Hello everyone, thank you very much for joining us today. We have a cutting-edge and interesting review for you, an update on approach to using orthobiologic injections in the knee. We have a wonderful agenda with Kelly McGinnis starting us off on tendinopathy, Dr. Eugene Rowe on knee osteoarthritis and cartilage disorders, and Dr. Michael Oryema on patient selection, approach, and post-procedure rehabilitation. To introduce our speakers, Dr. Kelly McGinnis, my wonderful colleague at Harvard as an assistant professor and team physician for the Red Sox, Patriots, Ballet, the Bruins, and the New England Revolution. We'll then follow with Dr. Eugene Rowe from Stanford who's a clinical assistant professor in orthopedic surgery and team physician for Stanford Varsity and Team USA and medical director for the World Ice Hockey Championship. We will then clean up with Dr. Michael Oryema who will be teaching us about patient selection, approach, and post-procedure rehabilitation. He hails from Regenerative Orthopedics and Sports Medicine, fabulous group in North Bethesda and the DC area. So to get us started, our first speaker is Dr. Kelly McGinnis. So thank you, Joanne, for putting this all together. It's such a pleasure to present with two excellent former fellows and Dr. Oryema and Dr. Rowe. So I'm going to be discussing over the next 20 minutes focusing on the tendon, primarily the patellar tendon. So I thought we'd start with defining the structure, the normal architecture of the tendon before we discuss how to promote healing and potentially regenerate tissue with cutting-edge orthobiologics. There are three basic elements to a tendon, the collagen, the ground substance, and the tenocytes. The tenocytes are the really active cells that help to synthesize the extracellular matrix components as well as the collagen building blocks. The extracellular matrix is the scaffold for the collagen fibers and helps to reduce friction. It also contains a good portion of water content. The collagen bundles are arranged in a hierarchy of enlarging bundles and they are encased by an epitenon that provides the neurovascular supply. The function of the tendon is to transmit the force produced by the muscle tissue through the tendon to the bone. And that insertion site is called the enthesis. And it's a fibrocartilaginous interface that has four different zones of tissue differentiation that are important to point out. The tendon transitions into the unmineralized fibrocartilage zone, which has a different collagen composition than the tendon itself, which is primarily type 1 collagen. Then that transitions at the tide mark into the mineralized fibrocartilage, which has more mature chondrocytes. And then that transitions into bone. What's important to note is that the tide mark, the transition between the uncalcified fibrocartilage and the calcified fibrocartilage, it's essentially a vascular. However, it has rich innervation. So this is a region where the pathology exists and you develop pain at the enthesis. So to talk about the anatomy of the knee extensor mechanism, the quadriceps muscle transitions into a trilaminar tendon composed of the rectus femoris superficially, the vastus medialis and lateralis compose the middle layer. And the deepest layer is the vastus intermedius. The rectus femoris portion traverses over the patella, the sesamoid bone of the extensor mechanism, and courses down to attach to the tibial tuberosity. An additional component to the patellar tendon attaches to the inferior pole of the patella and courses down to its second attachment site on the tibial tuberosity. So there's a question of semantics of whether the patellar tendon is actually a ligament. When you look at it histologically, its composition is very much like a tendon, much more like a tendon than a ligament in terms of collagen organization as well as composition. A portion of the inferior pole tendon of the inferior pole is embedded within the patellar tendon. When we think about pain at the patellar tendon, the primary pathology is degenerative. The histopathology at the bone tendon junction is composed of pseudocystic cavities. There are degenerative changes that occur at the insertion and the fibrocartilage where there's thickness, as well as hyaline metaplasia. It's the classic degenerative tendon that we see in many regions of the body in terms of tendinopathy where we have lipid deposition, we have decrease in the total collagen, we have interstitial gaps and micro tears in the tendon, as well as mucoid degeneration. And there's a paucity of inflammatory cells. This is primarily degenerative situation. We know that there are neo vessels in the region between the patellar tendon and the fat pad that may have a role in terms of pain and that there are neural changes at the fat pad as well. We know that patellar tendinopathy occurs in 14% of athletes and it's really a sports medicine condition. We don't see this really in non-exercising individuals. It really occurs in folks that have a higher volume of training at approximately 20 hours per week or more and occurs primarily in jumping sports where there's explosion and increased demand and load through that extensor mechanism. It can have tremendous morbidity with an average duration of two and a half years. Many athletes play through at least one season of pain before they seek care. Greater than a third of athletes are unable to return to sports within six months. And the standard of care is really not great with a 50 to 70% success rate. So patients as well as physicians are looking for alternative treatment options. This patellar tendinopathy is primarily a clinical diagnosis based on history and physical examination. Patients present with anterior knee pain that's worsened with activity. It generally does not bother them at rest. They will have very focal tenderness on exam at the inferior pole of the patella. And one pearl is that you can get to those deeper fibers that are involved in pathology by a superior, by a compressive force at the superior aspect of the patellar tendon and digging on into the inferior deep fibers at the inferior pole. The imaging really is only indicated advanced imaging with an MRI if you're concerned about other pathology, particularly intra-articular pathology. If you're not concerned about that and it appears to be an isolated patellar tendinopathy, an ultrasound is very much adequate in terms of confirming diagnosis. And the classic typical lesion is the increased signal