Good evening. On behalf of AOFAS and BOFAS, I want to welcome you to tonight's program, Use of Biologics in Foot and Ankle Surgery. It will be moderated by Drs. Rick Brown and Sheldon Lin. Joining them are Drs. James Calder, Samuel Adams, and Rod J. You can find their full biographies and disclosures in the program document posted in the chat box and in the PRC. The 2021 webinars are provided free to AOFAS members and orthopedic residents and fellows with funding from the Orthopedic Foot and Ankle Foundation, supported by grants from Arthrex, Inc. and Stryker. I'd like to run through a few housekeeping items before we kick off the presentations. For technical difficulties, please try closing your browser and logging back in the same way you did the first time. Registered physician attendees may earn one hour of AMA, PRA, Category 1, CME credit by completing an evaluation in CME claim form at the end of the webinar. You can find the link to claim CME in the chat tab, and we will also follow up with an email at the conclusion of this broadcast. This webinar is being recorded and will be available for on-demand viewing in the Physician Research Center at www.aofas.org. If you have any questions during the presentations, please enter them in the Q&A tab on your navigation column. If we cannot get to those questions during the live broadcast, the faculty will reach out to you at the conclusion of this broadcast. I will now turn the program over to Dr. Brown to begin. Welcome to this evening's first joint webinar between BOFAS and AOFAS. My name is Rick Brown from the University of Oxford in England, and I'm the chairman of the BOFAS Education Committee, and we've put together, I hope, three interesting webinars in a series through the winter. Each of these will be about 60 minutes long with selected experts from both sides of the Atlantic to discuss the crucial topic. This evening's topic will be about biologics and there'll be questions that we will pose, and we'll also discuss cases after the speakers have given their talks. So, hopefully, we will learn from each other as we are a group of people who share a common passion for ankle surgery and allegedly a common shared language. So, may I introduce the first speakers for this first webinar this evening is James Calder from Imperial College London, who will talk about how biologics could work. Then Sheldon Lynn from Rutgers Medical School, New Jersey Medical School, followed by Sam Adams from Duke University in North Carolina. Then we'll move on to some case-based discussions, and I'll introduce Rod Jakes, who is the medical director of the English Institute of Sport. So, really, without any further ado, I suppose we should move to our first speaker, James Calder. Thanks very much indeed, Rick. My name is James Calder. I'll just get this thing up here. I'm at Imperial College and the Fortis Clinic in London. I'm talking about the introduction really as to is it a drugstore or are we actually dealing with proper stem cells? My disclosure is in the book. PRP, there's a massive ethical debate in sports medicine, because we know that there's a huge amount of placebo involved with it. But it's also, from a scientific point of view, we really don't know what we're dealing with. There does seem to be an element of bucket chemistry going on with some mad scientists, if you like. And the final conundrum is what we do about the money, because there is an awful lot of money that may be made from using PRP and so-called stem cells. If we look at the history of PRP, the publications have exploded in the last 30 years. And when I was talking about the money, the global market earlier this year is supposed to be $300 million, and in five years' time, supposed to have almost doubled to $570 million. The problems with PRP are numerous. There are various different commercial devices, and they all differ from each other. So we can see, say, the Arthrex and the Biomet system is separate. And when you start looking at the different papers that are published, they often talk about the differences between the results, but they very rarely talk about the exact differences that occur in the constituents at a cellular, not just a cellular level, but also at a growth factor level. Some patients don't produce PRP, and that's not just the patients who are over 60. Those are younger patients as well, and we've been looking at that at Imperial College. And some people on a day-to-day basis, they don't produce it, and on day-to-day variation as well in the constituents of their blood and their PRP. The type of PRP is obviously crucial. What's interesting is that, yes, we can have the high platelet PRP with the very high lymphocytes and neutrophils. Something that hasn't been looked at yet, and I think needs to be looked at a little bit more, is the monocyte constituents of it. And when we've been looking at the tendinopathies, most people have been looking at the overall poor effect seen for tendinopathies in PRP. No one's actually really drilled down into exactly what the constituents are, and it's perhaps some of the, if you drill down into exactly what the monocytes are doing, they may actually be useful. Some PRP companies can adjust for the white cell content, such as BTI and RegenerLab. I have no interest in any of these, but there are different ones out there, and perhaps this should be a way forward, and I'd be interested to hear what colleagues say about this in the future, later on today, because this probably is the correct way forward. So, if we're treating a cartilage problem, or a bone problem, or a tendon problem, we should be using a certain type of PRP or stem cells. Now, if we take it back to Arnie Kaplan, if anyone's ever heard him talk, Arnie has talked about the mesogenic process, and really he talks about the proliferation stage, which is the regenerative medicine, and then there's the tissue engineering stages, further down, which obviously then runs into the territory of problems with FDA approval. We know that there is a regenerative capacity, but are they really stem cells? We know that red cells die 2 million each second, apparently, and 60 billion cells die each day, and even articular cartilage has a turnover, so there is some regenerative capacity, but are we really dealing with stem cells that are so frequently talked about? When we look at the bone marrow, where much of the harvesting may occur, we've got the haemopoietic stem cells, which are very different from these MSCs that we're supposed to be talking about in sports medicine. If we look at where they're taken from, there are papers out there looking at all these different areas. I'm not sure how many orthopaedic surgeons will be taking samples from the brain or perhaps the pancreas, but there are various different methods and stem cells taken from all these areas, and very good papers, scientific papers, and narratives talking about it. What Arnie Kaplan talks about is MSCs are actually pericytes, and actually it's a pericyte on the vessel walls, and when the vessel is damaged, they're then activated, and once you get the activated MSCs, that's when you get the trophic effects and the growth factors are released, which then change to the growth and the healing effects in the cells before the pericytes then go back and sit back on the vessel walls again. It's perhaps not an MSC as an mesenchymal stem cell, but it