year at the virtual AAPMNR assembly. Look forward to seeing everyone next year in person. We're here today to present to you a discussion of orthobiologic injections for the elbow. Our agenda tonight will include a review of orthobiologic injections for elbow tendinopathy by Dr. Steven Mikovic. Dr. Christine Eng will follow with a discussion of orthobiologics for elbow arthritis, cartilage disorder, and ligament disruption. And that will then be followed by Dr. Joshua Rothenberg, who will discuss patient selection, approach, and post-procedure rehabilitation. To get into a little more detail, Dr. Mikovic is my esteemed colleague at the Department of PMNR at Harvard Medical School. He's team physician for the Boston Renegade and is quite expert in sports medicine, interventional ultrasound, and gymnastics medicine. We will also be accompanied by Dr. Christine Eng, who will discuss orthobiologics for elbow arthritis. She also is an instructor in the Department of PMNR at our Harvard Medical School. She's the director of ultrasound education for our Spalding residents and is very expert in gymnastics and regenerative medicine. And last, but certainly not least, is Dr. Joshua Rothenberg, who will talk about patient selection and post-procedure rehabilitation. He is the director of regenerative medicine for Boca Raton Orthopedics. He completed the prestigious sports medicine fellowship at University of Pittsburgh and was the founder of the online sports review journal. So with that, I'd like to turn it over to my colleague, Dr. Steven Mikovic. All right. Thanks, Joanne, so much for the opportunity to get in to speak with everybody. So as Joanne talked about, I'm going to go over orthobiologics and elbow tendinopathy. I have no financial disclosures. So we're going to talk about orthobiologics and elbow tendinopathy. We're going to go over basic pathology overview. We're going to discuss lateral and medial epicondylosis. We're going to discuss platelet-rich plasma injection, autologous blood injection, medicinal signaling cell injections, and needle tenotomy. We'll also discuss a couple small studies on distal biceps tendinopathy and platelet-rich plasma injection use. So before we get into orthobiologics, I would like to briefly review tendon pathology. So tendinosis is a label for a degenerative tendon pathology as seen on MRI, ultrasound, or a biopsy. Tendinopathy is the preferred clinical term to indicate a combination of pain and impaired performance of a tendon without knowing the specific tendon pathology. For the purpose of this lecture, I will mainly use the term tendinopathy. The pathology of tendinopathy is varied and includes things such as abnormal collagen production as depicted in the top electron microscopic image. There are many proposed mechanisms. Most commonly you will hear about overload. However, this may be due in part to impaired heat dissipation. The extracellular matrix of the tendon actually contains proteoglycans, glycosaminoglycans, which have a net negative charge, and this allows them to retain water, which in turn helps the tendon to dissipate heat. Also, recent studies have shown that proteoglycans actually regulate production of type 1 collagen, which is the main structural component of tendons. So historically, studies have highlighted the fact that there are no inflammatory or polymorphic nuclear cells in various human tissue specimens. So as an example, this is in vivo study of an extensor carpi radialis brevis tendon, and they said there were no PMNs basically. However, more recent molecular evidence suggests that there are many inflammatory interactions which may occur in the more acute and subacute stages when the patient may be asymptomatic. So let's start talking about the problem of tennis elbow. It's all, it's a very large problem that is common in outpatient musculoskeletal practice and in primary care. This was a population-based study which found the incidence of tennis elbow at 3 per 1,000, and 50% of patients only had one to two visits for this problem, and 74% were actually no longer seeking care after three months. However, 18% continued to receive care even six months after the diagnosis, and 12% went on to have surgery. Also, the recurrence rate of symptoms was 8.5% in all patients. So what about treatment options? Well, we always start with a simple conservative treatment options first, bracing, activity modification, physical therapy, and a detailed home exercise program. What about steroid injections? Well, probably not a great idea as we're going to discuss. This is a paper which summarizes the known effects of locally administered glucocorticoid on tendon tissue and tendon cells, which overall appear to have a negative effect on tendon homeostasis, with increased collagen disorganization and collagen necrosis seen after treatment. So let's take a look at the typical course after a steroid injection for tennis elbow. Prior study by Smit in 2002 randomly assigned 185 patients with lateral epicondylosis for at least six weeks to either steroid injection, physical therapy, or just wait and see. At six weeks, the steroid injection had a success rate, had a higher success rate than any other treatment. However, at 52 weeks, the success rates were 69% for injections, 91% for physiotherapy, and 83% for just