intensity in the case of MRI at the inferior pole. And in the ultrasound, it's really an anechoic or hypoechoic zone. And the classic lesion is really in the posterior, the deepest fibers of the patellar tendon, as well as the deep medial fibers. And that has to do with the line of force through the medial aspect of the patellar tendon, often as patients are in a position of dynamic valgus with sports-specific activities. The standard of care is really activity modification and physical therapy. And it's really important to shut these athletes down and to decrease the load through the tendon significantly at the start of treatment to have a success in initiating the strength training that's necessary for success with treating this condition. Physical therapy focuses on addressing the entire lower extremity kinetic chain. Some common dysfunction in the kinetic chain includes decrease in ankle dorsiflexion, weakness in the gluteal musculature, and decrease in flexibility at the quadriceps, as well as the hamstring muscle tendon unit. Quad strengthening is really the hallmark of treatment with the decline squat eccentric strengthening exercise, the traditional exercise that we prescribe patients. This has recently been challenged by heavy slow resistance training. And when you look at these two modes of strengthening in comparison, head-to-head, they are fairly similar in terms of functional outcomes and pain. However, the heavy slow resistance exercises, patients tend to have a greater satisfaction with, but they have similar functional outcomes. I like the malarious four-stage progression from isometrics to isotonics to energy storing exercises where patients are really developing a tolerance for load. And that's really one of the goals of physical therapy is to slowly increase load through the tendon. So you see here an isometric exercise, which is actually really useful if a patient is attempting to play through a season to focus on isometrics because this has been demonstrated to decrease pain burden so patients can tolerate their sport. However, if you really want to definitively treat this, you need to be doing the strengthening regimen and decreasing the sports specific loading. So you progress to isotonics with a heavy slow resistance program or decline squat sets. And when patients can tolerate that and by tolerate, I mean, they may have pain during the exercise and one to two to three out of 10 pain is acceptable for this rehab protocol to push as long as their pain does not persist for greater than 24 hours after the exercise. Once they have progressed through the isotonics, you go to the energy storing phase of exercise where you're introducing load with jumping and accelerating as well as cutting, pivoting, decelerating. And ultimately you enter the sports specific phase where you're adding specific exercises. However, despite this evidence driven rehab protocol, there are cases that don't improve 50 to 70% of patients do not improve with the above mentioned protocol. And I think in part that's because we as sports medicine providers often set unrealistic time frames for recovery. This is not a diagnosis that gets better in four to six weeks. You really need to focus on this treatment. It can take six months. It can take longer with the right rehab to get an athlete over this condition. Another reason for poor outcomes is over-reliance on passive PT treatment, failure to address the kinetic chain, poor landing mechanics and not addressing those mechanics. And also when patients have had pain for several months, they often develop central sensitization of pain as well as fear avoidance behavior and equate pain with harm or damage to the tissue. Whereas some discomfort progressing through rehab is actually necessary to overcome this condition. We see poor outcomes when a highly irritable tendon is injected. I've certainly seen that in the setting of PRP in season. And one study, this study by Goldman looked at patellar tendon thickness of greater than 11.5 millimeters on axial MRI or greater than 50% tear thickness, which is demonstrated here, the tear thickness from anterior to posterior. Those patients are less likely to improve with non-operative care. Hence the need for other treatment options. And so we've looked to orthobiologics as our standard treatment options often are not successful. And PRP has fairly robust basic science literature that suggests that in the setting of tendinopathy, PRP can promote healing generally by three mechanisms, cell proliferation and anabolic effect and an anti-inflammatory effect. So with PRP releasing growth factors from the alpha granules, this promotes tenosyte proliferation. We know that tenosytes are one of the main building blocks that is going to synthesize that matrix, that ground substance, as well as the collagen building blocks. And then the anabolic effect comes from that increased total collagen content and the matrix synthesis. The controversy is really in the clinical trials. Many of them have power that's too low to detect treatment effect. There are many variables in PRP as well as medicinal signal cell trials where there's varying leukocyte concentrations, injection techniques and rehabilitation protocols, and oftentimes no rehabilitation protocol associated with the treatment intervention. The strongest level one evidence is really in chronic refractory tendinopathies. And this was a meta-analysis done by Jane Fitzpatrick's group that showed their conclusion was leukocyte-rich PRP intratendinous injection with the tenotomy approach appeared to be most successful of the randomized clinical trials that they reviewed. These are four randomized clinical trials for PRP for the treatment of patellar tendinopathy. The one that's most frequently quoted is this Jason Dragoo's study from 2014, which takes a look at, it's a double-blinded trial that takes a look at 23 patients in each group with symptoms for greater than six weeks. The one group had dry needling and eccentric exercises versus the PRP group, which was a leukocyte-rich formulation plus dry needling and eccentric exercises. This was a 6cc volume of PRP. This was a crossover design and they found that the VSIP at three months and the PRP group was statistically significantly improved compared to the dry needling group. However, at the six-month point, both had improved, but there was no difference between the PRP group and the dry needling group. The most recent study was a multicenter study by Scott in 