welcome you to this AOSSM webinar titled How to Incorporate Biologics into Your Practice. Thank you all for joining us. I am Ryan Rock, tonight's moderator, excited to lead a great discussion this evening with the incredible faculty. Christina is the AOSSM webinar organizer. She'll be adding information into the chat regarding Q&A and CME credits for this activity. And we also ask that if you have any questions, please submit them through the Q&A feature throughout the webinar, and we'll try to answer them in a timely fashion. Great. So there's more information about the CME credit. And then the disclosures for the faculty and organizers are listed here, as well as the learning objectives on the following slide. And I'm pleased to introduce tonight's presenters. So there's kind of our general outline. So Dr. Scott Rodeo is a clinician scientist at the Hospital for Special Surgery. He has appointments in the Department of Orthopedic Surgery as well as Research Department. He's a professor of orthopedic surgery at Weill Cornell. He's a co-chief emeritus of the Sports Medicine Service at HSS, and he's the head team physician for the New York Giants. His particular role with biologics is he's the co-director of the Soft Tissue Research Program at HSS, and he has extensive clinical and research experience in biologics and gets asked to present nationally and internationally. So it's a honor to have him here to learn from. Dr. Jeff Abrams is an associate professor within the Department of Orthopedic Surgery at Stanford University, specializing in sports medicine as well as tendon and ligament reconstructive surgery. He's also actively involved in tendon disease research, focusing on the role of micro RNA in tendon-derived stem cells and the pathogenesis of disease. He too has been given numerous invited as well as original research talks nationally and internationally. As far as his sports medicine exposure, he serves as the director of sports medicine for varsity athletics at Stanford, team physician for the San Francisco 49ers and was previously an assistant team physician. And then last is Dr. Miszkowski. Her talk is prerecorded, but she's an associate professor of orthopedic surgery at University Hospital in Cleveland. She has fellowship training in sports medicine as well as foot and ankle and currently serves as the head team physician for Case Western and Lake Erie College. Additionally, she is a member of the Sports Medicine and Science Committee for U.S. figure skating and a consultant for Team USA. And I am Ryan Rock, assistant professor at Ohio State, specializing in shoulder surgery and sports medicine and serve as a team physician for the Ohio State football. So I'll turn it over to Dr. Rodia, I guess. 10 minutes, everything to know about orthobiologics. I'll try to go through this here and give you a little summary here. My disclosures, much of this supports our laboratory program. So I might just give you a little overview. It's a big, big field, obviously. So current indication, when might we use PRP? So probably the best data right now for the treatment of symptoms of NeoA, and this is due to the anti-inflammatory and immune-modulating mediators that are abundant in PRP. We know that PRP and many of these biologics are symptom-modifying, but very little data to suggest they are truly structure-modifying. We don't regenerate any tissue. The fundamental questions that certainly remain about the optimal formulations of PRP and a number of outstanding questions, leukocyte content, platelet number, number of injections, et cetera, et cetera. PRP is very complex, and there's a lot we don't know. Current data suggests that a higher platelet dose is probably the most important factor, more important than the leukocyte content. Just briefly to give you an overview of really the 40,000-foot view, recent systematic reviews demonstrate that PRP can be effective for NeoA. The Colorado group, PRP compared to HA, PRP was superior. Group from Beijing, multiple-dose PRP better than multiple-dose HA. Group here from Korea, PRP superior to HA at six and 12 months, and both single and multiple injections of PRP improved pain better than HA. So there's actually pretty good data now on PRP for NeoA. From our own academy, the Yellow Journal published last year a review. This is PRP versus control. The up green arrow means that PRP is favored. You see that there, and then here's the bottom part is PRP versus hyaluronic acid. Again, kind of summarizing a lot of these studies here. Now, recent data suggests that leukocyte content, in fact, does not appear to affect outcome. Giuseppe Filardo and his group in Italy have done a lot of nice work in this area. Just some quick examples. A double-blind, randomized trial. Patients getting three injections of leukocyte-rich or leukocyte-poor. Essentially, no differences between groups in efficacy or adverse events. Another study from that same group here. The first study used cryopreserved PRP. Here's the study here. They repeated it with fresh PRP. Again, double-blind trial, three-injection cycle. Again, no difference between groups in efficacy or adverse events comparing leukocyte-rich versus leukocyte-poor. So, much less concentration now on leukocyte content. Much more data suggests that, in fact, higher platelet number appears to be more important. Again, a nice study from the same group from Giuseppe Filardo published last year looking at platelet number. So, patients, this is all neo-aced, straightforward trials. Three intra-articular injections of PRP. And they had a low, medium, and higher platelet group. But essentially, PRP with a higher platelet concentration provided lower failure rate and better clinical outcomes. They then, just earlier this year, published a meta-analysis here. And again, looking at 18 randomized trials, they found that higher platelet yield, higher platelet PRP provided superior pain relief and more durable functional improvements compared to lower platelet yields. And this goes back to a widely cited study, Bound-Solomon in India here, where they had 150 patients randomized to PRP versus HA. They found significant improvements in both. But in fact, what they found was an absolute platelet count of 10 billion platelets in a PRP formulation was associated with a sustained chondroprotective effect out to one year. Question comes up, should we do a single injection or repeat injections? Really no consensus in this area, again, due to the heterogeneity in outcomes. Repeat injection likely does improve outcomes. A study from China, so this is a systematic review of seven trials where they found the triple dose PRP did seem to be better than a single dose PRP, but you're getting into basic kind of logistic issues. For our athletes, how practical is that to do repeat injections? You may have cost issues for your patients. I usually do a single injection and then monitor patient's response. Circumstances may allow repeat injections. For athletes, maybe in the off season or things like that, but in general, I do one injection and kind of see how the patients do. Tendinopathy. There is tremendous variability, of course, in the reported clinical outcomes. Again, this relates to the heterogeneity in all these formulations, which you can see for any of these orthobiologics, the heterogeneity is the biggest issue. So to start with, just a nice systematic review a couple of years ago, just gives you a sense of the landscape here. So randomized