may not be a stem cell. What Arnie Kaplan talks about is it's a medicinal signaling cell, and in that case, what we're dealing with is an injury-specific drug store, and perhaps that's what we're looking for here. We're not actually interested in the cells themselves. We're actually interested in what they've produced and the factors that are released as a result, because what's quite interesting is if we look at the MSCs, they can somehow tell what they need to do when they switch from one environment to another, so if there's an infection somewhere, they can have a pro-inflammatory phase. There's an anti-inflammatory phase in certain situations, so they seem to be able to suss out what they need to do in that situation, and the clinical applications of these pericytes are obvious, such as the group from Brazil who've looked at spinal fusions and atrophic non-units and looking at the differences in the scaffolds, how the scaffolds react to these different MSCs, so now that's why perhaps we're talking about as secretoids, as a state-of-the-art, and it's actually taking away the idea of the cells themselves, and it's actually a set of proteins that are secreted that's the most important bit, and in this situation, say, in fat and liposuction, can actually lead to, at the bottom here, an infusion of cell-free secretoids, and that's the important bit, and that's what we should perhaps be looking at. When we come to the adipose therapies, it's difficult, because there are various, various different types of adipose stem cells, and the top two aren't FDA-approved, and perhaps those are the ones that are the most important, because they're very different in the way they behave and the way they act, and when people are talking about adipose stem cells, they may be talking about something very different, and what is actually happening in real life. Then we don't know whether bone marrow or adipose stem cells should be better. Clinical treatment, there seems to be more papers on bone marrow, but in the systematic reviews that are out there, there is a high risk of bias, and we do not simply know which is the best at the moment. So, in conclusion, I think the therapy that we're using should be based on the understanding of the process, and I'm not sure that we understand the process yet. It is still bucket chemistry. The cytokines may be beneficial, but in a different combination, they may be deleterious, and we do not understand what we're doing in which situation, and I think the way forwards should be to look for PRP in preparations, and we should be looking for customised preparations for individual conditions. An expanded bone marrow aspirate concentrate is probably the way forwards, rather than lipogenic, for many different reasons, and it appears to have greater chondrogenic potential in orthopaedics, and can also promote tenosites through a monocyte-related and IRAP pathway. So, I think it is a drug storm. Different secretomes for different conditions. I don't think it's something you just splash in your cornflakes in the morning and hope that it's going to work for everybody. I think we need to be a bit more bespoke about where we go, and if you're having your muesli, you may want to have a slightly different combination. Thank you very much. Thank you very much. Thank you very much, James, and we'd now like to move on to the talk by Sheldon Lynn from New Jersey. Over to you. Thank you very much. It's always hard to follow Dr Calder. I would like to thank the ALCS and Belfast for the opportunity to talk about the World Bone Graph, the critical growth factors, and this new concept of the key traced elements. Here's my financial disclosure. In this talk, we'll outline the concept of deficiencies of critical agents in arthrodesis and fracture healing, the effect of some of the critical growth factors, and a new concept of key trace elements. Those who have time, the ALCS webinar on June 30, 2021 was amazing, and Dr. Daniel Gause had some really seven key points about autograft, and I'd like to really bring them out because it provides insight of what we actually know about bone graft and bone graft substitutes. Number one, autograft ain't free. I mean, from Judy Baumhauer's article in FAI 2014, we know that, number one, obtaining autograft increases the operative time, and sadly, up to 20% of the patients experience pain after graft harvest site, even after one year. Specifically, the more distal the harvest site, more pain. So while overall, the group had a graft harvest site pain of 8.5%, you can see those more distal were even higher. What does that tell us? It tells us that any cost analysis of the biologics must take into account the cost of the biologic, the cost of the increase over time, but also the likelihood of harvest-related graft site pain, and therefore, an indirect cost to the patient of this persistent pain. Furthermore, we learned that biologics is part of a normal healing cascade. These growth factors, I'd like to really talk further detail. If you think about when a bone breaks, the platelets release PDGF that works in conjunction with VEGF for angiogenesis. PDGF is a known chemotactic proliferating agent that expands the number of progenitor cells that allows the endogenous BMPs to differentiate them into osteoblasts, chondrocytes, and therefore, bone remodeling. Several articles have pointed out in high-risk populations, like the elderly, that there's a deficiency. Specifically, for example, Street et al. showed a reduced levels of PDGF in elderly populations, especially over the age of 75. Furthermore, I did a study with Mickey Pinzer out of Loyola, where we looked at patients undergoing hindfoot arthrodesis, and they looked at those who healed and went on to a nonunion. Those who didn't heal demonstrate one-third the levels of PDGF, 50% the levels of VEGF, therefore showing a correlation between the level, let's say, of PDGF and bone healing. So this is our goal, folks. We're trying to change this beautiful picture and working with the cells, working with the scaffold, working with the time and the appropriate environment of these bioactive signaling molecules, can we obtain tissue regeneration? Now, PDGF has been studied with over five clinical trials, 642 patients, demonstrating statistical significance from non-inferiority to autograft, and therefore sparing the patients from donor site pain. One of the recent articles by Burlett on JBJS Open Access in 2020, he looked at the impact of patient's age on foot and ankle arthrodesis supplemented with autograft versus RHPDGF beta TCP. What's interesting, if you break upon the age, specifically the fusion, those over the age of 60 and 65, the odds ratio 2.24, 2.74 showing an inhibitory effect of age leading to a non-union. But in contrast, by using RHPDGF beta TCP, there's a mitigating effect with the odds ratio less than one in all groups. Their conclusion was that RHPDGF beta TCP may dampen the negative impact on healing that comes with age. In my mind, the implication is a more individualized patient management in the years to come. Now, let's switch gears to BMP2. We know it's made by CHO cells. The solution is filtered, sterilized, purified, placed into vials, and freeze-dried. We've looked at the role of BMP2 in a high-risk population model, the diabetic rat segmental defect, and you can see here, left is the collagen sponge, right is the BMP2 