Good afternoon. So unfortunately, Dr. Kennedy is unable to make it today. So my name is Owen Hurley. I'm a graduate from the College of Surgeons in Ireland, and my research fellows worked with Dr. Kennedy over the past few years, so I'm giving this on his behalf. Unfortunately, I have no disclosures, but Dr. Kennedy's can be found on the app. Clinically, we've seen an increase in the use of biologics over the last few years to treat all forms of musculoskeletal pathologies, most commonly using PRP, BMAC, or mesenchymal stem cells. So for this talk, I'm going to focus on PRP for Achilles tendinopathy. So PRP, as we're all aware, is a biological product that's increasingly used and increasingly a source of controversy, not just in the treatment of Achilles tendinopathy, but throughout all of orthopedics over its questions, over its efficacy, its cost, and its evidence base. Despite these controversies, PRP is widely used and increasingly used, and these numbers from just a few years ago would be minuscule compared to today, but they do show a good representation that foot and ankle pathologies and soft tissue pathologies make up a significant portion of the uses. So PRP is made up of over 1,500 unique proteins, cytokines, growth factors, which help facilitate repair. So it promotes cell proliferation, migration, differentiation, and angiogenesis, all of which is important in bone, tendon, and wound healing. So one of the most important aspects of PRP, and one of its most important properties, and is often overlooked, is its anti-inflammatory properties, as has been shown to decrease interleukin-1 beta and TNF alpha, both of which play a significant role in tendinopathy. So in the treatment of tendon pathology, PRP has been shown to enhance tendon stem cell proliferation, tenosite-related gene and protein expression, as well as increase collagen production. This overall has been shown to induce differentiation of tendon stem cells into activated tenosites. These tenosites are highly proliferative and exhibit substantial collagen production capability, and further immunohistochemical studies have shown enhanced gene expression of collagens type 1 and 3 and alpha-smooth muscle protein actin, with PRP releasing in a dose-dependent fashion, i.e. the more platelets, the better. Looking exclusively at Achilles tendon ruptures, PRP has been shown in a New Zealand white rabbit model that it has significantly more angiogenesis, better orientation of collagen fibers, and thus it seems to enhance neovascularization, which may accelerate the healing process and produce scar tissue of better histological quality. So Nick Bash, who worked with John Kennedy, looked at all the basic science of PRP in tendon models a few years ago, and they found decreased tendon repair time, increased fiber organization, increased cell proliferation, increased growth factor expression, increased vascularity, and increased tensile strength. So the basic science is there to support its concept. Then clinically, recently in AJSM they published a study where they looked at all of the clinical level 1 evidence on PRP for tendon ligament healing. It found mostly focuses on rotator cuff repair and lateral epicondylitis, and while there was significant heterogeneity in the literature, overall there was a trend towards improved short-term and long-term pain relief. Looking exclusively at Achilles tendinopathy, multiple clinical studies have reported positive effects and good clinical outcomes with the use of PRP. Chris Maraschke published a case series with Dr. Kennedy and found a single PRP injection mid-substance resulted in improved clinical and radiological outcomes with 78% asymptomatic at 8 months. Then looking at the level 1 evidence, one level 1 study, Boesner et al., found four PRP injections two weeks apart resulted in improved VISA-A scores, VAST scores, and decreased tendon thickness at 6 months follow-up. However, the overall literature, level 1 literature, has been negative in the use of PRP, with three other studies finding it had no benefit. As a result of this, multiple systematic reviews and meta-analyses have been overwhelmingly negative towards the use of PRP in the treatment of Achilles tendinopathy. So where is this mixed message coming from? Basic science says it works. That doesn't always translate. Some clinical studies say it works, but where is the discrepancy? So what exactly are we looking at? And this is a really nice study where they looked at all the clinical literature on PRP, and they found that in over 100 studies, only 10% provided clear description of the preparation protocols and only 16% reported quantitative metrics on the composition of PRP. So when we're talking about these studies, we really don't know what they're using. Is it actually any better than just injecting a placebo? We don't really know with a lot of what's being reported, so this is kind of a big thing of mine is the actual reporting and kind of a call for standardization. So we have multiple different PRP preparation systems, and all of the PRP preparation systems are not the same. So most commonly, we talk about the rate and quantity of platelet collection, leukocyte collection, but other important factors include the detailed composition, whether an activation agent is used at centrifugation time. So leukocyte-rich versus leukocyte-poor PRP may be the biggest factor, or at least the one that the most interest is in, and this may be paramount to the success of PRP in treating Achilles tendinopathy. As you can see here in this study, looking at the cellular characteristics, there are different leukocyte concentrations can have wide-ranging effects, and I just want to highlight two main things. Leukocyte-poor PRP had greater anabolic properties compared to leukocyte-rich PRP, which would, in theory, improve Achilles tendinopathy. This study found that PRP had better radiological scores, histological outcomes, as well as local cytokines compared with leukocyte-poor PRP, or compared with leukocyte-rich PRP. What we know from the basic science is leukocyte-poor PRP may be more beneficial, and leukocyte-rich may be actually contraindicated in acute tendinitis if it can be pro-inflammatory. Keeping this in mind, looking at the literature again from this point of view, what do we actually say when we're looking at the Level 1 evidence? Well, the one study which found a positive benefit with PRP did use leukocyte-poor PRP, which we think, in theory, should be more beneficial, whereas the studies which had no positive benefit were ones which used leukocyte-rich. And you can also see here that they're quite acute, in that they're early stage, so leukocyte-rich may even make the problem worse instead of getting it any way better. So what are we kind of saying? Well, we kind of need to know what we're talking about in terms of PRP. Not all PRP is the same, and if we do want to clarify this further, we need to start saying, well, maybe leukocyte-poor is better. We should start evaluating that, because clinical evidence is there to say leukocyte-rich PRP is not beneficial, but we still don't know enough to say about leukocyte-poor. So in summary, we know that PRP upregulates genes to produce more tendon-like cells and reduces inflammation. The optimum formulation is not known, but basic science would say leukocyte-poor PRP is better in tendinopathy, and that's just one of many factors, as I mentioned earlier. The RCTs in the literature show no effect when they used leukocyte-rich PRP, and that's the overwhelming evidence, so of course it's expected to be negative. So the crux of the question here, really, with PRP and the treatment of Achilles in 2019, is we need to establish the optimal formulation for Achilles tendinopathy. That will probably involve basic science models, and there is some basic science models there to say it is there. So that's what we need to kind of focus the literature on before we can really say, well, PRP works and PRP doesn't, because right now it's just too much of a hot topic with too much debate, because that evidence is all over the place. So thank you for your attention, and thank you to John Kelly for bringing all of us here from Ireland. It's been a fantastic week, and thank you.

platelet-rich plasma

Achilles tendinopathy

tissue repair

anti-inflammatory properties

clinical studies