wait and see. So basically, there wasn't much difference between doing nothing in physical therapy, unfortunately. And this figure here is a depiction of three randomized controlled trials, including the Smit study that I just mentioned, and basically shows that steroid injections significantly improve things at six weeks. As you can see here, this is a picture steroid injections significantly improve things at six weeks. As you can see by the black lines there at six weeks, things really take a dip in pain scores. However, they show worse outcomes at six months compared to physical therapy, placebo, wait and see, and anti-inflammatory medications. So what do we do when conservative care just is not working? This is when we may turn to orthobiologics. So let's first start talking about platelet-rich plasma injection. There's no actual accepted standard definition of PRP, but it is autologous plasma with a super physiologic level of platelets, typically set at three to eightfold increase. However, the normal platelet concentration ranges from 150,000 to 350,000 platelets per microliter. So this also raises a problem when studies state that it's five times baseline concentration because it depends on the patient's baseline platelet numbers. It would be much better to report the actual platelet numbers and the studies that are out there. So we know that platelet-rich plasma contains numerous growth factors which can promote healing. But upon activation, platelets secrete more than 300 active substances from their intracellular granules. Some have positive effects, but others can also be detrimental. The effect also likely depends on the current and local tissue pathology and many other patient-specific factors. I included a quote from this paper basically highlighting our lack of understanding at the interplay of these hundreds of different substances, especially based on specific tissue circumstances. So there's still a lot of work to be done. Before we take a look at some studies on PRP, keep in mind that all PRP is not equal. In fact, there is quite a range in platelet concentration, leukocyte concentration, red blood cell concentration, and also whether or not an activating agent was used. Actually, if you take a look at some of the studies, it depends on what type of tube they used to actually spin the blood down. Studies should really be reporting the specifics of the type of PRP used, such as using the Mountner PLRA classification as cited right here, platelet count, leukocyte content, red blood cell content, and whether or not activation was used. In the box over here on the left, I'm going to try to use the standardization table during the different studies that I'm going to talk about. So this study is a two-year follow-up. It's a two-year follow-up data from a prior peer booms et al 2011 study, which most people have probably come across before. It included 100 patients with symptoms greater than six months. And this is important because the natural history, as I pointed out earlier, of lateral epicondylosis is that most will recover within six months and little gain is noted between six to 12 months. Patients were excluded if they had been treated for lateral epicondylosis with surgical intervention or the corticosteroid injection in the past six months. And the treatment included PRP injection to the area of maximum tenderness versus a steroid injection. Both groups also had five needle penetrations to the common extensor tendon. Now the primary endpoint was 25% reduction in the visual analog scale score or the dash score without a re-intervention after one year, which was significantly greater in the PRP group. And the majority of re-interventions, either repeat injection or surgery, occurred in the steroid group, 14 versus six. To my knowledge, this study had the largest number of participants. Although originally it was supposed to only be a 12-week study, it was actually extended to a 24-week study, and this only included 119 participants, so just keep that in mind. It again used a needle peppering technique to the tendon, but the control was bupivacaine only this time and no steroid. Success again was greater than 25% improvement in the VAS, which they did meet at 24 weeks. It was 68% for control versus 84% in the PRP group. And there was actually no difference at any time point with the patient rated tennis elbow evaluation. This is from a recent review and meta-analysis in the journal of PMNR published actually this year. They broke the outcomes down into short duration of less than two months and long duration of greater than two months. And as would be expected, in the short term, steroids went out. But in the long term, PRP seems best. Unfortunately, it was unable to evaluate leukocyte-rich versus leukocyte-poor, which would have been very helpful. Speaking of leukocyte-rich versus poor, this is the only study I was able to find that directly compares leukocyte-rich to leukocyte-poor PRP and lateral epicondylosis. It was a double-blinded randomized control trial with a normal saline control. 