Thank you, Jim, well, so biologics is always a hot topic, and it's always, it's come up a little bit earlier today, so already, and so I'll kind of try to give you a little overview on kind of some general thoughts and general concepts, something we've continued to study at HSS, both clinically as well as some work in our lab for a number of years. I'm supported by the NIH and Orthopedic Research Foundation, some, a lot of our laboratory work. So I'll start with my overall message, which is certainly, it's working, there's my message, no message, I'm pushing the button, any ideas, James? Just this forward button, right? It's new battery, and I'll start right here, clearly, let's see if this works, techniques and methods to affect the biologic events in tissue repair obviously have great potential. But I submit to you that a lot of these techniques are, frankly, probably not yet ready for prime time. We're going to sort of go through kind of all these things here, and we have a number of animal studies, preclinical works over the last quarter century that really do, okay, the animal models demonstrate real promise, but there are some limitations. I would submit to you that indistinct or indiscriminate use of what are sometimes unproven therapies may, frankly, hinder progress in this field, so let's kind of go through this little bit here. Where are we in 2023? Again, tremendous potential for these, quote, unquote, orthobiologics, but I would submit to you the clinical use of biologics is greatly outpaced the current scientific and clinical evidence. There are a number of false claims that are out there, again, often indiscriminate use. Certainly, this is driven by aggressive marketing, and we hear this all the time from our players, and they're susceptible to all this marketing that's out there. If you kind of pay attention here, you see in recent years, the FDA has really scrutinized some of these kind of fly-by-nights, quote, unquote, stem cell clinics that are promulgating these unproven therapies, often at great cost. Let's kind of jump in. We'll start with PRP and other blood-based products, so PRP, platelet-rich plasma, you are probably familiar with it to everyone in the room, but there are other autologous blood formulations listed here. In the interest of time, we won't get into all of these, but just to note that there are a number of different formulations that exist. Some are FDA-approved. Some are not. We'll kind of go through that here. Just to simplify and break it down, there are two basic PRP formulations, so-called plasma-based, where you're excluding white cells. You have very few, very little, frankly, platelet concentration in these studies, and this is like the arthrox, I'll call it autologous-conditioned plasma product, and then your so-called buffy coat techniques and preparations, which include both the plasma and the cell layers. You'll have more platelets. You'll have white cells, and these are more kind of leukocyte-rich, and I'll make a comment about that in a moment here, and this is just an oversimplification because within each of these, there are a lot of nuances as far as the centrifugation processes and which cells and which layers in the density gradient are actually chosen, but suffice it to say, these are your kind of basic dichotomy. To that point, one of the biggest classifications people talk about, you commonly hear, is leukocyte-rich versus leukocyte-poor. I think this is, frankly, a very rudimentary, and we need a much more refined analysis. Probably more important than leukocyte present, yes or no, is the type of leukocytes, is the type of white blood cells. In general, we want to eliminate neutrophils and concentrate monocytes. It can go down to a macrophage lineage, so we have to really differentiate the type of leukocytes. The ratio of platelets to leukocytes is probably more important, so again, we need a much more sort of nuanced view of all this. Understand, PRP is very complex, and in fact, the basic pro-inflammatory versus anti-inflammatory dichotomy of this leukocyte-rich, leukocyte-poor is really, truly an oversimplification. We're seeing from basic laboratory work, PRP is very context-dependent. What I mean is, PRP will inhibit inflammation in the setting of a pro-inflammatory environment. You have an inflamed joint, PRP can be anti-inflammatory. In contrast, PRP actually can be pro-inflammatory in a biologic environment where there's no inflammation, so it's actually quite complex. Furthermore, there are a number of other signaling molecules in the plasma portion, completely apart from platelets. As we continue to study PRP, we're learning it's actually very, very complex. When might we, as clinicians, use PRP? I think treating the symptoms of NeoA, there's good data to support that the anti-inflammatory and immune-modulating factors in PRP can be helpful for symptoms. I tell patients it is symptom-modifying, not necessarily structure-modifying. That is, we're not regenerating tissue, we're treating symptoms. Existing or emerging data suggest that a higher platelet dose is likely more important than leukocyte content. It's an important study from, actually, a group in India a year and a half ago. 150 patients received either PRP or HA. Essentially, better results in the PRP group, but what they found that you need an absolute platelet count of 10 billion platelets in your PRP formulation to have a real sustained effect. You need a higher