trials, so a well-selected trial. You see all the different tendons that were treated here. And essentially, here's the problem with our literature. The quality of evidence was low for most of these studies. And if you look at this review, they concluded in the majority of comparisons, the effect size was comparable to control groups. So not a lot of support here. Now, a lot of the generally accepted dogma has been that we should use a leukocyte-rich PRP for tendinopathy to sort of, quote unquote, turn on the biology or make a chronic process acute. This goes back to classic work from Jane Fitzpatrick in Perth, Australia, and a systematic review of 18 different studies. And they found a strongly positive effect for leukocyte-rich PRP systems. No really differences amongst the different controls. And so they concluded that there is good evidence to support the use of a single injection of leukocyte-rich PRP for tendinopathy. Now, that may be, this wasn't really looked at as much in the study, but the leukocyte-rich formulations often have higher platelet yield. So this may go back to platelet number. There were some studies that do support PRP for cuff tendinopathy. This group from Ian Lowe and his partners, a double-blind, randomized trial, patients treated with PRP or corticosteroid for essentially, you know, cuff tendinopathy or impingement. They found better improvement in the PRP group at a three months. Luciano Rossi, a friend of mine in Argentina, has done some nice work in this area. And they compared patients with cuff tendinopathy versus partial thickness cuff tears. And sometimes that distinction is hard to really make, quite honestly. But these are all known non-op treatment PRP. And they found better improvements in the tendinopathy group versus partial thickness tears. But they did find a positive effect of PRP. And then another study from Luciano and his colleagues, similarly, a double-blind trial where they looked at PRP versus steroids, again, for cuff tendinopathy, subacromial injections, and better outcomes in the PRP group as well. They had a higher failure rate in the steroid group. So some data here to support PRP. Summary, PRP for tendinopathy, again, tremendous variability in reported outcomes. This relates to the different tendons that are treated. Most importantly, the variable PRP formulations, other concomitant treatments, you know, et cetera, et cetera. But the bottom line is there's some limited support in literature for a positive effect for leukocyte-rich PRP systems versus leukocyte-poor. What about cuff repair? Meta-analysis do suggest improved structural healing. I'm just going to list four here quickly for you in the interest of time. But all four of these, Tom's Vang's Nest, the first one with Chen, and then a group from China there, Ian and Hurley in Dublin, and then a group from Athens, Greece, all these demonstrate decreases in retear rates using objective imaging, either ultrasound or MRI scan. And many of these, the patient-reported outcome measures are improved as well. So the bottom line here is PRP does appear beneficial to improve structural healing following cuff repair. And that doesn't always correlate or relate to or lead to improvement in clinical symptoms. We know there's this disconnect between clinical outcomes and structural healing, but certainly there's some data here on structural healing. Lastly, cell therapy approaches. I would submit to you we have essentially zero ability to use stem cells. Everybody uses this term. And here's just some thoughts for you. The minimally manipulated cell preparations that we currently use in the U.S., bone marrow, adipose, whatever, these need to be distinguished from sorted, culture-expanded cells that are produced in the laboratory. The term stem cells should not be used when discussing our current techniques for cell-based therapy. The number of true stem cells, by any cellular, molecular, or any functional criteria in our currently used formulations is very, very, very small. In fact, it's well-established and agreed upon in this community that the term MSC, mesenchymal stromal cells, should only be used to refer to culture-expanded population of cells that meet these formal criteria from the International Society for Cell Therapy. The term MSC should not be used to describe the heterogeneous population of native cells with undefined properties in vivo. So the freshly harvested tissue we get in the operating room or our clinics, those aren't merely stem cells. And the current understanding is that cells work via a paracrine mechanism. They produce a number of immune-modulating and anti-inflammatory signaling molecules that may modify the local or even distant environment. But there's very little data to suggest that cells we inject actually graft. Rather, they just produce a number of signaling molecules. Now, there is some data on cell therapy augmentation of cough repair similar to the story with PRP. It goes back to a kind of classic study from Phelan Pernigou in 2014. 89 patients with cough repair, half of them received bone marrow aspirate concentrate at the repair site. A 10-year follow-up intact repairs were 87% in the cell therapy group and about half that in the controls. And in fact, a long-term cough integrity is better in those patients who received a higher number of cells. Group from Seoul, Korea has similar study using adipose-derived cells. And the re-tear rate, again, is about half in those treated with cell therapy. And then last year, the group from Rush, Presbyterian, similar study in 90 patients, half received concentrated bone marrow aspirate. Re-tear rates based on MRI was lower, 18% versus 57%. But did not really lead to a change or difference in the clinical outcome. So again, that disconnect between structural healing and your clinical scores here. Lastly, what else cell therapy for osteoarthritis? Thought I'd put up this very kind of highly visible study you should know about, published in Nature Medicine last year. Phase two, phase three, multi-center study. Well-done study, 480 patients. They had three arms. Autologous marrow aspirate versus steroid, umbilical cord tissue-derived cells versus steroid, and then autologous adipose tissue versus steroid. So three different arms, simple and single injection for knee OA. At one year, all treatments led to improvements. But if you look at the graph here, see how those lines are all similar? Essentially, they found no difference between groups. No orthobiologic treatment was actually superior to steroids, in fact. And they're continuing to look at this data. But their early data and early analysis found also no change in MRI gradient of osteoarthritis. The question is, is there any structural changes? That will continue to be looked at. But so far, not much there. And I was asked to write an editorial for that journal. I just kind of helped summarize here that kind of where this field is as of this study. New findings suggest that current cell therapy approaches are not superior to simple steroid injections. So it clearly highlights the need for further research in this whole area here. So to summarize here, clearly orthobiologics, you have great promise. No doubt needs further work. I would submit to you we need to start identifying the biologic targets we're trying to treat. You know, is it decreased inflammation, turn on cell proliferation, matrix synthesis, chemotaxis, these are all important biologic functions. But they're all