I guess my talk, although we're going out of order here, will be a little bit on the science, more on osteoarthritis and cartilage. There's lots to say in biologics and Scott's going to go over a little bit of tendinopathy and of course augmentation of rotator cuff tears. Muscle injury we won't touch on much. It's kind of a new area in biologics, but if there are any questions with regard to the state of the art, we'll be sure to answer them by the end. Let's see. So today we're going to concentrate on arthritis, like I said, and we'll also touch on the cartilage defect treatment using biologics as well. So how do you choose your patients with osteoarthritis and may be good candidates for biologics? And I think one of the new largest understandings of biologics is that patients with osteoarthritis, some of them have an inflammatory component. Some of those are the traditional bone-dry types of osteoarthritis, but it is now recognized that a subset of patients with osteoarthritis have an inflammatory component, and this is separate from the inflammatory arthritis that we were taught in medical school. So we did some analysis on these two subset of patients and found that these two sets of osteoarthritis patients are entirely different, and one set with this inflammation, you can see a large amount of inflammation that is seen within the knee, and this is contrast again to very little inflammation on the traditional bone-dry osteoarthritis patients. And we see the differences in the clinic all the time, right? To the left side, we see a little bit of an effusion, reactivity with exercise, and certainly complaints of stiffness, and this is in contrast again to those where they just don't have a reactive knee, and it's just that throbbing pain without change with exercise and day-to-day. So with this, we can then construct a little bit of a biologic strategy with this using our main formulations, and one of the workhorses for inflammation is PRP. Now, as we all know, PRP is no longer just PRP, but there are many different types of PRP, and I'll go over most of the types of PRP today. But for osteoarthritis, we're talking about the PRP to the left side. This is a plasma-based, otherwise known as leukocyte pore, and although that's oversimplifying things, it certainly is a line in the sand. And you can see the very difference of this type of PRP because it is more yellow-based in comparison to the other type of product on the right, and with that, it carries with it very little red blood cells, very little white blood cells, and so you're left with the platelets and the platelet-poor plasma. And here's where you see that the formulations are anti-inflammatory. Now Scott, in his talk, will likely talk about the right side, and this is the red kind of PRP, where you go further down into the platelet fraction. Here, you're going to get a lot more white blood cells because of that. You're going to get a lot more platelets because of that, and it becomes more of an anti-, sorry, an inflammatory type of intervention, and that can be useful in biologics, but be careful not to get them confused, and especially in a treatment of the symptoms of arthritis. And so what we did as a group is we really looked at only the top-level studies, right? So then this systematic review is level one trials only, and trying to digest, really, what is the efficacy of biologics, PRP versus hyaluronic acid. And what we see on almost every way that you can measure it, that PRP, and this is mostly the leukocyte-poor PRP, performed better than hyaluronic acid, right? And I think that's pretty much seen as true across the board. But the literature is a little messy, and I think everyone would admit that as well. So if you look at the, all the way to the right side, the negative values are showing that it's the leukocyte-poor PRP that is performing better, again, than this mixed literature leukocyte-rich. So then producing clarity, leukocyte-poor PRP is the current standard for the use of osteoarthritis if you're going to be using the PRP product. But I wanted to take time this morning to mention this, right? Because we're seeing this more and more, and this is a JAMA article, and the conclusion of this article is that with this use of PRP versus placebo, PRP was not better than placebo in treating the symptoms of arthritis. And that's a pretty heavy conclusion to make, especially when I showed all the papers that were represented in that systematic review. So the question is, how do you think through something like this, right, that's coming? And by the way, it was a very well-performed trial. Well, the summary is, is that the product that was used for this particular trial did not meet criteria for PRP in the first place. So it was essentially the same as platelet-poor plasma, or baseline, it didn't enrich platelets at all. And so a good conclusion for this paper would be that this particular product did not perform better than saline, and that's true. And I take that as a truism, because again, it was a very well-performed study. But that's a far cry from saying overarchingly that PRP doesn't work. And as we go further down the road here of the new products and the new types of PRP, it's going to be on us as clinicians and scientists to study each of the new formulations. That's what biologics is. There is not one, again, PRP and not one product that we could just say summarizes all different products. So that is a really important distinction here, and you see some products not performing. But there are new formulations, right? And this is in 2022 and beyond, is that maybe PRP and the platelet fraction of blood is not the only biologic thing that's beneficial. This is a different type of product, where it's platelet-poor plasma. Care less about all the platelets, but instead what it does is it enriches this A2M molecule. And this is a potent protease inhibitor. It scavenges, and it's very potently anti-inflammatory. So if you have those patients that have that really recurrent effusion and nothing works, surgery