concentration, which is going to be, thank you, leukocyte-rich, and you need a decent volume. There's a number of systematic reviews. I just picked one right here from this group in Chen with Tom Zveng's nest a couple years ago. A number of systematic reviews demonstrating positive outcomes with PRP for NeoA on symptoms. Most of the studies now, well-done systematic reviews, suggest PRP can be more beneficial, more durable, longer-lasting than HA, hyaluronic acid. More recently, there's data demonstrating combining PRP with HA. There's one particular study from Shanghai that randomized patients to either HA, PRP, or the combination. They had three injections in these individuals, two weeks apart. They found that those individuals treated with the combination of PRP plus hyaluronic acid had better results, better results based on standard outcome measures. They looked at these patients with second-look arthroscopy, some of them, as well as imaging, increases in synovial hyperplasia, reduced levels of various inflammatory mediators. So in fact, the positive effect combining the two, and we started to do this more and more in our athletes. Certainly, you have to get into cost issues for your average patient. And to that point, in cost issues, do we do one injection or a repeat injection with PRP? There's really, frankly, no real good consensus due to this tremendous heterogeneity in the outcomes. And the heterogeneity is something that's a principle you'll see holds true for all biologics across literature. But some studies suggest better outcomes if you use a series of injections. Again, you get into cost issues and logistics issues. In our athletes, that may not be so practical for a player in season. So in general, I'll do one injection, even in my normal patients, and kind of see how they do. And you might consider repeating it at two weeks. If they're not doing great or if the patient wants to repeat it, you obviously have cost issues for your patients paying out of pocket because these are not covered by insurance. For our athletes, circumstances may allow you to do repeat injections if it's off season or they're on IR or something like that. So, again, we need more data on the types of injections, but also the frequency of injections. Again, I mentioned at the beginning, there are other autologous blood products. Just to kind of briefly mention, autologous condition serum, you've heard of this, Orthokine or Regenikine, developed in Dusseldorf, Germany some years ago. This is a technique where blood is actually heated, it's incubated overnight with chromium etched glass beads. Essentially what that does, it induces monocytes in the blood to produce IR1 receptor antagonists, which is essentially a potent anti-inflammatory cytokine. This is not FDA approved. That level of, quote unquote, manipulation, heating the blood, culturing overnight, can't do that in the United States. Now, it is available here. It's off-label. I'm sure we've all had players that have used it. There's some data out there. So, I just picked this particular study because this is a pretty well-done study here. Patients treated with autologous condition serum, again, Regenikine versus PRP. They found better results in the Regenikine group here over time. This has been used for a number of years, in Europe in particular. So, there's some data to support this. What about tendinopathy? My goal is to give you an overview here on all these different areas here. I would submit to you to summarize, again, tremendous variability in the outcomes. Again, the biggest thing is there's heterogeneity in all these various formulations. Okay, thank you. Here's a couple of representative studies for the common things that we see. Patellar tendinopathy, very common in our athletes. What does the literature say as far as PRP? Systematic review here, well-done study. A short-term eccentric exercise is actually the best. We know that basic rehab principle, but in fact, multiple PRP injections actually found to be better at a longer-term follow-up. This forest plot just demonstrates actually better results. This is doing multiple PRP injections in this review of several studies. So, some data here. Now, in contrast, this group is from Stanford and Stedman Clinic and a group in Italy. This is a trial, a randomized, controlled trial, athletes with patellar tendinopathy more than six months, so multi-sites. They received either a single injection of leukocyte-rich PRP, leukocyte-poor, or just saline. They also went through a standard rehab. In fact, they found no real differences in the mean scores in these athletes. They concluded that a single injection of either leukocyte-rich or leukocyte-poor was no more effective than saline. This is a well-done study. Again, in the literature, I've tried to pick out your higher-level, randomized level of evidence one studies to point out here for you. Mark's talking earlier about rotator cuff tendinopathy, so impingement, cuff contusions, tendinopathy. So, what do we know? Again, try to pick the higher studies. This is one from Serbia, where they use autologous conditioning serum, the Orthokine, which Orthokine is what's called in Europe, it's called Regenikine in the U.S., same material. And they found a positive result, a positive effect. In contrast, this group from Turkey, a placebo-controlled trial using PRP, no real differences. This is, you know, subacromial injections. Andy Carr does nice work, he's in the U.K. Took