with everything that we see with regard to tendon, ligament, bone, cartilage, meniscus pathologies, is inflammation. What are our treatment options short of surgery? Well, we have steroids. They're effective, but they have limited duration, and they add up over time. Hyaluronic acid, controversial, not always covered by insurance, but it does have some anti-inflammatory properties, and we wonder if it has a longer duration of efficacy compared to steroid. And then biologics, PRP, stem cells, and other biologics. That's the new frontier, and the whole goal is to stop this cycle of inflammation. What's allowed in the United States? Well, we're gonna get into this more in some of the next talks. But essentially, these products have to be minimally manipulated, and they cannot be more than minimally manipulated, and they can only be for homologous use. What's not allowed? All of the things that you see here, culturing cells, taking cells out of the OR and clinic, sorting cells, adding factors, and adding enzymes to aid in harvest. And so, that's where we're at with biologics. What's this 30,000 foot view? I like to keep things very simple. We have patients who have an injury. At that site of injury, we get growth factors, and then ideally, we get some sort of repair mechanism, and our goal with biologics is to better understand how to manipulate the growth factors and create a better biologic environment to help repair and healing. Growth factors can be both good and bad, and the goal of orthobiologics is to manipulate intrinsic growth factors already present in the body, turn up the good, and turn down the bad, and we're gonna hear more about the specific growth factors with some of our additional lectures coming up. What are orthobiologics in general? They're bioactive, anabolic, and anti-catabolic molecules that modify the arthritic or regenerative process, and the common agents are the ones that you see here, including visco-supplementation, PRP, and stem cells, which can come from a variety of sources, including bone marrow, adipose, amniotic sources, peripheral blood, and synovial sources. A quick word on visco-supplementation. We know that this is a product that's thought to lubricate the joint, hyaluronic acid. Insurance coverage is changing, seemingly, at least in Colorado now, by the day, and there's mixed results in the literature depending on the indication. Probably minimal risk, other than some inflammatory reactions, but unclear reward, particularly over the long term, and particularly with regard to changing the biologic environment of the joint. What about PRP? Well, we'll hear about this from some of the world's experts coming up in the next few lectures, but PRP is platelet-rich plasma, and we can manipulate this based on the way that we spin the product into having any number of different concentrations of platelets, white blood cells, red blood cells, and we use that manipulation to our advantage depending on the indication that we're using the product for. Platelets have a normal biological role in tissue healing, and they form a clot, as we all know, in the response to an injury. Growth factors are present within the proteins found in those platelets, and PRP offers a high concentration of platelets to help us heal injured areas. With regard to cartilage and osteoarthritis specifically, PRP is thought to modulate repair and regeneration of damaged cartilage by bringing those growth factors into play, and delay the degeneration of cartilage by stimulation of mesenchymal stem cell migration, proliferation, and differentiation, and overall decrease inflammation, which is, I think, what we see in many of our patients, particularly at the first six weeks or so after treatment. Does PRP work? Well, if you do a PubMed search, and this is as of about three hours ago, there's over 10,000 hits when you look at PRP in PubMed, and then when you look at Google, there's 20 million hits, and again, that's as of today. I did this same search about one month ago. There was about half the number of hits, so this is growing by the day exponentially in terms of the information that's out there, and the bottom line is we don't know if it works because there's so much data, and a lot of the data's confusing. That's the whole purpose of this course. There's many different PRP formulations that leads to confusion. We have leukocyte-rich PRP for certain applications, leukocyte-poor PRP for other applications, and a lot of the literature that we have, including the systematic reviews and meta-analyses, confuse these preparations, making the results very unclear and not able to be relied upon. PRP interop and postop is starting to show some early promise, and so the bottom line is, and we'll hear again from some experts, PRP's promising, but we have to extrapolate the literature very, very carefully to our patients. What about stem cells? Well, stem cells are very, very fascinating, and we have the dream that's promised by a lot of people with regard to stem cells, and then we have reality in terms of what actually happens when we get stem cells implanted. This is very popular in Colorado. This is an area of stem cell implantation in Colorado, where if you look on their webpage, and these are just some screenshots, and I have patients coming to me, literally every single clinic, asking about this product, if I provide it, and what it does, and if you look on their website, this is the information our patients are getting. ACL surgery has its issues. First, the graph goes in at a steeper angle than the original ACL. I'm not sure about that. Causing more compression of the cartilage. Again, not sure about that. For this reason, most young adults who get surgery will end up with arthritis by age 30. This is what our patients are seeing when they Google stem cells, and this is what they're coming to our office asking about, and this is what we need to understand as providers to better educate both our patients and our colleagues about the benefits of stem cells, and potentially the inability of stem cells to do certain things like heal a completely severed ACL. So that's the purpose of this course, is to better understand what stem cells do. The goal of stem cells, again, from the 30,000 foot view, is to recruit other stem cells to the area of injury, secrete bioactive factors, and help with local modulation of the joint or tissue. There's a lot of different stem cells out there, and the terminology is