Hello, I'm Dr. Brian Cole, and I want to thank you for attending the Anna Arthroscopy Shoulder and Knee Course. My lecture is going to be on rotator cuff augmentation and take some consideration on biologics and the use of patches. My disclosures are at the AOS website. So we know that rotator cuff tears are still the most common cause of shoulder pain, especially in individuals over the age of 50. And despite having very favorable clinical outcomes, we know that at one year, there tends to be a failure of structural integrity as evaluated by anatomic assessments, specifically MRI and ultrasound. There are a lot of factors that relate to this, and there are several biologic challenges when it relates to the rotator cuff, including patient age, chronicity, the number of tendons, vitamin D levels, bone density, the effects of smoking, and so forth. And it's interesting, if you ever had the chance to read the book by Atul Gawande called Being Mortal, there's a great expression in that book where he says that our bodies are rotting from the inside out. And I would argue that the extension of that is that that's happening and we don't know it until we get an MRI. If you look at the incidence of rotator cuff pathology, we know that patients over the age of 60 to 65, there's probably over 6 million people in the United States who have a rotator cuff tear. The good news is that most of them don't have symptoms and they do quite well. The problem is they tear because of deteriorating biology. And that's probably why we re-tear. We do such a good job at time equals zero, but over time, the re-tear happens mainly because the tissue quality is still bad to begin with. Some of the basic science that supports this poor tissue quality is, this is a study that we completed at Colorado State, CSU, and looking at the metabolomics of the rotator cuff in normal tissue that retrieved from total shoulder arthroplasty, and then diseased tissue such as reversed arthroplasty, or those who have acute or acute on chronic rotator cuff tear. And clearly there are metabolomic differences across cuff tendon that's consistent with aging and degeneration. And then the question that's often answered is, look, does structural integrity really matter? And if you look carefully at the literature, it's very clear that patients with a healed rotator cuff have greater strength and satisfaction. The problem is our sensitivity of our measuring instruments is sometimes lacking and the strength measures, for example, represent a very small part of the overall assessment tools. But I think it's very clear that if you look to the literature, having an intact cuff makes a difference. Now, what we'd like to get is this transition of a healthy tendon, fibrocartilage transition, mineralized fibrocartilage into bone, this emphasis regeneration. The challenge is that what we get is often reactive scar and a failure of the creation of the mineralized fibrocartilage zone. Why does it happen? Well, it may happen because the inflammatory response, which leads to fibrosis rather than tissue generation, rather than generating that emphasis, we just get a tremendous inflammatory response that leads to this change. So the question then becomes, can we improve the tendon bone interface? Can we change the material properties or the structural properties so that we can reduce retail rates and maximize patient outcomes? And these are the options, basically. We can change material properties by the use of scaffolds, and we maybe can change structural properties by the use of biologics. Now, there's a number of scaffolds. There are a number of allografts present, as you see here, that we have available. There are a number of xenografts that are available, and there are a number of synthetics. And if you just sort of tie it all together, there's an abundance of data preclinically that's looked at xenografts, dermal matrix, polymer patches, and so forth, some work we've actually done at Rush. And suffice it to say there's a good preclinical support available for the use of these patches as either an extension or augmentation. Now, the data looking at interposition, there's a number of level of evidence for studies, which are basically case series. But basically, if you look at the intact rate of these tears, some of which were large when it's used as an interposition, those anatomic assessments rival the best of any of these standard non-patch augmented procedures that you might see in the literature with 80 to 90 percent being intact. There is some data that's actually looked at using patches as an extension, and it actually can work in that fashion. It's not exactly an SCR, but actually using it to attach the cuff and attach the tuberosity, and the data has actually been quite favorable in this regard. And in fact, retear rates using a polypropylene patch were actually very low, no worse than 17 percent. Does retear always equate with clinical outcome? I can't tell you. We have to go across the literature and look, but it isn't always the case. So I think the general take-home of the use of these scaffolds is that we've seen success both with augmentation and extension. It can be arthroscopically challenging, so if you have the opportunity now to be in the lab at the ULC, that's something you'll look at and learn about these techniques. Cost is still a consideration, especially in an inventory setting, but the data to date is actually pretty compelling, especially with the dermis. When asked for my indications, I would say it's unexplained failure in physiologically repairable patients, okay? So why does someone fail who has a great-looking tendon, great biology? That's one that I might use as an augmentation, considering a scaffold. So this is an example of a patient who had a previous arthroscopic cuff repair with a small tear. He fell three months later and had a recurrent tear. Then he had a revision cuff four months later, and he was referred eight months out, and he came in with an acute bicep rupture, but we obtained imaging. His x-rays look good. He doesn't have any evidence of proximal migration. There's no evidence of osteoarthritis, but his MRI shows a re-tear, and so this would be his third attempt, but he's a pretty young guy and otherwise good physiology, but you get in there arthroscopically, and you can just see it's inelastic tissue. You can get it over to the tuberosity. You could probably repair it to the edge of