doesn't work, etc., this has been used across the United States to really help on those troublesome patients with severe levels of inflammation. And although the clinical trials are being done currently, you can see the basic science of this, and that is as the amount of A2M in the preparation increases, the amount of inflammation in basic science laboratory study decreases. So stay tuned for the clinical trials, but I wanted to introduce it because this is going to be right around the corner, basically the next generation of the PRP products. Well, here's another one that's not new, and most of us have heard about this. And these are formulations that you can see around the world, and especially in Europe. And this is the PRP formulations that are rich in IL-1 receptor antagonist. That's the RA part of it. And what the RA does is neutralize the IL-1, right? So that's the point of this whole thing, because we know that IL-1 produces inflammation. And so if that's present in your body, then this can decrease it with the receptor antagonist. Well, that's all fun and great, but it's not available in the United States as of now. There are some products that are kind of flowing through the FDA process, but no one has made it through in the United States. For the most part, I think the reason that it hasn't is because of two reasons. Number one, the IL-1 RA levels have not been high enough to be clinically significant on the eyes of the FDA, and to be honest with you, many scientists as well. The other equation is the one at the bottom of the box there. And that is, make sure that if you're considering using a product like this, that you ask the reps that provide the machining for this, is that you have to have much higher ratio levels of the IL-1 RA compared to the IL-1, because many of the historical products did a great job of increasing the IL-1 RA, but guess what? They also did increase the IL-1 in their product. And so we have a net equation of zero benefit from it. So there's a little way to go from this product, and you can pretty much be assured that, you know, because the FDA has had their eyes on this type of product, that if you see one in the market, that ratio is going to be there, right, just because that's well known now. I also included this slide for a more of overarching look at PRP before we leave it and get on into the cellular medicine side of this. And that is that, again, the left-hand side preparations, the leukocyte-poor PRP, symptoms of osteoarthritis, inflammation, and any time that your goal as a clinician is to decrease inflammation in your patient locally. The flip side is on the right, and you see this is a long list of tendinopathy indications, and those are the leukocyte-rich, although there's a little controversy in this that leukocyte-poor can have some efficacy. If you look at most of the literature, it's strongest with the leukocyte-rich formulations for the treatment of tendinopathy. I put patellar tendinopathy in there. We won't have time to talk about it today, but I'm happy to talk about any of these subjects that you want during discussion, but that's so-so information or so-so efficacy with patellar tendinopathy, so FYI on that. Okay, well, what about the experience of using biologics and you asking a question, okay, well, what if my osteoarthritis patient doesn't have that reactive knee, and you don't think as a clinician that there's that inflammatory component, and you ask the question, does PRP work for that patient, and I have to say I've been a little bit disappointed in the routine use of PRP for that kind of patient because PRP again works mostly on the inflammatory pathways for decreasing pain and symptoms. So maybe there are some other solutions for the use of biologics without that inflammatory side of the fence. I wanted to show you this review. This is now a very old review, but I wanted it up for a couple of reasons. Number one, it uses the word stem cell in the literature, and I'm going to explain in the next slide where we don't talk like that anymore, and we have to be really careful, and I think Steve Weber is going to talk about now that that is not even legal anymore to say that you practice stem cell medicine, so he's going to go over that side from the FDA. But I wanted to show that these historical reference to stem cells are no longer. You're going to see that they're going to be going away in modern-day reviews. The second, randomized trials, and this is comparing five of them, and summary statement is that you see efficacy of cellular medicine in almost or maybe every clinical trial that's done. And so then the question is there's got to be something. If these are randomized trials, there has to be something to this whole use of cells in medicine, and I want to show you why, the whys to the results. But first I want to show you the whys to not using stem cell, and here is a very immature stem cells as they're going through to our adult cells as you see here, and stem cells are the ones at the top, and they, the definition of a stem cell is to be able to make any cell in the body, and what we, what we use as clinicians are these adult progenitor cells, and these cells are below the line, below the biologic line, so although they can enjoy many stem-like qualities, right? If you use a MSC for the sake of discussion, and you want to make fat, sure, you know, that, that, that, that is reasonable, but making liver, not so. It's below the biologic line, so therefore we cannot call them stem cells because in, by definition, they are not truly stem cells, so progenitor cell is the new modern way of discussing it. So then if we look at the mechanism of action, if these clinical trials, and I'm going to show you quite a few here today, and if it, if they're really true, how do they actually work, right? How do they actually show good results, and I think this is our strongest evidence that we have today from these basic science studies that really show that these progenitor cells relieve pain. Okay, how? By blocking