2019, also published in AJSM. That was a study done at University of Washington as well as an institution in Italy and institution in Norway. This was a single-blind study that looked at 57 patients with symptoms greater than six months, which I think is more reflective of when most of us bring orthobiologics into the clinical scenario. And this was a study that compared leukocyte-rich PRP versus leukocyte-poor PRP versus a saline injection, all with a volume of 3.5 cc's of solution. There was no dry needling. There was a standard rehabilitation protocol and their outcomes at three months with the VSIP as well as pain showed no difference between the groups. And there was a trend towards the leukocyte-poor group being more effective in terms of pain and function in patellar tendinopathy with a single injection. So are more injections better? This was a trial that looked at two injections versus one and concluded that one PRP injection was adequate to improve symptoms in patellar tendinopathy and that there was no added benefit with two injections. This was a meta-analysis looking at five randomized controlled trials on minimally invasive techniques in the treatment of patellar tendinopathy, looking at not only PRP but dry needling as well as skin-derived tenosyte-like cells. And these were combined with exercise. The best short-term results in pain and function were the studies that injected more than four milliliters of PRP and that had an exercise program that lasted longer than six weeks. High-volume image-guided injection has been proposed as an alternative to PRP in terms of treatment of patellar tendinopathy. And this is injecting high volumes usually of lidocaine and saline in between the patellar tendon and the patellar fat pad to hydro-dissect out those neo-vessels and to disrupt some of the ingrowing nerves that may be contributing to pain. These authors looked at high-volume injection versus PRP versus combining the two and found that the combination of the two had significant improvement at three months and six months compared to either intervention alone. Stem cell treatments or medicinal signaling cell treatments are lagging behind in terms of quality of evidence and research for tendon disorders compared to PRP at this juncture. And there's really only one study here that I could find that was a case series that looked at bone marrow aspirate for treatment of patellar tendinopathy. These were eight patients that did have improvement in pain and function, but this is one very small case series level one evidence. Surgical outcomes as an alternative, this is a systematic review looking at 17 level one to four studies comparing the results of scope versus open treatments. And the average success rate was 60 to 90 percent, so a lot of variability. They found that the return to play was three months compared to eight to 12 months in the open group. This additional systematic review looked at two randomized control level one studies, surgical studies that looked at, I'm sorry, two studies that looked at surgery versus non-operative treatment. And they concluded that surgery was not clearly better than therapeutic exercise or injectables in terms of treating patellar tendinopathy. And that surgery is really indicated for late stage tendinopathy when patients have failed non-operative treatment. This is a novel approach that looks at arthroscopic debridement with ultrasound assistance in terms of using devices and using ultrasound to identify the region of tendinosis similar to percutaneous injections, but this is done arthroscopically to remove the tendinotic tissue and a portion of the inferior pole of the patella. So, you know, in conclusion, this is our algorithm for managing patellar tendinopathy as well as quadriceps tendinopathy. We start with PT and activity modification, make sure that patients are doing all the right things in terms of PT. We image if we need to most often with ultrasound. If there does not appear to be a tear in the patellar tendon, we'll try PRP and physical therapy or shockwave and physical therapy. If there is a tear and it's a partial tear, we'll try PRP and physical therapy. If there's a full thickness tear, we get a surgical consult as these often need to be surgically, as these really do need to be surgically repaired. All throughout this algorithm, we're educating patients on the importance of relative rest, on the importance of the proper strength training and conditioning, and setting expectations for both the rehabilitation as well as the injection therapy if that's the route that we need to take. So I thank you very much for your attention. I'm going to turn the slide deck over to Dr. Eugene Rho. Sorry if I advance that too much. Who's going to discuss orthobiologics for knee joint conditions? That was a great talk. Let's go inside the joint now. I'm Eugene Rho from Stanford. I did my fellowship in Boston under Dr. McInnis and Dr. Volkstein. Thanks for having me again this year. And also, I'd like to appreciate, thank all authors who published their articles for us to review today, and I appreciate all other leaders in this field and who led me to a very exciting area. So my session, I'll discuss mostly the PRP bone marrow adipose placenta dry tissue for knee osteoarthritis treatment, and also briefly touch nomenclature of MSC as well. So let's start with the PRP. That's most common, and we use a lot. There are more data out there. So I'll find a combination between different treatment options. So PRP with hyaluronic acid, I used Dr. Brian Cole and Dr. Lisa Fortier's study as my reference. They did 111 patients compared with PRP versus HA and used for KL2 or 3 mild to moderate knee osteoarthritis. As a result, as you see in the right side of the screen, there was no statistical difference between two groups, but PRP seemed to have a slightly better pain in the functional level at the end of a follow-up. In 2020, just April, Dr. Dragoo published a great review article about platelet-rich plasma versus HA use, and he analyzed 18 studies out of 116 studies, and he only chose a randomized controlled trial, high-level studies. The study also included sub-analysis in the different clinical scenarios as well. So he broke PRP into two different groups. One is a leukocyte-poor versus HA. The other one is a leukocyte-rich versus HA, and they use a latest follow-up point for comparison. In their result, there's almost 62.5% possible outcome values would significantly improve, while leukocyte-rich, which