patients to the OR, they did a chromioplasty, but then they injected PRP at the end of the case or just left the shoulders alone. And they did a biopsy at 12 weeks, an interesting study, hard to do that in this country. They found actually worse results with the PRP treatment. They found increased apoptosis, decreased cellularity in the tendon biopsy, so they thought there was an adverse effect. And likewise, a group from Switzerland, another randomized double-blind trial, patients injected, this is a subacromial impingement with two injections of PRP. They found, in fact, higher instance of adverse effects in those patients to the PRP. So bottom line for me is, it's not really recommended for rotator cuff tendinopathy at this time. So again, this is basically your non-op treatment of your tendon, this is tendinopathy. If you go to some systematic reviews to get a little bit more of an overview here, this is a recent one, 33 randomized controlled trials. So this is a well-done, these are higher-level trials. You see here all the different tendons, elbow, plantar fascia, Achilles, cuff, patella tendon, all the usual offenders here. They found, as you may expect, the quality of evidence was low or very low in all of these studies. And that's unfortunately holds true of a lot of this literature here. They concluded that in the majority of comparisons, the effect size was actually comparable to control groups. So not real good data here to support this. If you kind of summarize the literature on tendinopathy, obviously wide variability in report outcomes because there's different tendons treated, different formulations, different concomitant treatments, rehab, what's done in addition to the PRP, very different post-injection protocols. So this is what makes it very challenging to study this whole area here. Bottom line, if you look at the literature, I haven't followed this for a decade or more, there is in fact some limited support for a positive effect of leukocyte-rich formulations. Again, as I mentioned earlier, we need a better classification of our PRP or a more refined understanding. But I do suggest a leukocyte-rich formulation, which probably has higher platelet levels, can be effective. I mentioned cuff tendinopathy there, no real data to support its use. Well, it's different for rotator cuff. Meta-analyses do suggest improved structural healing following rotator cuff repairs. This is on the surgical side. Just briefly, this group, Tom Svanknes, USC, systematic review. In general, these studies show better scores, and in fact, importantly, retail rates were lower in those athletes treated with PRP. This group from Harvard, Havid, Mark, yes, Patrick Vovkin. They, in a meta-analysis, found the risk ratio for retail was lower in the PRP group, although it was not fully found to be cost-effective. And then Eoin Hurley in Dublin, Ireland, another meta-analysis, where they compared athletes or individuals, rather, treated with PRP or platelet-rich fibromatrix, just yet another formulation. It's interesting, the PRP group, PRP has a positive effect on your healing rates, whereas the platelet-rich fibromatrix does not. And that parallels a study we had published from our group at HSS, a randomized trial, where platelet-rich fibromatrix did not work. But the bottom line is that PRP does appear to be beneficial for improvement in healing following cuff repair. So again, surgical repair. Briefly, what about meniscus? Little data out there, certainly variable. The study from Poland, a well-done study, double-blinded study, where they found a positive effect. This is patients undergoing meniscus repair, and they were treated with leukocyte-rich PRP. They looked at these carefully with MRI and sacroiliac arthroscopy and found a positive effect, improved healing. This group from Stanford University, Seth Sherman and the group there, at Stanford, this is a systematic review, where they reported, their summary was that meniscus tears augmented with PRP did have lower failure rates, but no real differences in your patient-reported outcomes. And then a colleague of mine, Nicola Mofulli in London, another meta-analysis, where their conclusion was different, that the published scientific evidence does not support PRP augmentation for meniscus repair. So again, incomplete and inconclusive data on meniscus. What about muscle? Obviously an important factor for us, an important thing. And again, a lot of variability. I've picked two studies here on muscle, because they're well done. This is one just a year and a half ago from the Rothman Institute. It's a neat study. It's a mixture of athletes, different ages, different sports, you know, kind of standard, moderate hamstring strains. What they did is they compared athletes treated just standard conservative treatment versus a later group treated with hematoma aspiration with the PRP injection. They used a leukocyte-rich from the Biomed GPS system. They injected six millimeters, or six mils, pick a good amount, at two different sites, and they aspirated the hematoma. And they found that PRP was effective. The return to play time was about nine days better in the PRP group. They thought that the recurrence rate was lower with PRP, quite a bit different. They found an almost 29% recurrence in the conservative group, just standard treatment, versus just less than 4% with PRP. Interestingly, in 69% of their athletes, the hematoma they aspirated was adjacent to the sciatic nerve and this suggests that sciatic nerve irritation may be more common than we think. And maybe the hematoma aspiration does play a role. This is an earlier study back in 2014 from Kuala Lumpur, from Malaysia, but a well-done study. 