very different. We need to rigorously define the composition and biologic activity of what we're putting in our patients. And only then can we match the biologic agent we're putting in our patient with the desired biologic target. You know, one size does not fit all. I think that no doubt changing the regulatory environment, allowing us to manipulate cell formulations will advance the field. We'll hear more about that in the next talk, I think. But this would include enzymatic digestion of adipose tissues, the ability to do cell sorting or culture expansion. I submit to you what we need to do is be able to select the desired cells and importantly eliminate computing cells from a heterogeneous cell mixture. And on the horizon, some exciting areas. You've heard about exosomes, certainly needs further work. I think we're learning about methods to stimulate the intrinsic progenitor cells that exist in many tissues. And lastly, a lot of the work in this field now is look at the interaction between cell therapy and stem cells with immune cells and that in the interaction there, which seems to be very important. Okay, so I'll stop there. Some thoughts on the regulatory environment. I'm gonna try to move through this again in the interest of times. So, you know, it started around 2017. The FDA put out some important guidance documents in 2017, just to kind of set the stage. This whole area of orthobiologics, they're regulated as HCTPs, human cell tissue and cellular tissue based products under the CFR 21. It's not important to understand, but it's the Center for Biological Evaluation and Research, CBER, to regulate seeds. If you've followed a lot of the changes in the FDA, you'll know there's been important and distressing changes at CBER. The important aspects related to regulation of regenerative medicine, number one is this concept of minimal manipulation. That refers to the processing of human cells or tissues in a way that does not alter their original relevant characteristics. Examples of minimal manipulation would be just, you know, centrifugation of bone marrow, for example. More than minimal manipulation would be using enzymes to digest fat, you know, from adipose tissue, or expand these cells in culture, certainly. Other important concept is this concept of homologous use, which is using human cells or tissue products to perform the same basic function in the recipient as in the donor. And this gets kind of gray and murky, but some examples would be, if you're using amniotic membrane, homologous use would be using this as a barrier or for its anti-inflammatory properties, because that does have that role in the fetus. If you're using adipose tissue, for example, homologous use would be using fat tissue for cushioning or for support, as fat naturally does in the body. But you'll see this gets kind of murky and gray, some of these definitions here. This is a chart from my, I put together a summary for our yellow journal last year. And just briefly, there's section 361 and section 351. Section 361 is your lower risk formulations that undergo minimal manipulation, and they're intended for homologous use for only a simple example would be bone marrow, aspirate concentrate, or your microfragmented fat. In contrast, section 351 is your higher risk things, such as cultured cells, or using any of these perinatal products, such as the amniotic membrane. These need to undergo a formal biologic license application, so very distinctly different. These perinatal products have been out there, including materials derived from amniotic membrane, umbilical cord bloods, wharton's jelly, et cetera, et cetera. These can only now be used under an investigational new drug application, or essentially an FDA-approved trial. So, as of the end of this discretionary period four years ago. So, these essentially are off the market, unless, you know, you and I can't use these unless it's used under a clinical trial. The reason is they fail. They often fail the minimal manipulation criteria. They often fail the homologous use test, and sometimes they're combined. If they are combined with other substances or intended for any systemic effect, then that's called a drug, and that's going under a 351 pathway, very different pathway, again, which requires a biologic license application. So, long and short of this, these perinatal products can only be used under an FDA trial right now. What about PRP? So, PRP is not FDA-approved. This is not approved as a standalone product for any indication. FDA has cleared the centrifuges used to produce PRP. These centrifuges are essentially class two medical devices cleared through the standard 510K process. PRP, though, is considered minimally manipulated autologous blood, and of course, we can use this in practice under essentially what is off-label use, but manufacturers, they can't go and market PRP for unapproved indications. They can't say it stimulates joint repair or cartilage replacement or cartilage regeneration, anything like that. Autologous condition serum, Regenikine or Orthokine, this is a process whereby blood is heated and incubated overnight to stimulate the production of IL-1 receptor antagonists, a potent anti-inflammatory cytokine. This is then injected in the patient the next day. This process exceeds the minimal manipulation criteria and does not qualify for exemption under the Section 361. It has not received FDA approval via a biologic license application. It has not been cleared as a device or a drug. It's been out that it's used, but it's understand this is the current regulatory status of an autologous condition serum. Microfragmented fat, the lipogens. I have no relationship with any of these companies, by the way. This is a sterile single-use medical device that essentially processes adipose tissue. It's kind of mechanical emulsification of fat. Fat is washed and then microfragmented. No enzymes are used, so it's not stromal vascular fraction. The FDA has cleared lipogens, so under this 510K pathway, due to substantial equivalence to other Class II medical devices. So they cleared the device, like PRP. It's thought to be minimally manipulated. The microfragmentation does not alter the standard characteristics of fat, and it seems to qualify into the homologous use that it's criteria, so basically as a cushion or a barrier using fat. So again, as I mentioned, homologous use gets a bit gray sometimes. This is just a summary from this review I put together a year or two ago, but just to kind of highlight a few things. So PRP is regulated under a 510k pathway. Bone marrow aspirate concentrate, again, the preparation devices are cleared under this 510k pathway. Lipogems, microfragmented fat, again, it's the device that are cleared under the 510k. In contrast, using the stromal vascular fraction or adipose-derived cells that are culture-expanded, that's all under 351. That needs a biological license application, needs an investigational new drug application. All of these perinatal products that I mentioned, these are all under Section 351. So amniotic membrane, amniotic fluid, things like that need a biological license application. Lastly, exosomes, just to highlight again, these also require an investigational new drug or a biological license application. Beware of the same surgical procedure exception. Basically, this is a regulatory exemption that allows certain products to be removed and re-implanted in the patient during the same surgical procedure. And to qualify