Andrew Sheean:              Welcome to the Arthroscopy Association's Arthroscopy Journal Podcast. The views expressed in this podcast do not necessarily represent the views of the Arthroscopy Association or the Arthroscopy Journal. 

                                                Welcome everyone, I'm Dr. Andrew Sheean from the San Antonio Military Medical Center. Today I'm talking to one of the thought leaders in the exciting field of orthobiologics, Doctor Adam Anz. I've had the pleasure of listening to Doctor Anz speak on this topic on a number of occasions, and so I was particularly excited to read his paper entitled “Exercise, Mobilize, Platelet Rich Plasma. Short Term Exercise Increases Stem Cell and Platelet Concentrations in Platelet Rich Plasma” and learn more about yet another variable we should be considering when it comes to PRP. 

                                                Doctor Anz welcome to Podcast and thank you for joining me. 

Adam Anz:                          Andy thanks for having me today. 

Andrew Sheean:              Before we get started and get into the meat of your paper, I'm hoping you can give us your two to three key things to think about when you're reading the literature on PRP. I'm confident that the listeners are getting the message that not all PRP is created equal, but I'd like for you to give us your approach to reading papers about PRP. How should we become smarter reviewers of papers like yours? 

Adam Anz:                          Well, with PRP it's a term that we've labeled so many products with and in my mind I've gotten away from that term, and instead I think of point of care blood product. Because I'm taking blood and at the point of care I'm making a product with it, and with two simple principles I'm making that product. And those principles are first, that with centrifuge you create a density gradient from a liquid. So if I take blood it's got a number of different components within it, if I put it in a centrifuge everything's going to layer out based upon their molecular weight and the red blood cells are going to predominantly get pushed to the bottom. The lighter materials are going to stay towards the top, like plasma. And then the in between layer, or the buffy coat, is typically where we harvest a product. So that first understanding of, I'm putting a fluid in a centrifuge and it's going to layer out is the first principle. 

                                                Then the second principle is selective harvest. By that I mean I'm going to select a component of what's layered out and it's going to be my product. Understanding those two principles are all you need to understand and maybe think about further when you read all these papers to understand exactly what product they're reporting on. And so that's one thing that I really liked about this paper: Figure 1, the whole intent of it was to help drive that point home. 

                                                So if that concept is still a little bit vague in your mind, look at Figure 1 in that article. Because the purpose of figure one was to help drill that home. That we're taking that blood, we're spinning it, and if we spin it hard and long like with the buffy coat based systems you get hard stack. Which is predominantly platelet poor plasma at the top, that buffy coat which has platelets and white blood cells and neutrophils in it and then red blood cells at the bottom. 

                                                And then if you alternatively take that blood and spin it a short time at say 5 minutes at 1500 rpm you're going to get that top layer, which is basically plasma and platelets, and then that bottom layer and that's the basis for plasma based systems. 

                                                So Figure 1 we really had a lot of fun with and the whole purpose was to try and drive that point home so that readers could start thinking in those ways when they think about platelet rich plasma. 

Andrew Sheean:              I see, and that distinction between the two then, and that figure really nicely defines I think that is why you typically get higher volumes of product with the plasma based systems, correct? 

Adam Anz:                          You got it. So with a system where you just do about a 5-minute spin at 1500 rpm's you then select that top layer. You have a top yellow layer and a bottom red layer and you don't quite get a buffy coat when you just do 5 minutes at 1500 rpm. But that's the basis for the majority of the plasma-based systems. Shorter spin, slower spin, and then you're taking all that top layer which is a larger volume. And that's typically the basis for the plasma based PRP's which are typically considered leucocyte poor PRP. 

                                                However, if you take that same sample of blood and you spin it harder and longer you get that top layer, which is predominately platelet poor plasma, that middle buffy coat and that bottom red blood cell stack. And the plasma, or the buffy coat based systems take that buffy coat and it's the product, which has a whole lot of platelets in it but also has other white blood cells and neutrophils as well, which can be a little bit more reactive of a product. 