the mu-opioid receptors. Fascinating. So they produce mediators, these cells, that sit on the mu-opioid receptors and satiate them, therefore producing pain relief, pretty much across the board, and so that is the popularity, that is likely the mechanism that are being used, and the evidence is strong for that. Well, it's also strong as anti-inflammatory agents. Now, they work totally different than NSAIDs and, and different than PRP. They work by modifying the local inflammatory environment, so they, they go way back in the cycle of cutting off inflammation from the mechanisms much higher up in the chain to modulate our body's response to things, and if our body's reacting to arthritis or reacting to something else, it will help blunt our body's reaction and therefore drive down inflammation. Strong evidence to show that. But the question remains, and I'll show you some evidence of this, can these cellular medicine progenitor cells actually rebuild our tissue? I'm gonna say that there's some evidence that the answer now is yes, through highest level of trials. I don't think it's across the board. The evidence is not strong enough to put a green light on it, but we're getting there, and I think that's the really fascinating thing. Okay, well, let's start launching off in a talk here about the, the harvesting of cells. If you're gonna do this in clinic, there are two main routes to be able to do this. I'm gonna talk about the right side, which is the abdomen. This is below the umbilicus and above the pubic symphysis. So that's the number one way worldwide. Also, what are we gonna do with folks that are marathon runners? You know, is this adipose subcutaneous harvest on the right gonna work? No way. And so then we have to have another method, and in orthopedic surgery, our method is the infrapatellar fat pad, and I'll go over that as well. Okay, and that's a ripe source of cells that we can access arthroscopically. So let's talk about this for a second. Here's the keys to the technique of doing this. Putting in this tumescent solution, and that's in the middle. That's the mix you see on the slide. That's the solution, and you need to put it in and let it wait for a minimum time of 20 minutes. That's the key right there. If you're in a busy clinic, and you try to rush it, you're not gonna get the cell harvest, and so really letting that solution sit within the subcutaneous tissue is really important. And then it is always feeling your liposuction cannula with your fingers, and you see here in the video, not in this area, but otherwise, you're feeling with the tip of your fingers, and you always feel that you're subcutaneous, and that makes this a very safe procedure, as long as you have the boundaries of the umbilicus above, and again, the pubic symphysis below. There's a couple of things we've learned about this over time and maybe I'll take just a little a couple of minutes just to talk about it. Number one, be careful around the belly button and if you really put your liposuction cannula really roughly around that that will cause bleeding. The other thing to be careful is women with c-section scars. That's a very vascular dense area without adipose tissue and if you try to forge through that you can really cause some bleeding as well. So those are a couple of the tips that are really important. Well here's another one and this is one that is you hear about still to this day and that is doing liposuction in this sort of harvest around the gluteal area. You know quite frankly it's probably the thing that most patients want. Yeah a little help take a little bit dock off the backside and it is tempting because the patients are prone so they're relaxed and it's not tempting because the gluteal artery. So please be careful there have been some near-death situations in the clinic of major arterial bleeds so there this has been recognized that you really understand your anatomy and where the gluteal arteries but this is not a place just to be tinkering around. With regard to use of the infrapatellar fat pad the key to this procedure is using an FDA approved canister. You see that's that plastic canister below the arthroscopy screen. You see the arthroscope in this technique is placed against the articular cartilage. You see that this is only a harvest of the posterior synovial layer in the very back part of the fat pad and this is not about harvesting the whole fat pad which we all uniformly know would be associated with poor results in that because of the importance of the fat pad within the knee. And so then the back tissue is harvested and I'll show you how to prepare it here in a second but I wanted to show you this right so this is without the use of a tourniquet and you see there's the posterior border of the fat pad and again how vascular the fat pad is. So it always needs to be respected if we're going to use this technique and to make sure again you see that I'm now cauterizing all the areas of the bleeding to prevent arthrofibrosis a key part to the step and also there is much less arthrofibrosis and of course overall bleeding by the time the procedure is done by using a tourniquet so that's highly recommended if you're going to be harvesting portion of the fat pad. Well here's modern-day adipose processing which is kind of weird from 2006 to now there's a lot of technology here etc but I want to I want to narrow this down here to really two ways that in orthopedic surgery that this is typically done. To the right side is the ball bearing system there's at least one manufacturer of this and another one that is a similar product and you see this is mechanical taking the fat and mixing it with ball bearings and screens to decrease the size of the fat clusters so they become more biologic in nature. The one to the left is popularized by the plastic surgeons and that's doing the same thing through a lure lock adapter and you see at the bottom there there are decreasing size of lure lock adapters so then you just keep decreasing the size again of the fat clusters and so then