for this exemption, they need to be removed and implanted in the same individual during the same surgical procedure. They can only be minimally manipulated. They can't be altered. So no additional processing beyond just simple rinsing, cleaning, or sizing. And this allows routine use of things like autologous, you know, using bone graft, things like that. So a lot of these things qualify under the same surgical procedure exemption here. Again, enzymatic digestion or cell isolation and acculturing, that is not allowed under the same surgical procedure exception. I submit to you, you should have a consent form for your patient. This is an example of the consent form that we've put together here at HSS, and we use it for, just to summarize here, PRP or any blood-derived product. We use it for bone marrow and adipose. So patients sign a consent form. I understand also there's the FDA right-to-try process. This allows patients diagnosed with a life-threatening condition who have exhausted really all of their treatment options to be able to try to use a drug that's not yet approved by the FDA. Now, the drug needs to have undergone at least a phase 1 safety trial, but this is another pathway that's out there, uncommonly used, but just be aware that this is out there. Lastly, Ryan asked me to put some thoughts on billing. So just again, a quick overview here. PRP, this is, you know, not covered by insurance. You should use the CPT code 0232T. It's suggested using an ABN, Advanced Beneficiary Notice, that should be signed by the patient prior to the procedure. The patient needs to be informed of the cost and the variability and unpredictability in outcomes. I think I always tell the patient that, that they are well aware. Understand the cost may be higher if it's done in a radiology suite, under ultrasound guidance, serial injections, of course, you know, you get into cost issues there. But you should use this ABN, this example of the Advanced Beneficiary Notice we use at HSS, where we state that clearly to patients, most health insurance plans consider this treatment experimental or investigational. We say that this non-coverage agreement must be signed by the patient, and we try to list some of the different health insurance plans that have confirmed non-coverage, which essentially, it's about every insurance plan, does not cover PRP. Intraoperative use of PRP. Some surgeons go ahead and charge the PRP procedure to the patient prior to surgery, and have the patient sign you an ABN, like you would do if he's in the clinic. If PRP is performed at the same surgical site, most insurers will bundle the codes, and only the surgical procedure would be paid. So, you're probably not going to get paid by the insurer. Our hospital goes ahead now and tries to bill the patient preoperatively, including both the surgeon's fee and a hospital fee, and they're kind of working through that actually just right now here. Some thoughts, lastly, on cell therapy. So, majorities are done in the operating room, you know, adipose or bone marrow aspiration, although it can be done in the clinic and are being done in the clinic. So, bone marrow aspirate, confusing. You should use this 0232T if it's centrifuged, and while you should use 20999 if it's not centrifuged. Now, it gets even more interesting. Lipogems. You should use the unlisted code for the body system where it's injected. So, you see here, knee, hip, or ankle, these different codes that they suggest we use from our coders and billers at our institution. Now, if you're using lipogems, or if lipogems are not being used, you use 15771 for the first 50 cc's, and then if you inject more, you use code 15772. So, again, at the end of the day, this is, you know, you need to talk to your coders and billers. Understand that many insurers don't pay. This chart just kind of summarizes how it's different. If you aspirate and centrifuge or not centrifuge your bone marrow, you have different codes here. And then on the fat side, if you're using the lipogems, you can use 15771. This is the other pathway as well. So, long the shorter here, talk to your coders and billers at your institution to see the best way to bill for these things here. This is just showing the B of the liposuction, which is based essentially on the lipogems. So, I'll just conclude briefly here. The regulatory environment certainly continues to evolve. As I mentioned, talk to your billing and coding experts as far as some of these nuances. Have a consent form. Have an ABN, Advanced Beneficiary Notice, for PRP. Do not use perinatal products unless they're in a formal FDA-approved trial. I still see patients in whom they're being treated with these materials. Be careful. The FDA will come after you. And, you know, avoid any aggressive marketing or false claims in your websites and things like that. The FDA is continuing to scrutinize this area. I'll stop there. Thank you. A question for you, Dr. Rodia. Is there a limit to the degree of osteoarthritis in the knee where you would offer someone a PRP injection? Or will you treat it similar to a steroid where, regardless of degree of arthritis, it could try, or you can try it and, you know, obviously not guaranteeing any benefits? There is a, I mean, if you have to bone on bone or particularly if there's architectural remodeling, flattening of the condyle in addition to bone on bone, I'm largely reluctant to do these. I think it's going to be less predictable, quite simply. And I make sure I tell the patient this is, this is, there's some unpredictability here. This is not magic. I tell the patient that the degree and duration of relief is variable. So, they need to go in eyes wide open because they're paying out of pocket. So, yeah, I think you need to, common sense would be that higher degrees of arthritis is less likely to be effective. Thank you. All right. Hi, everybody. So, talk about biologics in the shoulder. Spend about one slide on when to think about doing it. And then a bunch of others, the rest of the nine minutes on how. We know that if you do enough rotator cuff repairs, you're unfortunately going to see re-tears. Lisa Galitz talked now over 20 years ago about basically almost certain re-tear rates, at least partial re-tears in some and full re-tears in other. And those are really large, massive tears. And we've really spent the past many years looking at different techniques and different biology and different biomechanical constructs to try and get these improvements and get these tear rates down. And it's been a long journey and we haven't made a lot of progress, unfortunately. And so we're still working on it. And this talk will summarize some of those efforts from the biology standpoint. The talk will first start out just some basic surgical technique. You know, in a talk like this, there's a border between biology and then just simple kind of back to basics. And I just have to mention some of the basics, because if those aren't adhered to, improving biology and your repair construct is probably not going to help too much. We'll start a little bit on microfracture, blood-derived products. And then as Scott did also, you have stem cells are in quotes, and I maintain his thoughts on that. And then we'll finish off with tissue graphs, different types and different ways to use them. And then just a brief slide on kind of experimental approaches, which will be a quick overview. First one to talk about is when to use it. I think we all kind of think