with the collagen sponge, and close analysis under histology shows the left is the collagen sponge, right is the BMP2 with collagen sponge, shows that the cortex is re-established at six weeks with recapitulation of the bone marrow as well. There's been prospects around my trials. Alan Jones looked at 30 patients, six level one trauma centers, comparing BMP2 with allograft versus autogenous bone graft in really high energy tibial fractures with traumatic bone loss, and you can see here, here's the BMP2 with the allograft wrapped with the collagen sponge. In this study published in JBGS, they demonstrated 10 out of the 15 healed with autograft versus 13 out of 15 with BMP2 and allograft at the one-year follow-up, and here's pictures showing really comparable data showing the power of the BMP2. In regards to foot and ankle, we know it's an off-label use in the United States. RHBMP2 has been published by Chris Dibbo in looking at 112 fusion sites, majority smokers, a lot of them high energy, they got a 96% union at a mean of 11 weeks, whether you look at ankle, subtalar, TN, or CC fusions, and they demonstrated only a 4% non-union rate. They demonstrated that RHBMP2 is an effective adjunct for high-risk ankle and hind foot fusions. Lastly, I'd like to bring a new concept of key trace elements. We've done some work with zinc chloride published in JLT in 2014 and Spine in 2016 looking at the effect of zinc and demonstrated that the addition of zinc salt to bone allograft increases their osteogenic efficacy. We presented at ORS our studies looking at the role of zinc, a cation, plus two cation that binds to the negatively charged of the hydroxyapatite of allograft, 30-minute processing step, this generates scaffold impregnated with the zinc compound. As shown here, you can see that by soaking the allograft in 1% zinc chloride solution, there's a time increase, a temporal increase of the zinc concentration, and even when we try to shake it out 24 hours in a TRIS buffer or PBS buffer, it doesn't separate. And then we placed it into the nude rat or the RAG2 knockout rat. These are T lymphocyte compromised rats, and using a segmental defect model, you can see left is the bone chips alone, the middle low-dose, and the right is the high-dose zinc. And furthermore, further analysis looking at histomorphometric and micro-CT, the top row, A and C is histology, B and D is the micro-CT, we can see there's statistical significance in the amount of bone that is formed with zinc allograft. This study, and really it's again experimental and emphasizes, it shows a significant amount of bone formation occurs at the site treated with zinc-laden allograft. There appears to be an optimal dose range for the osteogenic effect, and the clinical implication is that this is a potential adjuvant to allograft for increasing their osteogenic capacity. So therefore, we've shown that RHPDGF mitigates the effect of age and is equivalent to allograft. Number two, BMP2, while it's an off-label use for foot and ankle fusion, appears highly efficacious, and clearly with the experiments there's more data to come of key trace elements such as zinc. Thank you very much. Thank you very much Sheldon. It's important to emphasize that point that just using allograft is not free, and therefore that's one of the reasons we're searching for these adjuvants, and it seems to be in those animal experiments that they've shown evidence for the PDGF and the BMP, and I'm very interested to hear the potential of this new aspect of using zinc. So now if we go across to North Carolina to Sam, you're going to scrutinize the evidence more thoroughly again, please. All right, thank you everyone. So yes, I'm going to talk about the evidence behind some of the more commonly used biologics that we have, the ones that are used most commonly in foot and ankle surgery. These are my disclosures, however I have nothing related to biologics. So show me the evidence, and I think, you know, a lot of times there's two sides, there's two sides to every story, and I think if you, you can probably divide most of us surgeons on whether these biologics are truly some of the greatest inventions we've had in medicine or whether they're more of a snake oil type thing that have actually no utility. And I will argue throughout this presentation that there are certainly people behind both sides of this that are trying to push one way or the other, and we really don't have anything conclusive about these biologics. Here we are certainly led to believe through advertising that these biologic therapies are a revolution. I mean, some of these are actual these are actual ads from from the internet about treating back pain, improving your life, improving your lifestyle. And these are all obviously fee fees associated with these either whether you're going to go to a court or have one of these injections. But I'm going to argue tonight that there is really no literature to support any of these ideas. So what do we actually know this is a summary slide. And this is how I would summarize, we really don't know much about any of these biologics. There are a lot of articles out there will highlight some of some of the more important ones tonight. But there is really no way to make a conclusion about these biologics. So why don't we know, you know, when I'm looking at the literature, or even doing experiments, I think these this is a natural progression, right? We can do a lot of this stuff in basic science studies. And I will say that that for these biologics, the basic science data is very strong. And partly because the lab is a controlled environment, we can make our animals do what they what we want them to, we can make them eat what we want them to sleep when we want them to, we can control a lot of things about their life that we all know is not true about our human patients. The next step in evidence is really kind of what it's out there is I call this anecdotal evidence or case series. So we might have a case report or a case series kind of a major win that somebody is excited about that that a journal agrees to publish. And, you know, one of these major wins, here's one of my patients that had a which is very rare to have a calc slide non union. I took him back and I did a bone marrow aspirate concentration injection and got him to heal up. And so this would be a major win. But there's no, there's really nothing that we can include from from one patient, or even a lot of the case series that are out that are out there that are a few patients. And then there's what I think is the next step. The final step is that strong clinical evidence. And that's the randomized controlled trials, systematic reviews, meta analyses. And for the most part, these are lacking in the biologic space about what we know. So, and these are really where these these studies are really where the rubber meets the road and what we should be looking at or should be striving toward biologics therapy. But let's dive into some of the literature I chose these three to look at specifically that I mean, there are a host of other biologic we've heard about some of them tonight. But I felt that these were three that that have a lot of literature behind them. And they're also used for a lot of different purposes in the foot and ankle. These have been used for bone healing, all tendons, fascia, ligaments, even wounds. And so these were kind of the