28 athletes, they were randomly allocated to PRP and they used here, again, a leukocyte-rich formulation. So, and then they all went through a standard rehab. And they found the return to play time was also better in the PRP group, 26 days versus 42 days. And lower pain severity scores in what was a well-done study. So, there is some data out there. Our experience with the Giants has frankly been a bit mixed. We don't use it routinely. We have used it on some occasions. A common issue that comes up is, should we avoid non-steroidal medication or other anti-platelet therapies after PRP? So, we did a little literature review a couple years ago with one of my students in the laboratory. We reviewed studies that looked at the effect of non-steroidals and anti-platelet therapies on the effect of PRP. They were mostly reported on NSAIDs. Most were in vitro studies, just in the laboratory, in cell culture. Only one was an animal model. Essentially, six of these studies showed no effect of NSAIDs or anti-platelet therapies on PRP. Six showed mixed effects. Zero showed any effects, any consistent effects. As we go through all this data, our conclusion was there really is very little and maybe no support for the common clinical practice of withholding anti-platelet therapies in patients being treated with PRP. Cell therapy, we'll go through a little bit here. The rationale for use of cell therapy is obviously numerous signaling molecules are produced by cells, cytokines, and other anti-inflammatory molecules that have relevant effects on biologic activity. Understand that cells work via a paracrine mechanism. The secreted molecules from these cells probably modify the local environment. Very little data to suggest that cells are actually engraft into the injected area there. Well, obviously, we can use cells derived from a bone marrow aspirate or from lipoaspiration, so a fat aspiration. You've probably heard of lipogems, which is so-called microfragmented fat. That should be distinguished from other adipose populations or preparation, in particular, stromal vascular fraction or adipose-derived stem cells. Essentially, those need to be done under an IND, Investigational New Drug, at this point. A brief word on these perinatal products, amniotic fluids, amniotic membrane, umbilical cord bloods, things like that. These do contain various immune-modulating proteins, but essentially, almost zero viable cells, and they're marketed as stem cell therapies. Importantly, all of these preparations now can only be used under an Investigational New Drug in a clinical trial since the end of this FDA discretionary period, so essentially, all of these perinatal products, they're off the market, and they're still being used here and there, and they shouldn't be, because the practitioner has exposed himself to real liability if they use these. Cell therapy has tremendous potential, but a lot of unknowns. I would submit to you that these minimally-manipulated cell preparations that we use in the U.S. need to be distinguished from sorted, culture-expanded cells produced in the laboratory, and we shouldn't even use the term stem cell when we're talking about cell-based therapies. A better term that we use is connective tissue progenitor cells, which is a population of cells in many tissues that can, in fact, proliferate and differentiate, but in a much more kind of limited repertoire. You can measure connective tissue progenitors in culture by measuring colony form units, and we do this in our laboratory on a routine basis to sort of characterize these cell formulations, but I would submit to you we have really zero ability to use stem cells. There are no stem cells available, none. The number of true stem cells by any criteria in currently used formulations is vanishingly small. More importantly, the classic definition of an MSC of stromal cells based on culture-expanded cells. That's very different than the populations that are contained in freshly harvested tissue, whether it's bone marrow or adipose tissue. We should only use this term to refer to a culture-expanded population of cells that meet these criteria and should not be used to describe these heterogeneous populations of cells with undefined properties. There's very little evidence, again, to suggest that these cells actually engraft or intercalate into the tissue. Rather, they work via a paracrine mechanism by producing a number of immune-modulating and anti-inflammatory signals that do modify the local environment, so it can have some effect, and we don't even know if the multilineage differentiation that we know occurs in culture. We don't know if that happens in the body, and it probably doesn't. These cells are cleared rapidly by immune cell subsets. The current environment in the U.S. prohibits cell sorting and culture expansion, so we can't take these out of the clinic and do cell sorting and culture expansion. We can't perform this, quote-unquote, manipulation, and these culture-expanded populations are highly selected and are fundamentally different from the mixed starting population of cells that contribute to their generation. The heterogeneous populations that we use are currently very poorly characterized. The basic biologic activity