about this, or at least people who do a lot of, or do some rotator cuff surgeries, of course. And these are all intrinsic probably to our thinking in the clinic in terms of deciding what to do for that patient in front of us. But it's in the literature, and we should know about the rotator cuff healing index. Basically gives a point score from zero to two or zero to three for when you should kind of think about adding augmentation or biology to some of these things. And of course, the older you are, the bigger the terror size, the more retraction, et cetera, worse fatty infiltration. Higher BMI was a second paper that came out a few years afterwards showing that higher BMI doesn't do quite as well. And so if you're above a certain point threshold, the original papers at seven points, you should think about adding biology or augmentation or biology to the construct. The first way I talked about kind of just back to basics that any of us who are doing rotator cuff repairs are doing, if there's too much tension on the repair or you don't have adequate biomechanical stability to your construct, no amount of biology is really going to help you. So don't forget just going back to the basics of if you need to medialize a footprint to take tension off the repair, if you need to add an extra anchor, if your purchases aren't good, if you need to have partial footprint coverage, good studies coming out now, including the one on the bottom right, showing that we don't have to get that lateral edge of the cuff all the way over to the lateral edge of the footprint. And some of the bigger tears, we can just get 50% footprint coverage and that's okay. And there's good healing rates. I think the most important thing in these repairs are having a tension-free repair, regardless about how much footprint you have coverage. And then if you need to add augmentation after that, that'd be a good time to do it. The first and easiest way going into really true biologics now or quasi biologics for this one is microfracture, originally coined the crimson duvet from the look of it after you microfracture. It's simple, fast, easy. I just use a smaller punch for the footprint when I'm doing it. I still do it in some cases, but I'll be honest, looking at the literature a number of years ago and also just updated in this talk, it really probably doesn't help. There was a couple of early papers 10 to 15 years ago that talked about it as a case series that had some promise. But when you look at it in some of the more recent randomized trials over the past 10 years or so, it really doesn't make much of a difference. That being said, I still do it in some of my larger tears if I'm not adding anything else, because I think there's little downside as long as you're not compromising your anchor fixation, of course. PRP, we got a nice overview of it just a few minutes ago, but I would agree with what Scott says in his slides. The literature is mixed. I can't argue that, but really the trend for the literature for PRP use and rotator cuff repairs is really favorable. That favorability really centers around improved healing rates. A majority of studies will show that. Some, but fewer studies will show improved outcomes with PRP use. Part of the reason, as mentioned, just techniques and preparations vary. Do you squirt it under the tendon? Do you squirt it on top of the tendon? After you turn the water off and put it in, how much of it actually stays there? That's just technique variability. And then, of course, you have the PRP concentrations. You have white blood cell rich versus poor, so just a lot of variability. But in general, it is favorable. And again, in some of my larger tears, I will utilize this. There's reimbursement issues that were just talked about, so that's a factor sometimes in decision-making on what the patients will and won't want. You can activate the PRP. You can make it a little more viscous and stick it under your repair site so it stays there and may not wash away when you turn the water back on or you're exiting the shoulder. So just a little thrombin activation can be used. I tend to not use that for me personally. There's an extra step there, but that is an option. The stem cells, again, in quotes, these are really not true stem cells. I would, again, agree with Scott on that. But the bone marrow-derived stem cells group in Brazil and then Brian Cole out of rush kind of looked at this. Again, the literature is pretty limited, but favorable tendon healing outcomes. A little bit just because the literature is so minimal on these things, on this technique, the patient-reported outcomes are really not there yet. But some of the more healing rates have been shown to be improved with some of these BMAC and also adipose-derived stem cells. And there's different ways to do it. Lipogems, loaded in fiber and glue. Again, similar trends towards improved healing on MRI and also ultrasound in some other studies, but really haven't been able to nail down the PROs in a consistent fashion over larger studies for some of these things. The last kind of main thing that we use is, of course, tissue grafts. I just want to highlight that there's different ways to use that regardless of what you're using. You can use it as a bridge construct where there's no chance of you getting any part of the rotator cuff down to the tuberosity. And so you have to use it as a spanning bridge on the bottom left there. And there's augmentation where you can get part of or most of the tendon down and then lay the tissue graft on top. And then lastly, there's interposition. Interposition is a little bit more of the hotter topic recently, but all of these are important and it's important not only to distinguish what you're going to use, but how you're going to use it in one of these three fashions. The bridge and augmentations I'll consider as a group for the purposes of this talk. So again, it's spanning it where you can't get the tissue back at all to the tuberosity versus getting some down and laying it on top. That comes in many different ways. Autographs with the bicep tendon and fascia lata. Fascia lata, of course, being the original technique by Miyata for superior capsule reconstruction. I'm not going to talk about that, although it is part of biology, of course. But biceps tendon is a newer thing, maybe past 10 years or so that we've been thinking about it. And then, of course, there's a dermal allograft or allograft, but most time in the United States that comes in the form of dermal allograft. And then xenograft, so bovine, which is your regenitin product or other kind of collagen patches that don't come from humans. Larry Field, you know, was one of the first to start to report in the bio SCR technique, which is just the use of the biceps tendon. And I'll say that, you know, certainly it's a technique, but it is adding biology and adding collagen content. There's different ways to do it. You can leave the bicep tendon attached. You can not leave it attached. In this particular study with it was left attached and just kind of rerouted. It's another kind of key term or a key point phrase that we've been using. Just add collagen to your construct and get extra purchase there. The dermal allografts are popular. I think they, you know, they did have some more initial excitement. And now that we've been using them for a while, we've seen the good and the bad of them. In general, though, they really do help healing rates. This is just a study by