three that I chose to give us some more information about. James did a great kind of initial summary on platelet rich plasma start with this. Basically, it's it's why why would we even think about doing this? Well, it is the body's first response to any injury is to deliver platelets. And those platelets, as we've heard already have a lot of growth factors in them. But they also have been shown to attract stem cells. This seems like a very logical thing to do to introduce somebody as a biologic therapy. What is PRP exactly? So basically, PRP is taking these platelets and concentrating above the baseline value. There are a lot of growth factors. These are only a few of the growth factors that are in playlists. And they've been these growth factors have been shown to do a host of things, things that we want in a reparative site, where we want to introduce these biologics. So angiogenesis, myogenesis, even cell growth, proliferation, differentiation, excuse me, and bone regeneration. And also, they've also they've been noted to have anti inflammatory and analgesic effects where maybe that are the initial hype around PRP and the effects that we see clinically, maybe do these inflammatory analgesic effects. It's actually quite easy to perform PRP injections in the clinic. And what it does, you know, bias a lot of people, unfortunately, is the cash payment for injection as we've seen. So PRP, I just introduced sounds great. And there are some studies that show that it does reasonably well. Here's one study on the left that shows injecting PRP for chronic Achilles tendinosis, 30 patients. But there's no control group, they had 93% success at 24 months, but again, no control group. On the right, also tendinopathy. And we have very similar success rate, at least 93% satisfaction. But really, again, not, not a no control group. So not not great studies. When we start to get into a little bit better studies where we're getting control groups, data is not so clear or positive, I should say. So here's one for chronic plantar fasciitis, where the patient's got three weekly injections of one of these four therapies, injections slash treatment, excuse me, of one of these four therapies, shockwave therapy, prolotherapy, PRP injection, steroid. And when you look at the data, there's actually no difference between these groups, or even from baseline outcome scores. Another study with a much better study, now we have a randomized control study. So this is a double blind placebo controlled study. And as I mentioned, randomized, it's either four ml injection of PRP or normal saline control. And there were 27 patients in each group, and they followed them out for 2024 weeks, and there was no. Another study, again, a double blind randomized placebo controlled trial, still showing no difference with the injection of PRP. And this is for chronic Achilles tendinopathy. And here are two studies from this year from from JAMA. These are two really good studies. So this first one is effective platelet rich plasma injection versus sham injection for mid fourth and Achilles tendinopathy. And basically there was there was really no difference. And then another good study, a little bit different application. This is platelet rich plasma injecting for early osteoarthritis of the ankle, and they found no difference compared to placebo injections. So two really well done studies in JAMA showing no difference of PRP. And then some of the other studies I just showed with randomized placebo controlled studies also showing no difference. So why isn't PRP successful? This is my personal opinion. But I think these are just some of the reasons. But, you know, one of the main factors, growth factors is PDGF and angiogenesis, which causes or produces or promotes, excuse me, angiogenesis. Well, you know, a lot of these studies that I've shown are for intrasubstance tendon injections. And a lot of these tissues that we're injecting to tendons, ligaments, even fascia are relatively avascular. So I'm not sure that that this is the right complement of growth factors. And it's kind of what James was getting to earlier, more about the personalized medicine, I think we also need to structure these biologics for a particular action. And so maybe PRP isn't the best for our tendons. Another big thing is it's a liquid carrier. Now those studies that I've shown are all injections. And as we know, and as you can imagine, the local residence time of the PRP in the area has to be very small. And then also that was said earlier is that the preparations vary and are not tailored to the patient and the patient's needs. Another interesting thing I think is a reason that why PRP isn't successful is really I think we need to PRP right when the injury happens. The problem is, is that by the time we're usually injecting PRP or really any of these other biologics, we're so farther along in the healing cascade that maybe it's a little bit too late. Now, what you're probably interested in that I haven't mentioned so far is PRP for cartilage. And there is a little bit different information on or results or literature on PRP for cartilage. So there's just one of the studies, this was a study comparing microfracture versus microfracture plus a PRP injection. I think it's important to note that this group used to drain after surgery and the PRP was injected through the skin after drain removal, so not at the time of surgery, but in the close carryout period. And what they did find for the addition of PRP is significantly improved AOFAS, FAMS and VAS scores in the PRP injecting group compared to the microfracture group. So there is some data to show that and this is a control study that show that there is some benefit for PRP for cartilage. And then getting a little bit better evidence is a systematic review. Now, when they really drill down onto the number of studies, there were only four studies in this systematic review. Only one was one of them was a level one study. But they did show that adding PRP to microfracture significantly improved function and reduced pain. So where's PRP on this kind of spectrum? And if we make this a little bit into a graph, we have evidence versus kind of the pregame promise or the hype. And I think there was a lot, you know, pretty good hype around PRP. But the evidence is still for the most part in this anecdotal and case series evidence as far as it working. And again, I showed a lot of evidence that it may not work at all. But there is some if we nudge this over toward the stronger clinical evidence, there may be some utility for PRP for cartilage restoration. Let's go on to a bone marrow aspirate concentrated bone marrow aspirate. So I think the benefit I'll just summarize quickly is that this is kind of like PRP, but plus it has stem cells. So it's taking it to the next level. And these stem cells can then potentially do whatever we want them to based on what tissues we introduce them to or maybe even what growth factors we add. And this was this, this became popularized by the Hernegau study, injecting the concentrated bone marrow aspirate and tibial non unions. And basically what they showed is that concentration matters. But we don't only use it for and most of the people on this webinar necessarily using it for tibial non unions. We've used it for a host of other things that are reported in literature. Here's a case of using bone marrow aspirates for