that will allow biologic activity but you cannot just inject fat within a joint right because that becomes inflammatory so you must process it in one of these two ways. You can centrifuge it using FDA approved systems and you see there you have more of a it's not a complete cellular product but you have more of the cells that condense down to the bottom after centrifugation. Now I want to just talk a little bit about arthroscopic technique so here you see a regular arthroscopic setup you see that there are two portals as we traditionally use the key to this technique though is having a second section and you see that's hooked up to the area of the arthroscope cannula and then a second section from your working portal and you need some sort of flexible cannula because this is dry arthroscopy so the the saline is removed and then this helps hold the soft tissues away from your area of treatment. So I've already done a little preparation with this one I've removed the calcified cartilage layer we all know that in any biologic procedure that includes that you want cartilage restoration that you must remove that calcified cartilage layer first and then we have a layer of fiber and glue this is the mixture of the fat derived cells along with a acellular matrix cartilage matrix you see how it kind of fills the gap from day one here a second layer of fiber and glue to produce a cocoon and I want to show you that because that is the more modern-day technique of doing this for chondral defects and it is also the technique that is being used for the clinical trials. So here's the clinical trials and this is early on and here now we have much more data the two-year trial of the integration of the cartilage and want to show you how it's being judged right so these MRIs immediately are transferred to Europe we don't even get to see them and they're neutrally analyzed at a company in Germany and what they do is they take reference regions of normal cartilage in front and back and then they compare it to the regrown cartilage and as you see here the goal is to get to a ratio of one meaning that the surrounding cartilage healthy cartilage is the same as the reconstructed cartilage and so we're getting there and and early data showing these adipose cells provide a better type of cartilage that is more similar to the reference regions in comparison to the comparator which is micro drilling. Stay tuned that's not finalized data but I want to give a sneak peek on it as well. If you're wanting cartilage regeneration and you do not want to use adipose shrive cells there's actually really good data to show that bone marrow concentrate cells that you aspirate can be used this is popular popularized in Italy with good now greater than 10 year results on their patients. This is through a mini arthrotomy so it's not using that arthroscopic technique there is a patch that they use it as a scaffold and to help protect the cells but nonetheless this has shown over time to be a beneficial technique. Well here's the clinical trials that I was promising these are the double blind clinical trials that are comparing the adipose derived cells right to saline and so this is the first trial from China and you're gonna see some similarities of these high-level trials number one every one of them across the board like I said at the beginning increase sorry decreasing pain increasing function across the board right and maybe it's because of the mechanisms that we discussed earlier but this one very uniquely found an increase in cartilage thickness and this is through the same sort of automated MRI quantitative t2 analysis and so you know you can see some images there but bottom line they're reporting actually for for now the second time increasing thickness this is the first time in a randomized trial. Well here trial number two from China decreased pain increased function and again different investigators significant cartilage thickness improving using a different MRI method nonetheless MRI analysis for this so alright now we're getting a little more promising that this is becoming more consistent. Here's the third trial this is for from Korea and so again a decreasing pain increasing function okay that's good but they failed to show the thickness change with their osteoarthritis patients so I think we just need to stay tuned we're not quite there yet but there's more more promising information coming across with higher level trials. Wanted to talk real quick about bone marrow aspirate for the treatment of osteoarthritis this time no good clinical evidence to suggest that that's what we should be just injecting into our knee and that's that's clearly different than putting in it in a protected chondral defect right as what I showed previously from Italy this is just injecting it into the knee and at this point there's no good evidence. Well maybe this is the reason why in that we haven't mastered our bone marrow concentrate techniques and this is one of the papers that are showing that there is same patients BMAC or same patients bone marrow aspirate and you put in a different machine and it makes a totally different type of concentration of biologic right so they're not the same just like pure P is not the same yet we're lumping things together and saying BMAC doesn't work BMAC does work well we can't we can't use those conclusions so stay tuned about BMAC and the use for injection into osteoarthritis but this time no good evidence and this is just a little bit of what I talked about. Now the second topic is the subchondral bone this is more modern approach to biologics with the very now clear understanding that the subchondral bone affects the cartilage and affects the pain generation of osteoarthritis and there are emerging types of data to show some very curious things here's a trial that showed the comparison of injecting PRP and the second group is PRP with an injection of PRP in the subchondral bone who did better the injection of the bone and the joint Wow you know but it's all giving more evidence to suggest