30 participants were in each group. Injections were performed blind and the follow-up was very short, only eight weeks. They did not find any significant difference between groups with regard to VAS, patient reported tennis elbow evaluation, grip and pinch measurements, extensor tendon thickness, and cortical derangement. However, they did note that grip and pinch significantly increased from four to eight weeks with a leukocyte-rich PRP group. It would have been really nice to see at least a few months here. Regarding leukocytes, they do have known deleterious effects, such as increased inflammatory cytokines and increased reacts of oxygen species. However, they have a lot of beneficial effects, including increased release of growth factors, they have antimicrobial effects, and they may switch the inflammatory process to more of a regenerative phase. There was a 2017 review by Fitzpatrick looking at all types of tendinopathy, not just elbow, and found that leukocyte-rich had a stronger effect than leukocyte-poor in general. Still need more studies on that. We have reviewed studies comparing PRP to local anesthetic, saline, and steroid. Many of the protocols use a needling technique as described with the five passes through the tendon. This study specifically compared PRP with two different needling techniques, a five-pass needle fenestration as described in the prior studies, or an actual needle tenotomy, where the needle was used to abrade the common extensor tendon footprint until a change in feedback was felt. At a mean follow-up of 40 months, there is no significant difference in VAS, functional outcomes, or grip strength. However, the fenestration group underwent additional procedures to treat recurrent symptoms versus the tenotomy. So this leads us to surgical technique. Surgical treatment for recalcitrant lateral epicondylosis pioneered by NERSHL includes lateral release with deridement of the common extensor origin and has been shown to result in sustainable relief for over one decade. NERSHL and Patron suggested that the success of this procedure was secondary to the removal of diseased tissue, combined with bony decortication stimulating local blood flow. Seeing that we are talking about blood here, here's a fitting quote by Andrew Taylor Still. And today I am, as I have been for 50 years, fully established in the belief that the artery is the father of the rivers of life, health, and ease, and its muddy or impure water is first in all disease. There is newer technology available for performing a tenotomy, which is percutaneous ultrasonic tenotomy, or TENEX. The technology is based on the process of phacoemulsification for cataract treatment. The specialized needle uses a piezoelectric effect to produce around a 28 kilohertz frequency, and this allows for targeted debridement within one millimeter of the needle tip, in addition to aspiration of diseased tissue. Here is one study looking at percutaneous ultrasonic tenotomy, which included 20 patients with refractory lateral epicondylosis. Symptoms range from 4 to 48 months, and associated pathology was noted on ultrasound evaluation. They underwent percutaneous ultrasonic tenotomy and were assessed at 1, 3, 6, 12, and 36 months. Sustained pain relief and functional improvement was found. In addition, none of the patients required further treatment procedures, and all expressed satisfaction with the procedure. They all demonstrated also sequential improvement in ultrasound findings, as seen in the pictures here, with reduction in tendon thickness, hypervascularity, and hypoechoic scar tissue, all reduced up until the three-year mark. So now, what about PRP versus percutaneous ultrasonic tenotomy? Well, this was actually a retrospective study that compared PRP to TENEX in the treatment of both medial and lateral epicondylosis. Of note, five subjects in each group had medial epicondylosis specifically. Now, there is no difference in treatment, actually, prior to undergoing the PRP versus the TENEX procedure, and after the procedure, they did not find any significant difference in pain or functional improvement between PRP or TENEX. So what about just using autologous blood? Well, this was first introduced in 2003 by Edwards, who noted it may initiate the inflammatory cascade and promote healing in an otherwise degenerative process. It was also pointed out that autologous blood injection was minimally traumatic. It had a reduced risk for immune-mediated reaction because it's your own blood. It was simple to acquire and prepare, and was inexpensive. With an average follow-up of nine and a half months, it was noted patients had reduced pain and improved functional scores. However, nine patients did need more than one injection. Here are a couple other studies on autologous blood versus PRP. Creeney followed patients out to six months and defined success as an improvement in the patient-rated TENEX elbow evaluation score of 25 points at final analysis. Success rates were fairly similar, PRP versus autologous blood. There was a higher rate of conversion to surgery in the autologous blood group, 20% versus PRP group, 10%. Phantasys followed patients out to six months and used the VAS and Liverpool elbow score, and only the VAS was better at six months with PRP. Functional scores were similar between the two. This is from the previously mentioned recent review and meta-analysis in the Journal of PM&R. Autologous blood mostly ranked second in all aspects at both short and long-term follow-ups, actually. I'm only going to briefly address