a perineal tendon tear, injecting it intrasubstance, and then repairing it, and then showing MRI results of the repaired tendon in an asymptomatic patient. And again, I said earlier about the PRP, maybe that's not the right thing. But if this is bringing stem cells with it, maybe this is the right thing for some of our soft tissues. Here's just a bone application, one of the paper that that I wrote that we used it for a non union and showed that basically the PRP, sorry, excuse me, the bone marrow aspirate was able to to help with the non union. There are other studies in literature using it for bones, this is for fifth metatarsal fractures. And basically they showed in 26 athletes that the addition of bone marrow aspirate and plus a screw for Jones fractures showed a 96% fusion rate at eight weeks, and a mean return to support at 10 weeks. The only problem with this study is there's no control group that didn't get bone marrow aspirate. And then just one more study on Achilles tendon rupture repair, and using bone marrow aspirate as an adjunct. And they found that 92% of these patients returned to support for months, which I think is pretty reasonable, even in a non bone marrow aspirate cohort, which this study did not have. And similar to what PRP was shown for cartilage, there's also some evidence for bone marrow aspirate use, concentrated bone marrow aspirate use in cartilage. This study was 52 patients just with a microfracture of osteochondral lesion of the talus compared to 49 patients where they microfractured and added concentrated bone marrow aspirate. And what they found was a significantly lower revision rate with the addition of bone marrow aspirate. The outcome scores were similar in both groups, but they had less revisions in the bone marrow aspirate group. And then similarly, a systematic review of bone marrow aspirate. And there was, again, also four studies in this one, three of those were retrospective, and the authors conclude that there's really a paucity of long term data or evidence to support the use of bone marrow aspirate for cartilage repair. What I chose in these studies is really the ones with isolated bone marrow aspirate. There are a lot of studies using bone marrow aspirate concentrate on various matrices, but then that kind of waters down the literature, if you will, because everyone's got their matrix of choice, and it really is hard to compare really apples to apples. I mentioned problems with PRP. And I think one of the problems with bone marrow aspirate is, again, we don't know what we're getting. And I think you can imagine that obtaining bone marrow aspirate from these two individuals might be far different than your highly athletic patient, which might have more stem cells. There's plenty of data to show that as we age and with various comorbidities, we have less of a stem cell population and therefore give us less oomph, if you will, in the biologic. So where is bone marrow aspirate along this timeline? I actually think it is, to some degree, at least in the literature behind PRP, which is surprising, because I thought it would be much better given the fact that there's added stem cells. But the literature really isn't there to support the use of bone marrow aspirate as a biologic in many of the things that we do. And I thought I'd just review amniotic membrane quickly, because it is another very popular biologic, at least in the United States. The membrane basically has many collagen, there's no stem, many collagen, excuse me, there's no stem cells, but it has a lot of growth factors. And that's what the hype is around. The other big things is, even though it's an allograft, there's no immunogenicity, it has anti-inflammatory properties, antifibrotic, promotes epithelialization, and it's also antimicrobial. So a lot of potential benefits to the use of it, but it really isn't shown anywhere to be beneficial. Here's a study, and we say, well, I can't inject that. Well, you can, there are preparations where it's micronized, so basically a powder form that you can inject. And here's one study that showed potential benefit, but if you look at the results, they followed patients up 12 months, but they only report on three months results. And so, well, at three months, the injection of the amniotic membrane, micronized membrane was better. There's a reason that the 12-month follow-up results probably aren't presented. And so I don't think that this is a great study. Here's another one that showed, that did show significant improvement of using this dehydrated, this powdered form for plantar fascia, of injection in plantar fasciitis, but they only followed out to eight weeks. And there was significant improvement there, but again, eight weeks is not enough time to determine if these biologics are going to work. If we do follow them out a little bit longer, so now we're getting a better study, this is a randomized controlled double line study for plantar fasciitis, injecting the amniotic membrane, and they found no difference. And that was a 12 week follow-up. So again, as we get better studies, better level of evidence, the data really isn't there to support it. There is one study that shows that it may help with some of the wounds that we encounter in foot and ankle surgery. And this one was done out of the Charlotte group, which was a retrospective comparative study, 54 patients with amniotic membrane and 50 without amniotic membrane placed over the extensor retinaculum at the time of total anchor placement. And what they did find was a significant decrease in wound healing time by about 11 days, not necessarily the difference in wound healing, but the time to healing was decreased with amniotic membrane. So where's amniotic membrane on this timeline? You know, I think it's kind of in the same level as all these other ones, really, we're still in this anecdotal case series, level of evidence, really not strong clinical trials. And so in summary, what I can say is that there are certainly many more biologics than what I've covered here. What I can say is that all these papers did show that these biologics are safe, there's really not a reaction to a lot of your autologous tissues and harvesting techniques. So I think that these biologics are relatively safe, but we haven't really demonstrated any efficacy behind them. They certainly work for the basic science literature in a controlled setting, but we can't control our human populations. And the only advice I can give you is really know what you're using, what's in it, how it's supposed to work, and how much does it cost in today's environment. And those are the best things that I can tell you if you're going to decide to use a biologic. And I think we have to, you know, really, what all the data shows in this graph at the right, if we take a look at efficacy versus cost, our current biologics are really high, they have a high cost, but they have a low efficacy. And so we're in a danger zone where we shouldn't be, we should be on the other side of this line, where the efficacy of these biologics is high, and the cost is relatively low. So that's what I have for tonight. And I guess now we'll go into some some case studies and questions. Thank you, everyone. Thank you very much for three very interesting, fascinating talks. And I'd like to now take the next few minutes to pick the brains of this panel to discuss some clinical cases. So