really, really important. We can talk about pluripotent stem cells as well as adult stem cells, and that's what we focus on in the orthopedic world. And then adult stem cells can be autologous, meaning from ourselves, or allogeneic, meaning from a donor. And then there's a variety of sources, including bone marrow, adipose, placental tissues, amniotic fluid, synovium, and peripheral blood. Common sources of stem cells that we often hear about and we'll see throughout the day today as well as in our lab portion include those mesenchymal stem cells from bone marrow and adipose, and we often get our bone marrow stem cells from the iliac crest or other areas, which I'll show in just a minute, or from adipose, and we can take them from the flank, the hip, or other areas, and I'll show that in just a minute, and then spin those down and get them into the site of injury. With regard to bone marrow-derived stem cells, we have to be careful with terminology. Not all bone marrow-derived stem cells can be referred to as BMAC. BMAC is aspirated concentrated stem cells, and that's when we take the bone marrow, we put it into a centrifuge machine, and we actually concentrate it down. Some studies just talk about BMAC, but other studies talk about bone marrow-derived stem cells, and we have to be very careful with our terminology because those are two different things with two different concentrations of stem cells. BMAC or bone marrow can be harvested from the iliac crest, the proximal tibia, the distal femur, the proximal humerus, and the calcaneus, and then we typically centrifuge this product to concentrate the mesenchymal stem cells. It's easy to do. You get a large cell yield, but there is some cost to this as well as potential for donor site morbidity. There's many different areas to harvest these cells, and we'll see a lot of these in the lab. In terms of harvest pools, or harvest pearls, there's no data currently to support or prove a superior harvest site with regard to BMAC. Most companies recommend that you harvest between 40 and 180 cc's of the bone marrow aspirate, and ideally at least greater than 60 cc's, and then you put that into your system of choice based on the company that you're using, and then you can formulate what product you end up wanting to get based on the pathology that you're treating. With regard to picking a harvest site, it's interesting. When we do a lot of different surgeries, such as rotator cuff surgery, it may be advantageous not to take cells out of the hip or out of the tibia, it may be advantageous to take cells out of the humerus because you're there anyway, but are those cells out of the humerus any better or any different from the cells that you might get out of the hip, or out of the tibia, or out of the calcaneus? The bottom line is this has been studied in a lot of different studies in terms of looking at different sources for bone marrow aspirate, and what the take-home point is is that the posterior iliac crest is probably better than the anterior iliac crest with regard to cell yield. However, you have to consider the pros and cons of your room setup, time in the room, and difficulty positioning the patient, and that most of the sites, at least according to the literature we have, probably have enough of the stem cell product that you need to be effective for what you're trying to do. With regard to adipose-derived stem cells, we'll talk about this again in more detail with some of our further lectures, but these are basically coming from lipoaspirate, not technically liposuction, from the abdomen, the flank, the thigh, or arthroscopically from the infrapatellar fat pad, and we'll hear more about that technique, and then it's mechanically processed to wash out the lipids, but retain the stromovascular fraction that's rich in those stem cells. The advantages of this technique is there's really no significant decline of cell number with age, and that's different from bone marrow-derived stem cells. It's easy to do. There's minimum morbidity, and you get a large cell yield, and the disadvantages, like BMAC, or like bone marrow aspirates, are there's some morbidity, and there's a certain cost associated with the procedure. So that's the 30,000-foot view, and we're gonna talk about a lot of these different techniques and a lot of different ways to get these cells used for appropriate indications and how we can implement these into our clinical practice, but one thing we always have to ask ourselves is, is this safe? And so this has been looked at a lot. The good news is that the stem cells that we use in terms of orthobiologic applications, they're typically mesenchymal stem cells already differentiated beyond a point of where they might become a tumor or something along those lines, and so they typically are safe. This was a study done looking at nearly 1,000 procedures at an average of 21 months follow-up. This was a systematic review looking at all of these studies, and what the authors found following bone marrow-derived stem cells is that the adverse event rate was 3.4%, and the serious adverse event rate was under 1%. Of the adverse events, there were 22 that were procedure-related and seven that were product-related, namely pain and swelling either at the donor site or harvest site. And then for the serious adverse events, the authors found one infection, one pulmonary embolism, and two tumors. I would argue that three of those four serious adverse events were probably not related to the stem cell itself, and the infection may or may not have been related to the stem cell procedure itself. With regard to the key questions and what I'd like us all to think about and provide a framework as we move on throughout the rest of this course, for orthobiologics, we need to better understand what do we use, when do we need it, when do we use it, how do we get the product into where we're trying to get it into, how do we keep it there, and what about other factors, such as patient age, patient sex, their overall health, does that impact the quality of stem cells that we put into, or quality of biologics that we put into the patient? And I think this course is gonna answer a lot of these questions, but as Dr. Cole mentioned, probably drive up some more questions that we can figure out ways to research. So thank you all very much for your attention, and welcome to the course. Thank you.

orthobiologics

applications

tendinopathies

osteoarthritis

platelet-rich plasma