mesenchymal stem cells, or more appropriately termed medicinal signaling cells, as Christine will discuss in greater detail. Most commonly, we are deriving them from either bone marrow or from adipose tissue. There are few studies looking at, there are only very few studies looking at mesenchymal stem cells in the treatment of elbow tendon pathology. Singh used bone marrow aspirate in those with previously untreated tennis elbow using a blind injection to the site of maximum tenderness. There was significant improvement in the patient rate of tennis elbow evaluation scores at two, six, and 12 weeks. Lee treated refractory tennis elbow with adipose-derived mesenchymal stem cells with a fiber glue. Basically, thrombin was mixed with MSCs in one syringe and fibrinogen in another syringe, and then they were combined during the injection, which converted fibrinogen into an insoluble fiber clot to trap the MSCs in a fiber matrix. The VAS steadily declined from 67 down to 15 at 52 weeks. The modified elbow performance index scores also improved from 64 to 91, and the tendon defect size measured on follow-up ultrasound exams also decreased over time. As you can see in the picture on the right. Now, what about medial epicondylosis? Well, there are no studies exclusively looking at medial epicondylosis in PRP. The largest numbers of medial epicondylosis is by Varshney in 2017. However, no distinction was made between lateral and medial in the results. Overall, PRP in the study was superior to steroid injections at reducing pain and increasing elbow function at 60 weeks. The study also looked at medial function at six months. Let's move on to distal biceps tendinopathy. Only a couple small studies are available. The case series here by Barker explains how he sees 1,450 new patients with shoulder and elbow problems each year, and in the four-year period that PRP was available to him, there was only seven cases diagnosed with distal biceps tendinopathy. So there's really a lack of significant studies because the numbers are likely just so small in the general population. Six of these cases have PRP injections with a needling technique to the distal biceps. Overall, there was good functional improvement and pain reduction. A slightly larger study by Sanley in a prospective multicenter cohort of 12 participants used a single ultrasound-guided injection of PRP. At final follow-up, which ranged 36 to 52 months, there was significant improvement in the active and rest VAS scores and improvement in the elbow functional assessment. Let's switch gears to briefly discuss prolotherapy. Prolotherapy has been used for many years in various musculoskeletal conditions. It was formalized by George Hackman in the 1950s. Basically, a hypertonic dextrose solution is injected in order to initiate the inflammatory cascade likely from osmotic cell rupture and a needling effect which will trigger the release of growth factors and collagen deposition. There have been much fewer studies done on prolotherapy for lateral epicondylosis. Karyanopoulos compared prolotherapy versus steroid with repeat injection at one month. There was no difference at one, three, or six months, but the authors noted it was an underpowered study. Bayet compared prolotherapy versus steroid and found good improvement with both at one month as we would expect as we have discussed at length specifically with the steroid but then at three months the prolotherapy group noted continued improvement not with the steroid. However it was a short study with low numbers. So to summarize always always always focus on basics first, proper diagnosis, physical therapy, educating the patient, proper movement and biomechanics. Steroid injections only offer short-term relief and may cause harm in the long run and we need to educate patients about this. For the subset of patients who do not respond to either wait-and-see, anti-inflammatories, medications or physical therapy, PRP is a strong consideration with level one studies and a good safety profile. You could consider a tenotomy with PRP or percutaneous tenotomy alone which is in itself a completely different lecture. When cost is an issue you could consider autologous blood injection or just a simple tenotomy. Prolotherapy is lacking large long-term studies and there is also a lack of studies on medicinal signaling cells but you could maybe consider in larger tendon defects if someone wasn't a surgical candidate or didn't want to have surgery. I'm gonna pass the baton over to Christine Ng who's going to talk about orthobiologics in elbow joint and ligament pathology. Thank you for attending this virtual session on elbow orthobiologic injections. For my part today I'm going to discuss the use of orthobiologics for the elbow joint and ligaments. I want to thank Joanne again for putting these great sessions together and for the great virtual content on AAPMNR this year even though we can't be there in person. I have no relevant financial disclosures. Our objectives today will be a brief overview of some currently available techniques. I will coordinate with Steve's lecture not to repeat content. There will be a brief overview of anatomy and pathophysiology. Then we do a dive into the current literature pertaining specifically to the use of these techniques in the elbow. So whereas