let's try and share my screen. Right, can you see that? Right, so the first case is going to be a patient about resistance, resistant, mid substance Achilles tendinopathy. And I'd like to introduce Rod Jakes, who is the Medical Director of the English Institute for support of sports and, and has had a long history of running the British Olympic team and has immense experience in this topic. But really, the case we've discussed for a few minutes is what's the role of biologics and this patient who's a middle distance runner has a 16 weeks of pain in the mid substance, it's confirmed on this MRI scan, which is on the screen of the ultrasound, and it's a severe pain, they've tried all the other non operative, sensible measures of physiotherapy, and orthotics and shockwave treatment. And they've come to see an eminent sports medicine physician, like Rod. Rod, what do you see as any roles or what's your experience with the British Olympic team on biologics? Thank you, Rick, and good. Hello to everybody. So this is a 40 year old male distance runner. And my experience in mid substance Achilles tendinopathy, which is the more common location of tendinopathy rather than the insertional one, which is far less common, is that this does tend to be in the sort of fifth, sixth decade of life. But we have seen it, of course, in the second and third decade of life amongst our Olympians. When I first started work at the English Institute of Sport, we have an electronic medical database and on our 1400 athletes who are funded. And we had circa 33 lost days to training every year across our, our athletic population, of which over 15 of those days were due to some sort of tendinopathy. We started therefore, to do a sort of preventative strategy for tendinopathies, not on so much on those who've got it, but those who might get it, particularly in those sort of gravity dependent sports. And we had everybody three times a week doing mechanical loading, particularly eccentric loading. And in the last 16 years, we now have on average circa three to four days lost a year due to tendinopathy. So it's been a substantial effect on a prophylactic basis. As to the effect on as a treatment, well, I think it still is certainly in animal studies, we know that mechanical loading of tendons, plus PRP, there is some synergistic effect between these two. But of course, as James has pointed out, we really don't know what the well constructed studies are actually pointing to. In research papers, there are so many variables that one's looking at, not least of which is exactly where the PRP was placed in terms of ultrasound guidance, what the intervals were between the PRP from one injection to the next, and then what the actual regime of eccentric loading was. So in this case, I would be very cautious as a clinician to go back over exactly what eccentric loading was done. I would really question the patient very carefully to see what sort of regime they had been on. I would look at their technique in the clinic to see that they would match the technique that we use at the English Institute of Sport. When we talk about optimising orthotics, well, I think certainly the evidence shows that for medial Achilles tendinopathy, medial arch supports show some benefit, but as a generalisation, orthotics don't make that much difference. And shockwave therapy, I think the jury is still out there. What I think we've got to consider here, of course, is the whole apparatus from the triceps to your eye through the Achilles tendon into the plantar fascia and to look at the mechanics of that whole connective tissue sheet in the assessment of this individual. But I think the key issue for me would be to really question the supposition that proper eccentric loading had taken place. And I would not jump on the bandwagon of doing PRP, not least of which, because as soon as the changing room knows that you've done one PRP injection, absolutely everybody else in the changing room will want to come in for a PRP injection as well. And you suddenly find yourself with a very busy outpatients and a huge expectation on a course of treatment, which is very, very unproven. I guess that makes the evidence very hard to interpret too, is if you don't know how optimized our patients have been before they entered into any of the trials, it must make it difficult to interpret. Tom, what's the North American view and experience in this type of tendinopathy and biologic? Well, for me, I actually agree 100%. Much as patients often get a second opinion from their physicians, I often refer patients for a second opinion to their second physical therapist, just for the reasons stated. We don't know exactly what has been done here and are there other options to choose from? However, if we know that this patient had optimum therapy and orthotics, this far along and pain not going away, this is now a patient that I'm gonna consider operating on. And I agree that I wouldn't jump right to PRP or bone marrow aspirate concentrate, which has also been used. I just don't think the evidence is there for those this far along. And so I'd recommend surgery at this point. And so one of the things that my colleague, Matt Koster in Oxford, and their group published in the JAMA in July was a randomized trial of PRP in Achilles tendinopathy. They found no difference really. So I think that's tends to be where the clinical evidence is heading at this stage. Rod, the next case is a similar one. What about for that other Bette Noir, the patient who has plantar fasciitis that's refusing to get better? What's the evidence for that in biologics and PRP, for example? Well, a little like the last case, this is much more common in the sort of fifth, sixth decade of life, as opposed to within the 20 and 30 year old. So I have to confess a little bit of a heart sink when someone comes in with a plantar fasciitis or so-called plantar fasciitis, because I know this condition has very poor evidence-based treatments. And I think the first thing to do, I think, is to question the diagnosis. You and I, we all will be familiar with the other mimickers of publicly declared plantar fasciitis, not least of which I think is the sort of bone stress that can be associated with this in the calcaneus and the role played by the flexor hallucis longus. I think thinking carefully about the case and looking at the dynamics first, certainly of the first MTP joint of the midfoot around Liz Frank's line, looking at the flexibility of that. And again, the stretchability of the triceps uri and Achilles tendon complex. I think that's well worth close inspection on the plinth in your examination room. I think, again, in this instance, you've chosen somebody with a BMI of 28. We do know statistically over a BMI of 27, you're more likely to get this condition as you are if you're less physically active. And I think my suggestion would be in this case, double check the diagnosis, make certain that there are no other associated factors which make this plantar fascia more persistent. And then I think in the inexorable logic of medicine, you keep the patient occupied whilst mother nature actually starts to settle this problem down all by itself. So I wasn't quite sure what a normal BMI was in our side of Atlantic compared to the other side of Atlantic. Sheldon, are American sports physicians and orthopedic surgeons tending to use a PRP or other agent in