is still working, but about 50% improvement. So both leukocyte-poor and leukocyte-rich performed slightly better than hyaluronic acid, and there was no demonstrated superiority with HA, though. So the next question is leukocyte-poor, leukocyte-rich. From previous study and other support, a leukocyte-poor PRP tend to have interleukins that is more anti-inflammatory, while leukocyte-rich PRP tend to have 1-beta-6 and in the variant gamma. Those are more pro-inflammatory interleukins contributing to more inflammation, but leukocyte-rich tend to have more growth factors as well. So when leukocyte-poor PRP was compared with leukocyte-rich, there is no significant difference in WOMAC, the functional questionnaire, and pain scores, but there is slight improvement, better scores in the IKDC functional scale for the patient outcome. Based on the study, based on the analysis, leukocyte-poor seemed to have a slight more benefit than leukocyte-rich. In general, leukocyte-poor is a lot more commonly used option for intra-articular injections. Then I always get the question from the patient, single versus multiple injections. Review of other studies, most of studies used three PRP injections one week apart. There was only one study used one injection. So at least in the research setting, most of the studies preferred three injections versus just one injection. So whether single versus multiple injections work better for the patient is tested by several researchers, and this review article shows the different outcomes as well. The five randomized control trial from the 301 patients was done, and then about 50% of the studies used three injections, and outcomes are analyzed, and six months after the intervention, single injection versus multiple injections, there was no significant difference about the same pain improvement. But there is a better functional improvement in multiple PRP injection group. And furthermore, there is a study done, the single cycle versus a double cycle. So whether you have three injections from the one cycle or total six injections from two cycles were compared, and a single PRP, a single cycle injection, three injections also demonstrated significant improvement in their pain and function, but the double cycle group tend to have a more prolonged pain improvement and the functional improvement lasting more than 18 months. So using two cycles as a default rarely happens in my clinic, probably none, but probably at least it answered the patient's questions whether a double cycle would be beneficial or not. But I think in most of the cases, we are still using clinical judgment for the next cycles. So the then the patient usually asks, okay, what about mixing a PRP with HA, which was tested by different researchers as well, and the five RCTs and two cohort level one studies. Zhao reviewed those articles and assessed this as safety and outcomes, efficacy as well. And at least as you can imagine, it's a pretty safe option. In six months, PRP combined with HA demonstrated better pain score. But in three months, there is no difference. But once you reach the sixth month, there is a difference between HA and PRP. Maybe effect from HA is declining from sixth month, but PRP effect will continue from that point. So, well, let's switch gears to MSCs. Then MSCs, as you can see from the cartoon, from mesenchymal stem cell or MSCs can differentiate down to connective tissues, including bone, cartilage, muscle, and nerves and other tissues as well. But as you probably hear, the medicinal signaling cell, mesenchymal stem cell is a bit confusing. So I found this picture showing the history of its nomenclature. So in 88, it was called the stromal stem cell, and Dr. Kaplan suggested mesenchymal stem cell, and ISCT, the cell therapy scientist group, recommended mesenchymal stromal cell, and in 2010, Dr. Kaplan endorsed medicinal signaling cell. So MSC stands for merostromal or stromal stem cell, because stroma is a morphological term meaning from connective tissue, and this name is more focusing on its origin. So cell reside in stromal rather than the hematopoietic compartment, and also is called a mesodermal stem cell. It's not very common, but those tissues are coming from a mesoderm as well. Then in 91, Dr. Kaplan used the term mesenchymal stem cell for MSC, and these MSC stem cells are surrounded by a large extracellular matrix. They wanted to emphasize the self-renewal property and the differentiation potential of those cells, and in his other article, he also mentioned that stem cell is more attractive to the clinicians as well. So it was well received as well. However, later on, ISCT, the scientists wanted to drop the stem cell and want to use stromal cells because those cells did not favor their classification as we imagined, and there was no direct evidence demonstrating the ability of MSCs to self-renew and differentiate in vivo. So as you see the table on the right side, it should have some positive markers and negative markers. So negative markers will differentiate those cells from lymphocyte or the leukocyte, and positive markers like 70, 90, and sorry, 73 and 90 and 105, those should be positive. So later on, 2010, Dr. Kaplan started endorsing a medicinal signaling cell because those cells have a function of secretion of bioactive molecules rather than tissue regeneration in vivo. So that's how we ended up calling mesenchymal stem cell MSC, and also I had to change my title of a research project based on that, to drop the word stem cell and then try to find the other the kind of name is staying more neutral. So let's talk a little more about adipose, bone marrow, and amniotic tissues. There are also great review articles out there if you want to read more in details. Jerry Ram, Dr. Malanga, published in PMNL Journal in 2019. In 2020, Dr. Elizabeth Kahn and group also published as well. There are a lot of overlapping between two articles they reviewed. In Jerry Ram's article, he found the six human bone marrow study and the eight adipose tissue study. There was no direct or randomized controlled trial between the bone marrow and an ADSC. And Dr. Kahn's review, the most of the study used enzyme process or also, they used culture-expanded SVF for adipose-derived tissue and showed favoring outcome, promising outcome, but that's not the setting we can really use in the clinic here at least. So that's a limitation of the review. And so Dr. Mottner did some study between the adipose versus the bone marrow aspiration. So he