Steve gave a nice quote by Andrew Taylor Still, I'm gonna stick with nerdy humor. So a little bit to get us going in these trying times. One scientist says to the other I'm going mini human brains from stem cells and the other one says why there's no shortage of mini human brains. So I'm likely preaching to the choir if you're in this room but orthobiologic injections have to be part of a more comprehensive treatment and not a standalone treatment themselves. We counsel patients extensively regarding medical optimization and general health factors which likely impact the efficacy of treatment and recovery in general. We also have every patient undergo physical therapy and many times are repeating some physical therapy if we can identify specific mechanical issues. Generally orthobiologic injections are pretty low risk but they're always considerations we check for like any uncontrolled medical issues, thyroid dysfunction, diabetes which may impact healing response. For the procedures we're looking at bleeding disorders, any antiplatelet or anticoagulation agents depending on the type of procedure. This is not always a hard stop but sometimes we may modify the protocol depending on what they're on. More hard stops at this point are active cancer or active infection. Otherwise just like any other procedure the correct diagnosis is essential for success. They can have some multifactorial etiologies that can be treated with orthobiologics but sometimes we may include diagnostic injections prior if we're less certain to the etiologies that the patient may have. And so this is Medusa coming in for a scalp massage. And again as Steve discussed we used to think of corticosteroids as the holy grail for osteoarthritis and now we know that repeated corticosteroid injections are likely destructive to cartilage with production of proteoglycan synthesis and have negative systemic effects overall. So where these orthobiologists come into play is that they're filling a current treatment gap. Steve already went through some of the basic principles of these orthobiologics but here are some various ones that are available and we'll review some of the popular ones for the elbow joint today. Steve already reviewed the potential mechanisms of prolotherapy and where it came from. I will just add that most people are using a solution of hyperosmolar dextrose but one of the main limitations surrounding the study of prolotherapy or with generally orthobiologics is that everyone has their own protocol or special cocktail they use and it's really hard to compare these in group data. We already learned the proposed mechanisms for PRP in tendinopathy. In the joint additionally there may be alterations to joint physiology with PRP. There may be some regulatory role from shifting from catabolism to anabolism which may actually increase collagen type 2 and prostaglandin synthesis. There may also be some down regulation of apoptosis and increasing chondrocyte proliferation. As we already reviewed PRP contains a mix of inflammatory growth factors. Some are anabolic and some are catabolic. There's a natural homeostasis of the body that is often disrupted in osteoarthritis which PRP may influence although not always clearly for the better. At a basic level inflammatory cytokines and metalloproteases normally are tightly regulated to aid in the remodeling of cartilage but in unregulated quantities may be destructive for cartilage or cause pain. There may be some of the effect of Steve's mentioned before that PRP may work differently actually depending on the environment in which it's delivered so that sometimes in a inflammatory environment it may trigger a varied response of some of these growth factors and cytokines but this is still unclear. As we talked about before PRP is not PRP is not PRP. There may be an inherent variability in the product. There's also patient variability. There's variability across preparations and kits and there may be also contamination from RBCs which may lead to oxidative stress. Additionally Steve already talked about the role of leukocytes and is it friend or foe but in general what I would say is that for the joint we probably are using more leukocyte reduced preparations or leukocyte poor whereas possibly for the tendons or the ligaments we may consider losing using leukocyte rich as Steve already discussed. And regarding stem cells most people think of these cells as serving a precursor as precursors to chondrocytes or fibroblasts but for a cell to be truly called a stem cell it must undergo a tri-lineage differentiation at least into osteoblasts, chondrocytes, adipocytes under correct culture conditions. We've not been able to reliably produce this effect even in petri dishes. So in reality a large part function of these cells is mostly immunomodulatory or trophic to impact their local environment. These cells really serve more of a regulatory role leading to downstream growth factor regulation. They also impact other cells via cell-to-cell signaling. They can transfer exosomes organelles and other molecules. Their paracrine activity may help to promote tissue repair. This is why you've heard that there's a push not to call them stem cells even by Arnold Kaplan who first popularized the MSCs as mesenchymal stem cells but perhaps more fitting they