of the cells we're using is really not well-defined, and we need markers of cell purity, potency, activity, all these things, and things that we're working on in our laboratory. This, taken together, suggests that tissue healing and regeneration via cell therapy is, frankly, a bit unpredictable. A few last thoughts here. Be careful of the dangers of medical tourism. Patients or players want to go elsewhere. The regulatory environment's very different in other countries. There are some legitimate therapies, but it's really hard to know what's being offered, hard to evaluate that, hard to answer questions from our athletes. The processing conditions used overseas are often unknown, so I tell the players, this is at your own risk. We have a little paper we published with one of our fellows, Clare Lassberg, a couple years ago, a series of 14 patients with complications from six different institutions around the country. About half of these were infections. 43% were sterile inflammatory reactions, but these were serious. I mean, some patients required multiple surgical procedures, long-term antibiotic use. This just shows, in the red box, the different formulations that were used in these patients, and here's the complications. About half of these were septic arthritis, and you'll see all sorts of different formulations that were used, so beware. Briefly to finish up, what about cell therapy for tendinopathy? There's a little data out there. This is just a series of three individuals with Achilles tendinopathy, but this is using autologous peripheral blood-derived cells. This guy saw in Malaysia, and they, with MRI, demonstrated a positive effect on tendon structure. Another study, also Achilles tendon, but just a different cell type. This is from adipose-derived cells. Again, Achilles tendinopathy cells. In fact, they found a positive outcome, and I put these in because these are based on structural changes in the tendon, so cells do have some potential, and the last study here is using bone marrow-derived cells, and this is patellar tendinopathy. They compare it to PRP, and again, patients treated with cells had better improvements in tendon structure, so not just modifying symptoms, but tendon structure, so there's some data that cells may be helpful here. Recent systematic reviews. This is one from the Netherlands. They reviewed cell therapy for a number of different areas here listed here. Evidence, and they conclude the evidence-based recommendations for the use of stem cell therapy cannot be made, so they didn't find much support, whereas this one, this is just last year from Iran, another systematic review of various tendons. It felt there was some promise, so it depends on the various meta-analyses you read, but in general, my summary is that there is some data to support the use of cells for tendinopathy. This is rotator cuff repair, and I'm gonna go through this to move along some more on the surgical side with just some data as far as combining cells with time of repair. So to summarize, osteoarthritis, start right there. I think biologic approaches are supported for the treatment of symptoms. I think we should emphasize that the absolute platelet number is more important than leukocyte-rich versus leukocyte-poor. For hamstring, I think we might consider PRP with the hematoma aspiration. Meniscus, again, mixed data on the effect of PRP. And cell therapy, I occasionally use cell-based therapies only in conjunction with surgery. So I've used this sometimes at the time for meniscus repair. I've used Bomer Aspirate to augment osteocondyloallograft healing, meniscus repairs, and revision cuff repair. There's a little data mentioned there on ACL graft maturation. I've not used it there, but generally cell therapy approaches are only practical in the operating room. My current recommendation as far as tendinopathy, again, it's promising, but does require further investigation. If you're gonna treat a tendon, you probably should use a leukocyte-rich formulation. We generally use ultrasound-guided injection. Keep your anesthetic majors in the skin. You don't wanna inject it deep. The local anesthetics can have an adverse effect, actually, on platelet function. We start with a single injection. If symptoms don't improve by a week or so, you might consider extending into a series of injections, but usually we're doing just a single injection. There's some data to suggest, limited data, that repeat injection may improve efficacy. And lastly, the post-injection protocol. First, we need to record what we're doing, and we need much more data. The recommendations for rehab and activity are really empirical and based on very little robust data. Also, as mentioned, very little basic science or clinical data to support recommendations for avoidance of a non-steroidal. The current recommendation after injection is light activity for three days, followed by a gradual progression, because this is just sort of being kind of practical. You need to have some basic protocol for your athletes. Obviously, eccentric exercises are used for tendinopathy, but we certainly need further data on the effect of mechanical load. Therapy is load, so how does load affect the biology? That's what we need to understand to really understand much better how we can work with our rehab colleagues here after these injections. I'll stop there. Thank you.

biologics

tissue repair

platelet-rich plasma

cell therapy

PRP

symptomatic relief