the tuberosity anatomic neck junction, but you just look how inelastic and just visibly how poor quality the tissue is. So this is one where we actually did a patch augmentation, not an extension. I basically did a trans-osteoarthritis equivalent repair, and the technique is if you can do a TOE, which is a posterior medial-anteromedial anchor, and then there's tape of some sort loaded in the anchor that you're going to crisscross laterally. I basically do the same repair I normally would do, but I use the tapes medially that coming from the medial aspect of the medial row, and I pass that through the patch, and I essentially, and you can, it's very easy to introduce, and I essentially just dock it over the top of the patch, and it gets integrated into the construct. So it's not a difficult procedure. Just do your standard repairs, and then use the sutures that are present in the medial anchors to pass through the patch itself, and then crisscross over the top and incorporate it into your trans-osteoarthritis equivalent repair. This is that same patient now four months out, and obviously it's early follow-up, but you know doing quite well, and obviously four months is not the kind of follow-up you need for something like this. You're going to really need to have a longer-term follow-up, at least a year, to see if things remain intact. Then the question is, well, what if it looks like this? And this is another challenging problem. I think you probably know where I'm going here. This is when essentially nobody's home, right? Before, at least, we had something to repair. Here, there's nothing to repair, and this would be another area where we always use scaffolds, or we can use scaffolds to superior capsule reconstruction, and there's the data basically shows that while it doesn't increase concavity compression, it prevents superior translation, and the provisional results, this is one of the earliest studies, but new studies have actually replicated the same outcomes that, you know, about 75 to 80 percent of these patients can be satisfied with this procedure. The thing that we've learned over time, however, is that when they get beyond HEMATIS stage 2, it's a very guarded prognosis, so these are patients with an intact subscap, who have an irreparable or non-functional supraninfraspinatus, who have minimal proximal migration and no significant osteoarthritis. From a technique perspective, and again, this will be taught in the lab, the things that we've learned are that thicker grafts, using a trans-osteocequivalent repair laterally, and three independent repairs medially are the best way to get this done, and I will tell you that that sort of really improved our outcomes. When we've gone to three anchors medially, as well as repairing the patch to the infraspinatus or teres posteriorly and the subscap anteriorly, we've probably achieved our best results. Tensioning the patch is actually really important, and this is showing a biologic, in this case, using bone marrow concentrate, which I'll talk about at the end of the case, but it's become a much more reproducible operation, given the technical advances. So what about the concept of changing the material properties and tendon regeneration and what's required? So clearly, what we know is that it requires growth factors, scaffold, progenitor cells, and some type of angiogenesis that's induced to regenerate a tendon. It's not going to be a single thing that's going to get us there, but what we have to date is things that are minimally manipulated, a point of care provided, such as PRP and bone marrow concentrate. We don't have a whole lot. We also have access to adipose. When you look at the premise behind augmenting rotator cuff disease and saying, look, the biology is poor, what can we do to augment it? We initially looked at the effects of PRP with rotator cuff disease and showed that leukocyte-poor PRP and culture promoted collagen synthesis and decreased catabolic cytokines and disease tendons, and it actually did it better than leukocyte-rich in a culture model. There are some other important aspects, for example, of PRP used as a biologic, and it can actually signal from MSCs and can bring endogenous host MSCs into the area. So that might be particularly important. Now, there's some actually early data that often gets overlooked when this so-called poor man's PRP. Steve Snyder was the one who popularized the concept of this crimson duvet, where you basically denude the surface at the tuberosity, but others have actually performed microfracture. And microfracture is not designed to get fibrocartilage, but to actually get access to endogenous MSCs for these patients. And the data is actually pretty interesting compared to control groups and showing some benefits. So I think there's an initial foundation to support the use of PRP. When you look at the literature in general, where PRP is actually added to the equation, if you look at the bottom of the slide, basically there seems to be some supportive data when it's applied at the tendon bone interface in a setting where a double row repair is utilized. And ironically, not the big tears, but the small and medium tears did best. And the one area where we saw compromise was when PRP was applied in a platelet-rich fibrin format. And at least in that study, did not show improved outcomes. So I would say that I don't think we're in a place where we can say we can dispositively conclude that PRP makes a difference in every case. I think the data has become quite suggestive that independent of the economic factors, it may actually help. There's been some other applications when using PRP, the interstitial application for partial interstitial tears. In this case, it did make a difference in this particular study. Similarly, when it was used postoperatively, people have looked at it that way as well, that there was no change in function with leukocyte-rich PRP after rotator cuff repair. So just a couple other areas where it might be used. It hasn't shown a favor in interstitial application or postoperatively. So finishing up, what about the use of MSCs? Arne Kaplan has helped change the paradigm from the concept of a mesenchymal stem cell to something that's called a medicinal signaling cell. In other words, just speaking to the mechanism, probably works related to bioactive growth factors, creating all of these positive effects. And maybe most importantly is it might reduce