again that there is a link to the subchondral space with osteoarthritis and certainly with some forms of chondral defects so then this understanding has helped us biologically and so here we have a patient and this is just a anecdotal but to show you the process 65 year old medially based pain you see a fracture there they went to physical therapy for six weeks we tried to offload it there was no improvement with it so this is the process of instrumenting this area stimulating the bone marrow and so this is a fluoro guided placement of a K wire and then over that it's over drilling with a reamer drilled typically around four millimeters although some drill a little bit more with a vascular necrosis and then through that same bed after giving a biologic of your choice if you would like and I'll just skip this and show that you can inject right through the air the drill bit or the reamer and so then it's very localized to the area that you would want to place your biologics and I just wanted to tell everyone that industry is is going to come a long way in a year on these techniques so stay tuned there'll be a lot more instrumentation coming your way real soon I'm gonna back up in this just to say it is very unclear that anyone needs to spend a lot of money on the bone marrow concentrating devices and that is because this is George Muschler's data and some others suggesting that if you use good technique and there's tons of YouTube videos and and I'm happy to discuss at any time that you can you can get really good amount of cells if you use good technique right with small amount of aspirate volume and you don't necessarily have to use 30 or 60 cc so kind of interesting side note there here's our patient just a follow-up and although this hasn't you know there's the chondral defect but you see the bone and the fracture has has reorganized and this is after a period of time of six months so you know we can stimulate anatomy we're just starting to understand how to do this and then the main techniques for this type of patient would be let's reestablish the cartilage above because you can see the cartilage defect and let's treat the bone below so kind of a composite type of approach for this type of patient but can you can see the power of treating the the interosseous space here's the current data six studies 163 patients bottom line is a market improvement in pain again pretty much across the board downside is almost a 20% failure rate it's kind of a familiar statistic right because subchondroplasty what was the failure rate oh yeah somewhere around 20% you know so so there's something we don't know and we and we haven't learned yet about the subchondral bone and being successful in every patient nonetheless multiple home runs that I think any practitioner that does this would tell you it's definitely reasonable to consider you know final talk on biologics and the rest of our orthopedic armamentarium many of us have tried to push the limits of biologics to see their efficacy and see how they do and I'm here to report that no biologic is going to outweigh physics right and so then if we have an environment that's not good and you know whether that be pathologic varus or patella femoral joint etc that we really have to take care of our environment and then the biologics can take care of us otherwise the biologic techniques struggle it's basically one of the last slides and this was kind of again what we're starting to learn about this and that is which one of these two patients do you guys feel is the best candidate for biologics now the candidate number one has the subchondral bone lesion has the pathologic varus alignment has a huge amount of inflammatory areas synovitis within the knee patient two has a chondral defect normal alignment normal subchondral bone and so I think the lessons learned you know over the years is this that biologics adapt and especially the cells to the environment they will help police it and they'll help change it if you have seven things going on good luck what are the cells going to do they might decrease inflammation for a while but they're not going to be ultimately effective versus if the environment is right then patient number two have a much better chance of re and especially if applied locally of reestablishing cartilage for a cartilage defect right so that's I think some lessons learned over time so inside and summary osteoarthritis and cartilage really needs some very individualized treatment seeking inflammation really understanding subchondral bone environment changing the parameters of the joint to get a better interarticular environment are likely going to be more of the keys of success going forward and I guess this is the final couple slides of new pathways forward for biologics to keep us all in the driver's seat of the new things that are coming across the table first of all an understanding that osteoarthritis has many etiologies not just wear and tear or post-traumatic or post ACL so there's many different etiologies and testing mechanisms for all these etiologies will be coming forward over the next couple of years but also this is now the era of targeted therapy for for by for biologics we talked a little bit about inflammation but if we can identify that our patient has any of these pathways here we have now very targeted drugs that are in development and so that's really the key thing and I was talking with pharma the other day and they say oh geez well you know we have this great drug and it cures most folks but in the end it shows that it was a failure because it didn't really cure everyone I say yeah that's what we know right that you we can't use one thing and that we're gonna have to really discern what is the etiology of our particular patient to be ultimately successful in the end thank you guys very much and happy I think there'll be time for questions and discussion at the end thank you

biologics

osteaoarthritis treatment

cartilage defects

platelet-rich plasma

adipose-derived cells

inflammation

clinical trials