found 106 knees and patient knows, patient can basically choose which side, which treatment they can have. But they did a bone marrow injection or they tried an adipose tissue injection to the joint, which is not enzyme-processed or culture-expanded, so under minimal manipulation. And compared its outcome based on the function and pain and oval. They, the pre and post intervention pain level, functional level improved significantly. However, between two groups, adipose versus bone marrow, there is no clear difference. The study is limited because of open label, not really randomized control, no control group. I believe his group and others doing another study with the blinded test. So hopefully we can see the result soon. And for other FET studies, I'm just wondering because most of data includes SVF, more than minimal manipulation, and I could find that there are other studies going on and there's some study done in other countries as well. So hopefully we can see the result in the near future. We can just get a microfragmented FET or a minimally manipulated tissue injection for NeoA as well. So the next part is a bone marrow, the also common source of those treatment options. I think Dr. Shapiro studied probably the most important and guiding us what to do with this. He had a randomized control trial level two and compared a BMAC with a normal saline injection in the patient with bilateral NeoA. So patient gets a BMAC in one side and normal saline to the other side and its outcome showed both bone marrow or normal saline injection improved the knee pain. However, there's no statistical difference. The nice thing about this study is also they use MRI to assess the structural changes before and after the injection procedure and there was no significant improvement. So there's no evidence of a proliferation based on this study. So how about PRP versus BMAC and Hans and Andrew tried a randomized trial among 90 patients from mild to moderate NeoA. And he said the group said leukocyte-rich, but it was monocyte, lymphocyte-rich, but neutrophil-poor PRP compared with a bone marrow aspiration concentrate, no culture expansion. And the results showed there was no difference between PRP versus bone marrow. So those two studies showed bone marrow didn't show much a superior outcome compared with PRP. And I tried to find a study to compare all those three options PRP, MFET, and BMAC was done by Esteban and group and they have an interesting assignment in the treatment. So KL1, the mild group, will get the PRP and KL2 will get bone marrow. KL3 has adipose tissues and they compared three different treatment options and did not find any significant difference among all treatment options, all treatment groups in different arthritic stage. So I think because there is no comparison in the same stage of OA with the same treatment, it's hard to tell whether PRP or MFET works better in specific arthritic group. So I think in the future, there are more studies needed to comparing them with the blinded matter. And as a last treatment option, the placenta, which has been used for a bone treatment and it has a lot of collagen extracellular matrix and it was used, it has a good, it is good source of a stem cell. And as you see in the picture on the left side, in amnion and in chorion, it has a mesenchymal stem cell as well. But the issue is once they process those placenta derived tissues, the numbers of MSC, those cells decreases and also there are some questions about some regulatory issues of using placenta derived tissues as well. So in the market those there are 34 different commercially available placenta derived tissues. Most of them are amniotic suspension and membrane or cryopreserved form or dehydrated form. So McIntyre in 2017 reviewed those and they found only one placenta derived biologic injection and trial at that time. And overall the conclusion was those injections appear to be safe at least but they could not sell much difference. And this is a probably feasibility study done by Vines. Six patients, a very, very small number and used for a module to severe KL3 and 4. And the outcome was not impressive, but number itself was very small. I think it was done to see a feasibility to see the adverse outcome. This is a much bigger study. Dr. Farhan group recruited 200 patients and assigned them into amniotic tissue, normal saline, and hyaluronic acid. And they followed it up to 12 months and they found the ASA, amniotic suspension group, demonstrated much better functional outcome and decreased pain level. So amniotic tissue has some hope and the amniotic injection, the nice thing about amniotic suspension injection is it's a very simple that there is no much of an invasiveness involved with this procedure. So at the end what I recommend a standard is not commonly used unless it's some specific situation. I still recommend HA as an option if that is covered by insurance. And if a patient were more inclined to try PRP combined with HA based on the previous review, I think that's a reasonable option we can consider. If HA is not covered by insurance, I think a PRP would be better because all those biologic options we need to discuss efficacy, longevity, and it's a safety and cost related to that since a lot of them are not covered by insurance. Then as a second line or less options, I would consider bone marrow or adipose tissues. And hopefully we get the more data will come out. In summary, no evidence of proliferation, as I mentioned in the MRI demonstrated, possibly it modifies inflammation. Always the conclusion goes, we need a more high level studies and when you discuss with the patient, probably it would be a good idea to discuss efficacy, safety, also it's a cost related to that. And I usually make my own recommendation, what I will do if I have to treat my knee, but also I put all those options on the table so the patient can make their decision. And that's pretty much it. Thank you. I'll pass the torch to Michael for the next talk. All right. Thank you, Eugene. Welcome, everyone, and thank you for tuning in for this lecture. My name is Mike Ariyama and I'm honored to be collaborating with Joanne, Kelly, and Eugene for this presentation. This portion of the talk will focus on the practical application of the treatments thus far discussed. There will certainly be a little bit of overlap between Kelly and Eugene's presentations with mine, but we'll focus on the evidence as it pertains to the patient selection, the specific treatment