inflammation and modulate the immune system, T-cell surveillance, and so forth. There's a lot of data suggesting that it has this sort of paracrine effect and mobilizes the host parasites and so forth to do their thing, but probably doesn't function in a way that our patients would love it to function, either in a true regenerative capacity or rewinding the clock or rather driving cell lineage to tendon or bone or fibrocartilage and so forth. There is some data looking at, you know, asking the question, are they clinically relevant? And this is a study by Philippe Hernegau showing that MSCs were less prevalent in patients with rotator cuff tears. I think this is a little bit of the chicken or the egg concept, but it's beginning to look at that concept. There's also the concept of what happens in animal model. This is something we looked at in the gene expression of progenitor cells, which is really what MSCs are, isolated from rat rotator cuff musculotendinous junction. And essentially we identified similar progenitor cells with gene expression at the tendon and musculotendin junction. So we're repairing tendon. We don't get a lot from the musculotendin junction, but what's interesting is that these progenitor cells seem to be present, at least in an animal model, at the tendon, at the end of the tendon, but these were not diseased tendons. You have to keep that in mind. There is some other models that have looked at the application of MSCs in a small animal, and the take-home of this study by Gulotta basically suggested that cells alone did not solve the problem, and it may require some other soluble factors. It just speaks to this sort of trifecta where we need cells, scaffold, and growth factors, and the ability to induce angiogenesis. It's not likely to be a single agent. Bone marrow concentrate and adipose have been looked at in two different settings, and there's a lot of variables, including the dose, the timing, the preparation. The study that's most quoted is the Phillipe Hernego study that was a match control series, a level three study, looking at 45 patients with bone marrow concentrate and 45 patients without, who had rotator cuff repair. He used bone marrow aspirate from the ASIS and placed it between the tendon and the bone, and what was interesting is at the 10-year follow-up, they had a pretty profound difference in the anatomic integrity of the cuff. 87% were intact in the bone marrow concentrate group compared to 44% in the non-bone marrow concentrate group, so we've questioned, you know, it's not an issue of integrity. It's just those are really profound differences, and I'll show you what our study has found. There's also another study that has looked at the use of adipose-derived cells, and this is a level three match control group, and basically showed the anatomic healing was better when adipose was applied, so there's a suggestion that it may be relevant. Now, this is a study that is a prospective trial. We're not completely done analyzing the data, but it's a study where all patients undergo a single tendon repair, supraspinatus, and they have a transoxic equivalent repair, and then we inject bone marrow concentrate, and just to give you a snapshot of where we're at, we essentially showed that we had a significant and strong association between those who receive concentrate and a lower SAGAYA score, so the SAGAYA score is a five-point assessment tool used by MRI, and we showed a modest improvement in those patients in this small cohort when we used the scoring system by about 25%, so the data is not conclusive yet, but there is a suggestion that the addition of bone marrow concentrates making a difference. We're almost done with collecting the entire population of 100 patients with MRI data one year. There are some other options for bone marrow concentrate similar to PRP where it was used intra-tendonously where PRP did not show a difference when in this study published in arthroscopy when they injected MSCs that were autologous cultured. That's something that we can't do from an adipose source. They showed healing on the bursal side for partial thickness tears. I'll just mention another area that we've become very interested in. This is some collaborative work that we're doing with Gus Mazzocca in his lab at UConn. Basically, what we're doing is taking a device at the end of the shaver that you see right here. It's called a GraphNet device that basically will collect tissue, and here we're collecting the bursa, and we're basically almost emulsifying it. There is some evidence suggesting that it may promote a responsible healing environment when these are added back in, so when we do a bursectomy, we capture the bursa, fix our rotator cuff, and then we inject that back in as a potential for a local, very inexpensive supply of MSCs to improve the healing environment. Finally, there are some other biologics that we're looking at, and others are looking at, basically, for example, applying demonized bone matrix at the tendon bone interface. Again, what we're trying to do is to have a material change at the tendon bone interface that improves the anthesis, so this is an exciting area that may be an easy regulatory pathway, a low bar, that we can use in a less expensive modality to improve the anthesis. In conclusion, rotator cuff tears are associated with poor tendon biology and are largely degenerative in nature. That's why we have this problem to begin with. They heal with scar and continuity with poor material properties. Even if we can improve the structural properties, we do really well at time equals zero with repair, but I think we still struggle just because of the poor biology. Growth factors are not enough and likely need pluripotent cells that are signaled for and licensed to recapitulate the anthesis, and the evidence is clearly accumulating in favor of PRP and bone marrow concentrate. I think in the end, though, it's going to be multifactorial to get it right. That means cells, signals, and scaffold, and I think hopefully, if we can get there through additional research, that we'll be able to have a durable rotator cuff repair. I want to thank you for your time, and thank you for supporting the ANA-OLC initiative, and if you're attending the course, I hope you enjoy it and get something meaningful from this. Thank you and stay safe.

rotator cuff tears

structural integrity

scaffolds and biologics

metabolomics study

long-term outcomes