Pat Denard of Oregon, you know, looking, doing a large literature, you know, summary, the healing rates using the dermal allograft both as a bridge, as well as augmentation were much better than those without for the larger to massive rotator cuff tears. And it showed improved functional outcomes in general. Not all studies show that. I say similar to the biologies I talked about earlier, the where the rubber meets the road is really in the healing rates. And then some studies do certainly so show improved functional outcomes if you look at large, larger series. The Regeniton patch, again, I don't have any financial interest in this in this patch at all, but that I use the brand name there just because that's it's one of the biggest market makers here in the rotator cuff world. It's bovine collagen. The actual indication for the Regeniton Regeniton patch is for partial rotator cuff repairs. So partial rotator cuff tears where there's intact tendon and you're literally just stapling this down to the tendon. Of course, we use it for other things also. And the, you know, since it's an original approval and we've been using it for off label things or for full rotator cuff repairs and augmentation type of procedures. The study just came out of Spain, literally EPUB maybe a few weeks ago. It was a two year follow up on previous one year follow up study that basically showed similar results to their one year, but it looked pretty good. Decreased retail rates based on postoperative two year MRIs, no difference in fat infiltration, which we wouldn't really expect so much, and then improved functional outcome scores in the intact versus the torn tendon group. But if you look at them overall between groups and those who did and did not get the patch, it didn't show a difference in outcomes, but certainly MRI looked improved and there was some questionable correlations on, okay, well, it's helping tendons to heal and those patients are getting improved outcomes. So that may be worth it too, but definitely improved imaging. The last kind of category is the interposition. And there's a lot of newer products coming on the market now. I do have a conflict of interest on the bottom right product, which is a biphasic allograft interposition. But other than this, there's different ways. So the two pictures on the left are basically kind of synthetic nanofibers. One is just a patch you lay on down on your own and through an instrument through the cannula. The other is attached in the anchor as you guys see. And then there's other ways using a bone to kind of improve tendon to bone healing and really try and recreate that in thesis. So the whole goal of these interposition graphs are trying to recreate those, you know, that four stage transition between bone and tendon. And that's if you can recreate that, the retail rates are certainly low because you're actually recreating the actual biology rather than just having scar tissue between the tendon and the bone. Now, lastly, just experimental things I'll mention briefly. You know, there's a ton of animal literature. None of this is in clinical use at all. But the literature really centers around injectables, preloaded, you know, biodegradable polymers. Pictures on the right are just from my lab here, you know, looking at different biodegradable polymers and trying to recreate that in thesis in an interposition type of process. You know, gene therapy exosomes are mentioned. There's a whole host of other things that can take up hours, but many different things that haven't hit the clinical market yet, and certainly, but in the experimental world, people are working on it. It's just, there's a lot of questions to be answered here. So in general, don't forget the principles. And biology is not gonna work if you forget the principles. Flipper microfracture, probably not gonna make a huge difference. Blood-derived products, PRP, bone marrow aspirate, it does have some promise and is more easy to use. And then of course, we go into our tissue graphs and there's pretty good data on the tissue graphs that augmentation or bridging can really improve re-tear rates. And some studies show improved clinical outcomes with these auto-allo and xenograft-type products. Hi there, I'm going to talk about biologics in the foot. So thinking of biological adjuvants, there are many. I won't go through all of them today. We'll pick up the highlights. So in the foot and ankle, why do we want to use biologics? We want to stimulate bone healing, particularly in the acute problem fractures that don't like to heal. We want to promote cartilage repair in our osteochondral lesions. We want to facilitate tendon and fascial healing or provide an augment to our surgical procedures to heal faster and heal quicker. So the main players are listed here. The gold standard with respect to fracture and fusion would be the cortical cancellous autograft. We will talk about PRP being angiogenic. We will talk about platelet-derived growth factor, BMAC. And these are all in comparison to the standard of autograft. Going on to PRP, most people know about the preparation steps. The alpha granules are the golden eggs. They release all of these incredible growth factors that lead to tissue remodeling, angiogenesis, and extracellular matrix formation. The benefit of PRP, it's very well studied, level one and two evidence, and has an excellent safety profile and is non-invasive. Caveats would be variability in the formulations. Also the presence of leukocyte-rich PRP could detrimentally affect tendon healing and cartilage healing and the joint. And there are side effects that we have to warn patients about, but typically minimal. PRP has been well studied in plantar fasciitis, but these cases are recalcitrant, meaning that they failed the usual conservative treatment and we're considering cortisone injection, but we have the drawbacks of plantar fascial rupture, heel fat, fat pad atrophy, and these things we can't reverse. And so there's been some good systematic reviews that incorporate nine randomized controlled trials. Basically at six months and 12 months, PRP group did better with respect to pain and function. And so there is strong evidence to use PRP injection instead of cortisone. Looking at Achilles tendinopathy, again, recalcitrant cases, there's been a few systematic reviews, including five randomized controlled trials. Unfortunately, no PRP efficacy was shown and these trials did have patients do eccentric strengthening program, which had been shown to be helpful, but unfortunately still no outcome differences noted. There was a randomized controlled trial that did sham injection of saline versus PRP injection, but unfortunately there's no significant difference in the outcome scores. So the bottom line here with tendinopathy proximal and distal is PRP doesn't help. But what about Achilles tendon ruptures acutely? And so there was a nice randomized study that placed patients in orthoses with heel wedges, and there's two groups. One group had four PRP injections every two weeks, and the other group had four saline injections or sham injections every two weeks. The outcome score did improve for both groups over time, but unfortunately, again, there was no significant statistical difference. There was a systematic review that included 543 patients, surgical, non-surgical, and those that had PRP injection. And unfortunately, there was no difference in clinical functional morphological outcomes. And so