Andrew Sheean:              You hint that at your discussion section, but tell us a little bit more about the impetus behind this study. What got your wheels turning and interested in studying this? 

Adam Anz:                          Well, we know that an individual that exercises has a much different biology than an individual who does not exercise. And we started thinking along those lines when we were thinking about harvesting: whether we're talking about bone marrow or we're talking about blood. 

                                                And then we started thinking about well, I started looking at some of the physiologic literature out there that shows what happens when we have an acute bout of exercise. We know that with an acute bout of exercise you get a sympathetic response in some instances and that is accompanied by a cellular response too. And so we know that people's white blood cells spike right after an acute bout of exercise. Well that got us thinking that maybe it's more a just a white blood cell spike. Maybe you are mobilizing some cells to your blood stream. And this is something that's been sorted out in other domains literature, but we haven't really brought to orthopedics. So that's what got my wheels turning. 

                                                And then we started thinking about well, we know PRP is different based upon an individual. And we know that we can't more than minimally manipulate blood due to FDA constraints. But what if we could more than minimally manipulate the patient before we drew their blood. And that was kind of the concept. I know I can't necessarily take that blood and incubate it over night on glass beads, that's considered more than minimal manipulation. But what if I instead, in essence, incubate the patient before I draw their blood? You know what if I manipulate them before I draw their blood, with exercise? 

                                                And so we got that thought rolling and our first purpose was to say well can we consistently manipulate what's in their blood and/or the point of care blood products, i.e. the platelet rich plasmas, with exercise. And so that's where we went with this thought process. 

                                                And so we want to just exercise individuals, take their blood, manipulate, or not manipulate, just process it with a PRP device, both the plasma based and the buffy coat based devices and then see what happens. And sure enough we found that we could consistently manipulate the components of PRP with just exercising the patients before we drew their blood. And that was sort of first, this is our first proof of concept for that. And where we go from there we're still kind of pondering at this point. 

Andrew Sheean:              You guys mentioned, I should say you observed, that the Angel System increased the post exercise concentrations of neutrophils and hematopoietic cells whereas the ACP System did not. What do you think are the potential clinical implications of this difference? 

Adam Anz:                          I think it's more you can make a more cellular leucocyte rich PRP product that has a higher concentration of hematopoetic progenitor cells within it. And so that is something that clinically I've been using in certain situations. One example is if I really want to kick a SLAP tear with some biology I know that I'm probably not going to really get that SLAP tear to really heal with any sort of biologic injection. But could I kick it with a lot of biology in the right direction in an off-season. Because we know we're not too thrilled with how our throwers do with returning to throwing at high levels. 

                                                So that's one of the instances where I said, where I know with leucocyte rich PRP I've got a good amount of platelets. But what if I exercise these individuals before drawing blood to make a leucocyte rich PRP I'm going to have a higher cellular product. 

                                                Now that can be a cellular as if I do a bone marrow aspirate but it's still a pretty cellular product. And so that's kind of the concept of where we're going with this. With these point of care blood products, I typically think two ways.: Am I trying to dilute an environment to turn off inflammation, i.e. with knee osteoarthritis, which then I don't want a very cellular product I want a plasma based PRP that doesn't have a lot of neutrophils, if any., versus, am I trying to kick biology in the butt and get it moving in the right direction.? For instance, if I'm trying to get a latter epicondylitis to heal, or trying to push with some biology in off season, something like a SLAP lesion. That's when I want a pretty cellular product. 

                                                And so I may not want a cellular product to the extent of a bone marrow aspirate. And I want something in between an leucocyte rich PRP and bone marrow aspirate then I'm gonna do exercise induced leukocyte rich PRP. 

                                                And so the way that I think about this whole space is we're developing a golf bag. And sometimes you need a putter, sometimes you need a driver, sometimes you need a five iron. And this may be kind of like the three wood, in terms of exercise mobilize leucocyte rich PRP. Whereas the pitching wedge is our leucocyte poor PRP. 

Andrew Sheean:              I got it, that makes sense, I like that analogy. Or a third wedge. You need a third wedge. Were you surprised by anything that you found? 