approaches, and the post-procedure rehab. So here's our overview. And I have to admit that as I was completing my literature review in preparation for this presentation, knowing that I was responsible for presenting the evidence on how to identify the most appropriate patients, the optimal procedure approach, and the ideal treatment rehab, post-treatment rehab, I started to think that one might summarize the findings with a simple emoji. And the reason behind this is that interpreting the available literature continues to be a process that seems to mirror my daughter's eating habits as well as her painting habits. In a word, it's still messy. But all joking aside, let's take a look at what the published evidence is regarding these subtopics. And for this presentation, in regards to orthobiologics, we'll be focusing on percutaneous PRP, bone marrow, and adipose treatments. So let's begin with patient selection and that famous question that I believe Shakespeare asked, to inject or not to inject? Now, let's actually start with who not to inject. And we'll do so by looking at the absolute and relative contraindications to orthobiologic injections. When looking at the contraindications, there are a couple of things to note here. In terms of recent cancer, most practitioners would suggest waiting at least five years after successful treatment of a cancer before proceeding with any orthobiologic. An exception to this would be any bone marrow or blood-borne cancer, as most would agree that these patients are not candidates for orthobiologic treatments at any future time point. As for the inclusion of anticoagulation and antiplatelet agents as relative contraindications, these are relative in that they may be able to be held prior to or following a procedure, but the feasibility and safety of this should be explored in conjunction with the patient's other providers first. In addition to the contraindications, here's a look at the conditions that the majority of published studies have listed as exclusion criteria. So in deciding whether to offer an orthobiologic treatment to a patient with any of these conditions, you have to consider whether the results of the studies are generalizable to these individuals. Another exclusion criteria that has been identified in multiple studies, specifically regarding the treatment of NEOA, is the presence of significant genuvarum or genuvalgum. Some studies will exclude patients with greater than five degrees of varus or valgus, while others have set the cutoff higher at greater than 20 degrees, with the thinking being that these patients are poor candidates and less likely to experience improvement following treatments with orthobiologics. In terms of treating tendon disorders, remember that patients with complete tears, particularly in the setting of retraction, are not strong candidates for treatment with orthobiologics and should therefore seek surgical intervention. So for patients with knee pathology, who is a candidate for treatment with orthobiologics? Patients with NEOA, particularly if they have Kellgren-Lawrence grade 1 to 3, who fall in the treatment gap, meaning that they have not responded to standard treatments and still are not surgical candidates, are good candidates for orthobiologics, as are patients with patellar tendinopathy, particularly if their symptoms have been resistant to standard treatments. There's also limited lower level evidence to support the use in treating meniscus, MCL, and ACL pathology. Let's now turn our attention to the technical aspects of the procedure, starting with the pre-procedure preparation. In terms of the pre-procedure preparation, there is a general consensus that certain medications should be avoided prior to undergoing treatment. NSAIDs and corticosteroids are the medications most frequently cited as requiring avoidance prior to treatment. However, the time range for which these medications should be avoided is yet to be determined. Some studies suggest that time frames should range from 2 days to 4 weeks prior for NSAIDs, 10 days to 6 weeks prior for corticosteroids, and 7 to 10 days prior for aspirin. As for the technical aspects of PRP, BMAC, and adipose procedures in the treatment of knee pathology, let's focus on the details that are necessary for one to be familiar with in order to perform these procedures, such as the PRP composition, the volume injected, the number of injections administered, the needle size utilized, as well as the overall injection approach. And we'll start with using PRP for the treatment of knee OA. Here's a look at the studies that have been published just in the last two years evaluating PRP for the treatment of knee OA. And what immediately jumps out is the variability across these studies, whether we're looking at the platelet concentration, the white blood cell content, the volume injected, the use of an activator, the number of injections. What also jumps out is the fact that technical details are commonly missing from the manuscripts, as identified by the question marks on this chart. Now, if I can draw your attention to the bottom three slides, it should be noted that these studies also included the treatment of either extra-articular or intraosseous structures in addition to the intra-articular injection. Looking first at SIT's study from 2019, while there was a total of six milliliters of PRP injected, this volume was actually dispersed over three separate sites, including the intra-articular injection, over the MCL, and over the medial coronary ligament as well. Both of the Sanchez studies listed at the bottom included an eight milliliter intra-articular injection, as well as five milliliter injections intraosseous into both the medial femoral condyle as well as the medial tibial plateau. Now we'll look at bone marrow in the treatment of NeoA. And here are the studies that have been published to date on the use of BMAC for the treatment of NeoA. Similar to PRP, there is quite a bit of variation in the characteristics of the BMAC this time, particularly when looking at the volume of bone marrow aspiration, as well as the final BMAC concentration that's injected. But the injected volumes ranging from anywhere from five to 40 milliliters. If you look at Shapiro's study at the top, so even though there were five milliliters of BMAC injected, it should be noted that this five milliliters of BMAC was actually first added to 10 milliliters of platelet-poor plasma before all 15 milliliters were injected. In regards to