this type of case? Well, I think it's very controversial for a chronic plantar fasciitis. And sadly, I could tell you in my FDA trial, the BMI in my area was sitting around 40. So we have a maybe subtle more plump populations like to put it. But the things I would like to do is that a person who's a recalcitrant heel pain, you know what I need to do is get more information. So what I'll do is I'll put them into a cam boot for comfort. I might get them a night splint, but at the same time while we're doing all this, we'll order the MRI. The MRI has to get authorized, the MRI has to get obtained. That'll take about two or three weeks through our health system. And subsequently, but during those two or three weeks wearing the cam boot, having the night splints, as I think Dr. Ajok really pronounced it, nature sometimes will solve the problem on its own by doing these non-operative measures. I think to do the PRP is somewhat controversial because the data has not really been that substantial. So I think that's my thoughts on that topic. Yeah, so certainly my reviewing the data, it seems to be even less solid data for use in plantar fasciitis, but I'm absolutely delighted that you've got waiting times for MRIs as well on that side of the Atlantic. Fantastic. Yes, it has to get authorized. Can I ask you this next one then? Because we've had a great talk about fusion previously. So this is a patient who's had a non-union of their subtalar fusion. You see there's a single screw and he's a retired judge to get you a little bit concentrating. And he had vitamin D deficiency, which was corrected, but the pain is still there. And the CT shows there's no hint of union across this subtalar joint 18 months out. They have had a renal transplant, so they have been on immunosuppression, so they may have a reason for this. But is this the sort of case that you feel the odds are stacked against you? Is this one that you might intervene with biologics, either scaffolds or cells or signaling growth factors? I mean, clearly for hindfoot fusions, the non-union rate ranges between 10 to 15%. And I would sit down with the patient and I ask them, what truly is your goals? Because there are still non-operative measures that are FDA approved, for example, a bone stimulator that sends ultrasound waves that has approximately an 84% success rate. I mean, it might take a little bit of time. I asked the judge, what do you think is your timeline? What do you really want out of this? Because he is at high risk, but if he says, this is obviously a non-union, I'm not getting better, I have a lot of risk factors, then my mind is this triad, triad of cells. I need to add cells, I need to add the appropriate biologics, need to have the matrix. Because each one of them we've looked at from the article by Burlett showing how PGF-beta-TCP may mitigate the age. Number two, the matrix from DG Avani's article on GBGS, how fill does matter, the amount of fill of the defect, and more importantly, the cells, which we've all seen from bone marrow augmentation. This triad, I think something I would offer to the patient who has unfortunately has not healed, and probably with his risk factors has a high risk of still not healing. So that's what I would do is really sit down with him, non-op, consider a bone stimulator, give it more time. What's your timeline versus, here's my surgical intervention, here's the triad that we need to consider to help you. And James, in central London, if this was discussed in your 40s MDT, what would be your heart sink and what would be the sort of consensus opinion in London? Well, I think he's got a high chance of having an infection. So you need to do a biopsy before you do it. I think you need to get in there and do a biopsy. And then you have to counsel him. If at the age of 73, he's retired, you can give him an offloading brace and I have got a few patients going around with an offloading brace, which we've used in the military in the past. And they've actually functioned pretty well with that. If you're going down the surgical route, yeah, I threw the book at it. I think, yeah, you're gonna use cells, but I would use BMAC as well and a bone stimulator and give them absolutely everything second time round. So yeah, I threw the book at it next time round. And how about in North Carolina, Tom? Well, I think everything, I agree with everything that was said. Throwing the book at it also includes improved fixation. So for me, for this revision, it's gonna be at least three screws, probably some other devices in addition to bone grafting with stem cells. Thanks very much, Sam. So the final case to discuss is again, another difficult area where we have a osteochondral lesion of the talus, the cartilage is damaged. There's been a microfracture before and there's a, what we call a HEPL-5 with a cyst underneath. So a significant bone loss to the defects, obviously not just cartilage, but a deep loss of bone. What do people, people might consider oats, but with regard to biologics, do people intervene with any additional treatments? What do we start? So James. I wouldn't use a biologic in this just as a single therapy. I think I would use it as an adjunct. So I do use it if I'm performing an oats procedure for this. And I think there is some, there's some work, which obviously John Kendi has done with Lisa Fortier as well, Lisa Fortier up in Cornell. And there's some quite good work looking at the incorporation of oats plugs from the work that's been translated, obviously from the animal models with Lisa through to the humans at NYU and HSS. So I would use it as an adjunct. I wouldn't do it just as a primary procedure, just squirting it in. I don't hold out much hope for that. So an oats as opposed to an amic type treatment? Yeah, I've tried, I tried amic and I haven't had any success. And I haven't had the success that I've had with oats and I'm much more confident with doing an oats in younger people. I haven't seen the knee pain that's been reported previously, perhaps because we're harvesting from the knee a little bit differently from perhaps we were 20 years ago. So yeah, and I haven't had as good results personally with the amic. And that's the thing, that's quite a few of my colleagues in the UK as well. I know that reported well in Italy and in Switzerland, but I haven't had the results that have been reported there. Sam, you gave us a very good troll through the literature earlier on. What do you think is the evidence for intervention here with a biologic? Well, there certainly is some evidence to intervene with either PRP or concentrated bone marrow aspirate. But in most of those studies, we're talking just about restoring the cartilage. And as James mentioned here, you have to think about the bone. And if you weren't gonna go down the oats pathway, you at least need to put some type of allograft to fill that cystic area in, and then some type of cartilage restoration on top of it. I know we have a little bit different in the States on what's approved and what some of you all have, but in my hands, I would graft this cyst area, and then on top of it, either put some type of allograft cartilage matrix. There are various suppliers in the United States for those, and maybe even a juvenile cartilage, and use bone marrow aspirate concentrate as well. Thank you very much. So I've had some questions that I've collected, and I'm just going