Adam Anz:                          You know, no I was not, to tell you the truth. Because there's a good basis of study within the sports physiology world about what happens when you exercise. So that combined with the reliability of these point of care blood product devices it made sense. Nothing really caught us off guard but I think what we still are excited about is how are we going to use this to really individualize a point of care blood product. 

                                                For instance, if I can consistently get a whole lot of monocytes and immature granulocytes and maybe expose them to some environment that's not too concerning to the FDA could I preferentially get them to release anti-inflammatory proteins? 

                                                And that is the whole thought process behind IRAP, to tell you the truth. And so that's kind of what we're hitting around is that's in concept trying to take a blood product and really tailor it towards a disease process. I think that's where we're going it's just a matter of first just consistently being able to do that. 

Andrew Sheean:              Practically speaking, how do you implement this in your clinical practice? Do you have people on exercise bikes in the clinic beforehand, or how do you do it? 

Adam Anz:                          So, here's two ways that I do. One, practically speaking, because I definitely try and practice medicine in a practical way because we have to as orthopedic surgeons. You know one thing that works very well for osteoarthritis in clinical practices is leucocyte poor PRP. If you've got a device that only takes you 5 minutes to make. Because then you can really run a clinic in an efficient manner. And so that's something that I use routinely and it works very well. 

                                                If you have one of these devices that makes you a leukocyte poor PRP in 5 minutes, and I think the price point should be low so that the patients can get it. It's something that you can really move into your practice, and I've found that my clinical practice seems to reflect what Pat Smith published with his experience. The three injection series of leucocyte poor PRP at this point has the most evidence and is the best of what's around for osteoarthritis. So clinically understanding these point of care blood products helps you understand how that's going to help your patients with that indication. 

                                                In terms of leucocyte rich PRP and this study, at this point, when I've got someone who's got a good biologic system, they're a good athlete, athletic person with some good biology. I am exercising in some instances when I really want to pretty cellular product that I'm going to hit one of these pathologies with, such as a SLAP lesion, is an example. 

                                                The other side of that coin is if you are moving towards the idea of bone marrow aspirate and using it in your clinical practice at this point I'm not too impressed with the literature of bone marrow aspirate for osteoarthritis because the studies at this point are predominately older sedentary individuals. 

Adam Anz:                          Now going with that is, if you are really wanting to use a bone marrow aspirate product for cellular arthritis try and pre-treat that person with exercise for about 30 days because you're going to really improve the cellularity of what's in their bone marrow if you do that. And so if you do have someone who's say, in their mid 60's, with knee OA, think about getting that person's marrow ramped up before you do a bone marrow aspirate if that's sort of what you or they are convinced they need for their knee. However, practically speaking leucocyte poor PRP for knee OA is a pretty effective treatment from my experience and from the literature too. 

Andrew Sheean:              So rev their engine up if you want to get the biggest bang for the buck. 

Adam Anz:                          If you want more biology, just consider their exercise baseline when you think about different treatments for them. And if you really want to, at the point of care, ramp up a cellular product, exercise them before you draw their blood. But it's a very rare instances where I'm doing that—not every time I pull blood for a PRP for sure. And also in instances where I've got someone who really wants bone marrow for their knee. Usually I'm saying well first consider leucocyte poor PRP, but if that's what we want to do, consider having exercised for 30 days or so before I pull your bone marrow because I know your bone marrow is going to be a much more cellular product if we do that. 

Andrew Sheean:              Well Doctor Anz this is great, I really appreciate your time this evening in clarifying some of these more salient points. And thanks for expanding our knowledge and hopefully increasing or continue to increase interest in our listeners for this promising innovation. 

Adam Anz:                          My pleasure, anytime. 

Andrew Sheean:              His article, entitled “Exercise, Mobilize, Platelet Rich Plasma. Short Term Exercise Increases Stem Cell and Platelet Concentrations in Platelet Rich Plasma” was published in the January 2019 edition of the Arthroscopy Journal and can be accessed online at www.arthroscopyjournal.org. Thank you all for joining us and have a good evening.