Hernegau's study at the bottom, none of this listed volume was actually injected intra-articular, as all of it was dispersed amongst intraosseous targets, with 10 milliliters injected each into the medial and lateral femoral condyles, as well as the medial and lateral tibial plateaus. Next, we'll look at the use of adipose for the treatment of NeoA. And once again, looking at these studies, we see a significant amount of variability and missing technical details, particularly in regards to needle size and the intra-articular approach. The injected volumes varied from as little as five milliliters to as much as 35 milliliters. And looking at the study that injected 35 milliliters, this was actually done through co-performance of a diagnostic arthroscopy where a drainage tube was placed, and the 35 milliliters was actually infused through that drainage tube. Next, we'll look at studies that have examined the combination treatments for NeoA. So multiple orthobiologics used for an individual treatment. All of these studies included the treatment with bone marrow, with the Pedromo study using bone marrow aspirate rather than concentrate. This Pedromo study, as well as two of Centeno's studies, included the simultaneous treatment of bone marrow with PRP and adipose, while the third study from Centeno featured simultaneous treatment of PRP with BMAC. All studies here listed, in addition to the initial treatment, included a follow-up PRP injection, which occurred anywhere from two to four days after the first treatment or up to eight weeks after the initial treatment. Finally, Centeno's studies also included a pre-injection with dextrose. So the major theme when reviewing all of these studies is that there's an incredible degree of variability from one to the next. Next, let's look at the studies that have been published on treating the meniscus with orthobiologics, and all published studies to this point have used PRP as the injectant. As you can see, many details in these studies went unreported. Only one study reported on the platelet concentration used, two on the white blood cell content, and two on the volume injected. Two reported direct injections into the meniscus, while the third study consisted of an intra-articular injection in order to treat the meniscus pathology. We'll now look at the literature regarding the treatment of tendon and ligament pathology, with the vast majority of these studies focused on patellar tendinopathy in terms of the knee. So here are the studies that have evaluated PRP injections for tendinopathy or knee-related tendinopathy, with all but one examining patellar tendinopathy. The study, unfortunately, it looks like the bottom study here got cut off, which was published by the New York Times. And that study looked at the treatment of the pezanseride. Similar to PRP for the knee OA data, you can see a great amount of variability across this chart in terms of the platelet concentration, white blood cell content, volume injected, use of an activator, and number of injections. There is, however, good consistency here in terms of the needle size use and the injection technique. With the vast majority of studies reporting a 21 to 22 percent gauge needle, as well as direct injection of the tendon with or without multiple passes. In terms of knee-related ligament pathology, I could only find four studies that evaluated the treatment of knee pathology or knee ligament pathology with PRP. Three of these studies looked at the MCL and one looked at the ACL. Of the MCL studies, only two reported a direct injection of the tendon with or without multiple passes. Of the MCL studies, only two reported direct injection of the ligament, while one reported or consisted of an intra-articular injection. The ACL study here reported direct injection of the ACL. All of these studies utilize a series of injections. And as you can see, other details were variable or not reported. Finally, here are the only two studies I found that explored the treatment of knee-related tendon or ligament pathology with advanced cellular orthobiologics. With both of these studies being case series data. Both studies utilize DMACC, one for the treatment of patellar tendinopathy and one for the treatment of ACL pathology. The patellar tendinopathy study was scant on details, while the ACL study utilized a mixture of DMACC added to PRP and platelet lysate, with the listed volumes here being of that combination, with injections occurring both directly into the ACL, as well as intra-articular as well. Similar to the pre-procedure precautions, many of the studies also documented the restriction of anti-inflammatory medications following treatment. These restrictions range from anywhere from two days to three months after for holding off on NSAIDs, four to six weeks after for corticosteroids and seven to 10 days after for aspirin. Additional post-procedure precautions often included some degree of weight bearing restriction, with or without the use of bracing, with the most frequent recommendation being restrictions for one to three days following treatment, regardless of which orthobiologic was utilized. From weight bearing restrictions, we'll fully transition into reviewing the recommendations regarding post-procedure rehab. In regards to the studies I've discussed thus far, it probably will not come as a surprise that rehab recommendations vary considerably, with many not providing any specifics in regards to PT or rehab at all. This chart summarizes the different recommendations across the various studies broken down by region treated. And when considering the post-intervention rehabilitation, there's good reason for the reported variability, because in terms of research that's been dedicated towards rehab protocols following orthobiologics, there still isn't any. What we do have, though, thus far, are commentaries and qualitative reviews, the most extensive of which was published by McKay et al. in 2018, specifically regarding the rehab of NEOA following treatment with orthobiologics. In this manuscript, they propose a post-orthobiologic rehab protocol based on the best practices for NEOA with incorporation of the goals of regenerative medicine. They identify the following best practices as forming the basis for their post-orthobiologics NEOA rehab protocol. So one, moderate exercise, including endurance and strengthening is recommended as it reduces pain and increases functional capacity. Two, it's important to focus on strengthening around the