unfortunately, even with acute ruptures, PRP has not been effective. Moving on to osteochondral lesions of the talus, there's been good two level one and two level two studies and a systematic review incorporated results. The authors concluded that PRP plus microfracture improved pain relief and function compared to just microfracture alone. But looking closer at the review and the studies included, the long-term data wasn't present, the analgesic use was not recorded, and the differences in the outcome scores were not actually clinically meaningful. So again, the recommendation would not be to routinely use PRP with osteochondral lesions. Moving on to ankle arthritis, which is becoming a more and more prevalent problem, and we're trying to keep patients from fusion or replacement. There's only been one randomized controlled trial of a hundred patients. Unfortunately, no significant difference seen, but a definitive recommendation with respect to use is not there because we don't have the data. Moving on to bone marrow aspirate concentrate, or BMAC. There were a lot of growth factors in mesenchymal stem cells obtained along with interleukin receptor antagonist protein. So the MSCs help with cicratome that increases and encourages local cell turnover. IRAP inhibits inflammatory cytokine cascades. BMAC has an excellent safety record, but not a lot of evidence with respect to foot and ankle applications. And the drawbacks are complications, obviously you have to use a jammed sheeting needle, and so it can hurt at the harvest site. Bone healing with BMAC, actually very positive in animal studies with increased bone formation, higher torsional stresses or stiffness. However, in human studies, this has not panned out. A little bit of a glimmer of hope with fifth metatarsal fractures and ankle fracture non-unions and diabetics. But overall, there's a lack of evidence, but needs further study. Again, with osteochondral defects, animal studies were positive, showing more type two cartilage formed with BMAC plus microfracture. But again, sadly, in human studies, has not borne to be true, but there are some good findings. There appears to be better quality and quantity of repair tissue on MRI. There appears to be better outcome scores on larger lesions. BMAC when combined with juvenile articular cartilage allograft, however, did not show increased, just showed fiber cartilage formation, not type two cartilage formation. And there was no benefit over microfracture alone. So again, low-level evidence, there's potential there, but we need to study it more. Lastly, platelet-derived growth factor, typically with tricalcium phosphate, is used. Platelet-derived growth factor attracts MSCs, the surgery or injury site, promotes healing and angiogenesis. It has an excellent safety profile. It has level one evidence supporting its use. It has other approvals by the FDA for use. The cost is a drawback. And prep time in the OR is minimal, but still somewhat of a drawback. With respect to hindfoot ankle fusions, platelet-derived growth factor with tricalcium phosphate has been shown to be level one evidence and shown to be very beneficial. If you compare platelet-derived growth factor, tricalcium phosphate with autograft alone, there was non-inferiority. So with platelet-derived growth factor, tricalcium phosphate alone, there was comparable fusion rates, less meantime diffusion, less pain, and fewer side effects. So there's very strong level one evidence for use of platelet-derived growth factor. As we think about the foot and ankle, there are other applications that we really would like to get better data on. Osteochondral defects that are larger, that require some sort of scaffold to help our microfracture be augmented with healing. There's also problem child fractures like the navicular stress fracture or Jones fracture that could benefit from things like platelet-derived growth factor, but the data isn't there yet. And hopefully with time, it'll improve. So in conclusion, be thoughtful in using biologics. PRP has been helpful in recalcitrant plantar fasciitis, platelet-derived growth factor, and high foot and ankle fusions. Level one evidence that it's very useful. When you're considering implementation of biologics, make sure you have the appropriate infrastructure and keep in mind that a lot of these treatments are out of pocket for patients. For example, PRP can be $500 to $2,500 per injection. If you're doing it three or four injections, it can be quite financially burdensome. And further evidence is needed with respect to treatment of foot and ankle conditions alone. There's more studies on the knee and other areas, and we have to work on standardizing the formulations to get better data. Thank you once again for your attention. If you have any questions, please feel free to contact us or the presenters. My task is to fill in some of the gaps on the non-operative uses of biologic therapies. I wanna thank Dr. Rodeo and Dr. Abrams again for their presentations. As we get near the end, make sure you post any questions if you guys have some in the chat. In the meantime, I'll go through non-operative use in the knee, shoulder, elbow, and hamstring. We talked a lot about knee arthritis, but just to build off what Dr. Rodeo talked about, really trying to consider what are the goals of treatment. So for knee OA, it's restoring joint homeostasis, decreasing inflammation, providing some chondroprotective elements, trying to increase synthesis of prostaglandins, type II collagen, and stimulate HA production. And so interestingly, the Academy, three years ago now, downgraded PRP use for knee OA. This was in 2022. However, as Scott showed us, there's quite compelling evidence for PRP use in osteoarthritis. So just to reiterate, for knee OA, leukocyte-rich versus leukocyte-poor does not seem to make a significant difference. Again, historically it was thought you should use leukocyte-poor for the joint and leukocyte-rich for tendons. And while that makes sense conceptually, humans don't tend to read the textbook. And so a nice systematic review did show that there were really marginal impact made by leukocyte concentration. What has been shown is that the more platelets you have, the better response patients typically get. And so we know to summarize knee OA, it's a viable treatment. The more platelets, the better, but optimal composition and number of injections has not been clearly established. So the other topic in the knee that I think we commonly see is patellar tendinopathy. PRP has definitely gained popularity. It's had, like a lot of the literature, it's kind of mixed results, but I think generally that you can find some positive studies. One study that showed multiple PRP injections was superior to eccentric exercises. And this did extend out six months. However, when you do a randomized trial, looking at leukocyte-rich versus leukocyte-poor PRP versus saline, in addition to the six weeks of supervised PT, they found no significant difference in outcomes. So hard to draw strong conclusions, but I think there's some results that can support the use of PRP in patellar tendinopathy. So we've touched a lot on rotator cuff already, but specifically on non-operative or partial rotator cuff tears, a couple of systematic reviews to highlight. So one was of nine randomized controlled trials. It showed short-term benefit of PRP for partial tears or tendinopathy, where patients were better at six months, but they were no different