to move on to that phase if I stop sharing my screen. Yeah, so this question came in from Hiro Tanaka in Wales, that's a very similar product. So autologous conditioned plasma, which I understand is very similar to PRP, that's been used by rheumatologists for dealing with inflammation around inflammatory arthropathy. Do you think there's any role for that in the inflammation of synovitis we see with anti-impingement in the ankle? Do you think PRP or equivalents may have a role in that? Sheldon, any thoughts? Well, clearly the impingement is really inciting the inflammatory process. So if that's the major issue, then that probably should be dealt with. I don't think there's really strong evidence that the PRP, or in this case, the autologous platelet, will really do much to resolve the problem if the underlying impingement still exists. And that to me is the hard question. You know, what's really causing that inflammation, that inflammatory process? James? No, I haven't used it in that sort of condition at all. I haven't got any experience with it and I haven't got any, more importantly, I haven't got any evidence that it would work. So I'd be reluctant to go down that route, actually. But the physicians, the rheumatologists may disagree. And Rod, from your side, you may have something to say about that from the physician's side of things. I think the key point here from Rick is that there's evidence of mechanical impingement. That's the driver for the inflammatory process in the anterior synovium of this ankle. And, you know, for that, that requires a sort of geometric correction of the front of the ankle. I suspect the rheumatologist is using this modality on non-impingement inflammatory processes inside articular surfaces. So I suspect the driver, the genesis, for what they're treating is different to what we're considering in this case. Yes, so if we move on to the next question, just one of the problems when you discussed the evidence, lots of different preparations are used with different cell concentrations and different types of cells, very much to the drug store that you mentioned, James, but how are we going to standardize the methodology of experimentation and future studies and trials to be able to compare effectively oranges to oranges and apples to apples? Is there any progress towards trying to standardize? I know you've helped standardize with cartilage descriptions in tailor's damage. Should we be starting to internationalize this and standardize how we compare these? Yeah, I think we need to look at what the baseline level is. So some of the papers don't have the baseline level of what the blood constituents are, first of all, before they start looking at the PRP. And then we need to start looking beyond the cells. I think there are very good methods of looking at what the drug store is there. So you're looking at CD, the different constituents and different components within that. And that's expensive. That takes a lot of time. It's a lot of preparation, a lot of lab work. But that's the way we've got to be going. If we're going to compare any of these studies in the future, because just by saying we've got leukocyte rich, leukocyte poor, whatever, isn't good enough. So I think that's the way we need to go. We need to get the molecular biologists in there to actually do it for us. So we haven't got that much time left. So I've just got a couple more questions that have come in. One question from Tom Harty, the chairman of your AOFAS education committee. He was asking again about the question that we touched on a little bit before about oats. Has there been a study between a standard oats and oats with an augment? Has that been done yet as far as the panel are aware? So there was a review article by Tom Clanton and she looked at the role, let's say bone marrow with oats plus or minus the bone marrow. There's an article, personally randomized, one article by Hannan in 2016 and some case series by Kennedy and Giannini. But again, while the data seem to be supportive of bone marrow, there is again, these limited three or four articles. And therefore it shows you that more research is needed to understand the role of these other adjuncts like adding a growth factor, adding some other agents besides bone marrow to an oats procedure. I mean, I hope that answers the question. Yeah, it answers the question to explain that it's even more complicated as we start having more dimensions to what we can do. Yes, we're running out to just a final question. Maybe this is a question for my junior colleague in Oxford for you, Rod. So if you were a new consultant starting out dealing with patients with sports foot and ankle problems and he's a moderately thinking clinician, what advice would you give to him about PRP and other agents? Look, I think we have to keep a very open mind to the biologics. Potentially on paper and in animal studies, it's exciting. I think it's a great treatment, but we're trying to work out how best to place it in different contexts of both orthopedics and in sports medicine. I think we have to keep a very open mind in this area. I don't think we should reject it out of hand. I think we should engage with the process and get involved in well-structured, preferably sort of blinded placebo-controlled trials, which are really difficult to organize, but they are the gold standard, of course, of the medical sciences. So I think I would be positive with the junior consultant, but I would ask them on a patient-to-patient basis to be very circumspect, to do the basics well, to think both around the tissues that you're looking at and the tissues, both proximal and distal, as to how they might be influenced and why that tissue failed on the basis of how proximal and distal tissues might have contributed to that failure. But I'd be positive about this. I don't think I would do anything else than keep an open mind. Thank you very much. That brings us up to the end of the hour, really. So I'd like to thank you, Rod, and to James and Sheldon, and to Sam, thank you very much for your contributions. It's, in fact, been very interesting. We've discussed how biologics can work as a supply of cells, about what is mixed up in that cell, and we're gonna need to become more sophisticated to go to the drugstore and be specific about what we need for different conditions. We have to be careful with the choice of scaffolds, as Sheldon said, and then the signals we use and the roles of the various growth factors, all these things we can tweak and adjust. But at the moment, the data's not there for clinical studies in great depth, and we need to work on that, and that'll be something exciting, as Rod says, something to watch and to be positive about, but we need to evolve that in the future. I hope people have enjoyed this evening. We have two more shared topics with AOFAS and BOFAS. I think it's the 13th of January. We have a discussion on the management of complex pilon fractures, and then on the 10th of February, we're gonna discuss about failed problems after Hallux-Valgus surgery. So I wish you all a happy festive season, whether you're shivering in East Anglia in the UK or sitting on a beach in Hawaii. Thank you very much for joining.

biologics

foot and ankle surgery

standardized methodology

clinical evidence

PRP

Achilles tendinopathy

plantar fasciitis

diagnosis

mechanical loading

non-operative treatments