knee, as well as the hip and pelvis. Three, the gradual loading, stability, proprioception and neuromuscular training all have demonstrated the potential to stimulate chondrocyte anabolic activity. Four, that manual therapies can help address soft tissue and joint dysfunction by improving range of motion, modulating pain, reducing inflammation, altering muscle tone and improving circulation. Five, that blood flow restriction therapy promotes muscle hypertrophy and strength while also promoting improved serum growth hormone levels, peripheral stem cell count and protein synthesis. Six, whole body vibration therapy can be used to stimulate isometric concentric and eccentric strength. And finally seven, that the electro therapies particularly low level laser have demonstrated some ability to stimulate cellular oxygenation, the release of neurotransmitters associated with pain modulation, the release of anti-inflammatory mediators, improved blood flow and improved capillary permeability. Based on these principles, they designed the following protocol for knee OA. And as you can see, it's broken down into four phases. In the first phase, the focus is on relative protection of the treated region with a goal of controlling pain and swelling. The second phase focuses on progressing towards full range of motion. And the third phase loading is, is progressed further. And in the fourth phase, more dynamic activity is introduced. In terms of modalities that may assist with tissue regeneration, whole body vibration therapy is introduced during phase two and blood flow restriction therapy is introduced in phase three. In terms of taping tens, IFC and acupuncture, these are modalities that should be viewed purely as adjunctive treatments. Uh, and while they have not proven any additional benefit to regenerative or orthobiologic procedures, according to the authors, they're unlikely to, uh, have any positive effects. Earlier this year, Centeno and Pastoriza published their recommendations on post orthobiologic rehab, differentiating between rehab following treatment of OA versus treatment for tendinopathy. Here, you can see their post orthobiologics, OA rehab model, which is quite similar to the one proposed by McKay et al, with a highlight being the target of post orthobiologic rehab, which is a treatment for tendinopathy. This part, in my opinion, is particularly important for framing expectations for patients prior to undergoing treatment of their knee OA with an orthobiologic. Here's their post orthobiologics, tendinopathy rehab protocol. Unlike the OA models presented thus far, you can see that this protocol consists of three phases. Instead of three phases, there are four phases, and each of these phases is a treatment for tendinopathy. The first phase is a treatment for tendinopathy. The second phase is a treatment for tendinopathy. As compared to the OA models presented thus far, you can see that this protocol consists of three phases instead of four, which follows the phases of endogenous tendon healing, the stages of the endogenous tendon healing cascade, from inflammation to proliferation to remodeling. With phase two correlating to the proliferative phase stage, this phase can begin anywhere from day four up to day 14 post treatment, depending on the individual treatment. As compared to the OA models, you'll notice that there is a slower, faster progression to full weight-bearing activity, and the reason for this is to reduce the risk of possible tendon rupture by allowing for sufficient healing of the tendon after interventions that include direct infiltration. That being said, it is important for early gradual loading of treated tendons in order to optimize collagen stimulation and organization. Other important features of this protocol include the recommendation to avoid eccentric exercise following a treatment with orthobiologics until the six-week mark in order not to disrupt the tendon healing process. Gordon and Han have also proposed their post-orthobiologic treatment protocols from the following textbook. And in terms of their treatment protocol that follows the treatment of tendonopathy, here are some of the highlights in terms of how it differs from that presented by Centeno and Pastoriza. So here you can see the inclusion of four phases instead of three with the proliferative phase actually being broken down into two sub phases. They also specify that cross-body cardiovascular training can begin as early as the first to second week post-treatment. And finally, they actually suggest that concentrics can progress to eccentrics as early as the third to fourth week rather than sixth week, so long as the patient has already regained full pain-free range of motion. So in summary, let's begin by stating the obvious. More research is needed to optimize the delivery and performance of these procedures. Based on the best currently available evidence, the use of PRP is supported for the treatment of Kellgren-Lawrence grade one to three NeoA and is reasonable for standard treatment resistant patellar tendinosis. However, the optimal approach and PRP formulation is yet to be determined. Though the optimal approach remains at large when treating NeoA, recent studies suggest it may be beneficial to include treatment of extra-articular and or intraosseous pathology as well. Advanced cellular therapies, while promising should be thought of as more experimental than PRP for these diagnoses. There is a general consensus that anti-inflammatory should be avoided both before and after treatments without a clear cut timeframe at this point. Imaged guidance is strongly recommended to ensure accurate injection While we still have not identified the ideal PRP formulation or BMAC or adipose features, it is imperative that any providers performing these procedures know what it is specifically that they're injecting and thoroughly document this, which will help propel the field forward and ultimately lead to better patient outcomes. Finally, when it comes to the post-orthobiologic intervention rehab, I encourage you to consider the published protocols as a starting point, while still personalizing for your individual patient's needs. Thank you for your attention and all relevant citations can be found at the end of my slides.

orthobiologic injections

knee

patient selection

treatment techniques

post-procedure rehabilitation

platelet-rich plasma

bone marrow aspirate concentrate

knee osteoarthritis

patellar tendinopathy

rehabilitation protocols