at one year. And I think a lot of what we've talked about is that radiographically, the healing rates or tendon quality tends to improve, but whether that translates to patient outcomes has not been shown super definitively at this point. Another study comparing sham injection to PRP to physical therapy, showed that PRP did reduce pain at six months, but again, no change on functional improvements. And as Dr. Rodia showed, subacromial PRP did show improved outcomes compared to corticosteroid injection for these partial tears. But bottom line, there's limited support for leukocyte-rich PRP versus leukocyte-poor. But as with a lot of what we've discussed, the heterogeneity of all the studies make it difficult to draw super strong conclusions. Another injury that comes up quite a bit when discussing biologics is ulnar collateral ligament injuries. So there's case reports or limited case series that have shown some positive outcomes with PRP injections for UCL injuries. Modesta looked at 34 athletes with partial UCL tears. They got one PRP injection in rehab, and they had an 88% return to sport. And notably, that timeframe was three months. Dynes looked at 44 baseball players with UCL insufficiency. There's some variability. They had between one and three PRP injections. All the patients had rehab. They had 73% good to excellent outcomes. One interesting finding from that study was that on subgroup analysis, they found that the distal tears did worse in all seven of those failed PRP injections. Another study looking at throwers in high school and collegiate athletes with grade two UCL tears, they got two PRP injections in rehab, 88% return to sport, and then they did MRI follow-ups, and 80% showed evidence of healing. And lastly, another study showed 26 out of 30 athletes were able to return at three months with leukocyte-rich PRP plus a rehab program. So in summary, I think it's reasonable to consider, particularly in the partial tears. I think the protocols for administration vary, as well as the rehab protocols, which make it hard to draw definitive conclusions. But as we know, undergoing any type of surgery for these types of injuries leads to a much longer recovery. So particularly in the partial tears, I think it's something you could certainly discuss as a potential treatment modality. Lateral epicondylitis, something we all see quite a bit. It does have somewhat compelling evidence for PRP use. Again, still not covered by insurance, but there are multiple level one studies that support the use of leukocyte-rich or leukocyte-poor PRP for lateral epicondylitis. And there are studies comparing PRP to corticosteroid injections that demonstrate superiority of PRP. So in practice, I think it's, again, a useful adjunct once you counsel patients on the cost, you can kind of make a shared decision about whether it's worth pursuing for tennis elbow. And another common injury that we see a lot, particularly with team coverage, are hamstring strains or tears. And most studies have shown no difference with PRP use. There's one randomized controlled trial that looks at acute partial thickness, single tendon, proximal injuries, where they performed an intralesional PRP injection under ultrasound. And they reported improved recovery with earlier return to play and decreased pain. However, on a meta-analysis looking at the 10 studies that have evaluated this more robustly, they found no difference in return to play timing or re-injury rates with PRP. One thing that is gaining some traction is considering using platelet-poor plasma for acute muscle injuries. So there's at least one study showing some evidence of platelet-poor plasma being superior to platelet-rich plasma, particularly in the setting of acute muscle injuries. But all the literature on that is relatively new and up-and-coming, but I think has some reasonable evidence behind it so far. So to conclude and kind of reiterate what's previously been discussed, I think in general that the marketing has outpaced the research on many of the uses of orthobiologics. I think based on what we've described here, it's clearly an exciting field. There's abundant potential clinical applications. I think we all know that, especially with healing rates and certain injuries, there's certainly an element of biology that can be improved, but I think we just need to keep working to have more comprehensive research. And that starts with really first kind of defining what we're injecting, what we're using to augment, and then studying the outcomes pretty critically. And so I think in general, in practice, if you really identify what you're trying to accomplish or what your biologic target is, and then matching your agent to that target, that will serve you well going forward. Thank you. So we did have one question specifically about how do you start the conversation in the clinic about using biologics? And I think to your point, Scott, about the out-of-pocket cost, is this something that you, if you think a patient's a good candidate for, you mentioned to everybody, or do you have specifically the question asked, do you have flyers visible so the patient can ask you about it, or do you volunteer it as an option? Yeah, I'll go through all the options for treatment, whether it's a tendon problem or osteoarthritis, I think our job is to educate the patient. So for example, in EOA, I'll say your options are steroid versus hyaluronic acid versus PRP. Tell them kind of the pros and cons of each. I make it clear that existing, for example, for biologic PRP, the data suggests it supports its use, but it also makes clear that there's an out-of-pocket cost for the patient, that there's variability in outcome. I don't rush right to these things in general. I'll probably start more with the steroid, with HA quite commonly. It can work. It's usually covered by insurance, but that's the way we usually start. One challenging area in this whole area of biologics is, well, we want to, as I mentioned, I want to tell the patient, listen, this may not work. At the same time, if the physician portrays hope and you're positive and optimistic, the patient picks that up. I mean, call it a placebo effect. And so the challenge here is maintaining the patient's hopefulness. If you present something positively, patients will actually kind of get better. They'll see it that way. That's kind of the social part of dealing with patients in medicine. So I think the challenge here is being realistic to the patient, but not hanging so much creep that you give a pessimistic approach here. You want to be able to tell them, if this didn't work out, I may say, hey, remember I told you this is not magic. But at the same time, you want to let them be hopeful and optimistic there. But I think it's our job to educate the patient, give them realistic information, tell them what we know, what we don't know. And that's important. And then let them ask questions. That's great. I think we're a couple minutes over here. So we'll conclude our presentation for the evening. I want to give a big thanks to the faculty for tonight's webinar. I'd also like to thank our attendees for joining. Here's the additional CME information, which will also be up at the top of the chat if you need more information. So thank you, everyone, and have a good night.

AOSSM webinar

biologics

orthopedics

knee osteoarthritis

platelet-rich plasma

bone marrow aspirate concentrate

sports medicine

ethical considerations

patient counseling