should be called medicinal signaling cells. To demonstrate this here's an actual in vivo study that showed increases of two regulatory cells systemically after a single inter-articular injection of these adipose-derived stromal cells. This effect actually persisted for about three months and it seemed to have a lasting immunomodulatory effect. So we can extract these cells from various sites. For the purpose of this lecture we will mainly focus on cells from bone marrow aspirate concentrate and adipose as this is what is mostly being done in the United States and there's more literature regarding these. Some of the reasons for this is that it may be partly regulatory. Blood products like PRP are currently not under the FDA purview however when we're discussing MSCs if they're anything more than minimally manipulated or they're not used homologously they may be viewed as a drug. And so let's move on to a discussion of orthobiologics for ligaments. For this lecture we will mainly discuss the UCL since it's the large proportion of the literature is on the UCL. But both PRP and prolotherapy have been done to other ligaments in the elbow especially the radiocollateral ligament which is often treated in addition to lateral epicondylosis if there is disruption. And so this gentleman is coming in saying it's not overuse from tennis elbow but it's underuse from elbow macaroni syndrome. The UCL is often described as having distinct bundles but likely there are more ligament fiber groups that are overlaid rather than distinctly separated. These overlapping fibers work synergistically to support stability through various degrees of range of motion. And here's a nice paper which describes four functional groups of overlapping ligament fibers which may work synergistically and reciprocally. To correlate with the model that describes discrete anterior bundle the group four fibers may be similar to the posterior band while the group one fibers may be similar to the anterior band and all of these are working in coordination. This may be why PRP may be effective as it can spread along the fibers and be injected into the areas of diffuse fiber disruption. It also may indicate why most people are trying to use more of a needling technique which may help stimulate multiple fiber groups with the needle. There are several retrospective studies involving the use of PRP in the UCL with some promising results. The first was by Lugopodesta involving 34 patients with MRI confirmed partial UCL tears with a standard post-injection rehab and throwing program. They found improvement in the KJOC, the DASH, and dynamic ultrasound evaluation and all were statistically significant with an average follow-up time of 70 weeks. Lastly, 30 of these 34 patients were able to return to their previous level of competition. Next, Dynes et al published a retrospective case series of 44 baseball players who had one, two, or three injections of leukocyte-poor PRP depending on continued levels of pain. Outcomes were a little bit more mixed and four of the six professional players were able to return to play. It did appear that distal tears seemed to have worse outcomes, whereas more diffuse signal without clear tears had better outcomes, which goes back to potentially the functional classification of these ligament fibers. Lastly, Diehl et al had a retrospective study of about 25 people with MRI confirmed grade two partial UCL thickness tears with UCL insufficiency. Patients were braced with a varus force hinged elbow brace, then had two injections of leukocyte-rich PRP about two weeks apart, which was non-activated, after which they completed a supervised rehab protocol and progression to return to throwing program. They weaned from the hinged brace after they were pain-free and then they evaluated the ligament with an MRI four weeks after, with all 25 showing some ligament reconstitution, and 20 of which were complete reconstitution. 96% were able to return to the prior or even higher level of play with a mean time of 82 days, and two of the three patients who have failed prior repair reconstruction, indicating that maybe in this population it may be a little bit less effective. So to sum it up, there are a few studies in which all of them were retrospective with significant heterogeneity, so it's hard to generalize for all athletes, but likely PRP is safe and they all seem to have promising and good outcomes for the UCL. What about MSCs for the UCL? Well there is very little published literature on this, and so we had to dive deep with Dr. Borgstein, actually talking to Lugo Podesta, who published the initial first study, and he said he repeated the same study looking at bone marrow aspirate for severe lesions. In this he had used fenestration with three mls of the concentrate interlesionally. He noticed a similar post-rehab protocol to this prior study, and all patients were able to return to their all patients were able to return to their level of throwing or better, but patients were able to return to throwing faster, and so a little bit of communication there. So let's move on to orthobiologics for elbow OCD, and this person basically has selfie elbow. So what I will say is that right now the literature doesn't say much about orthobiologics and the elbow joint in general. So in order to take a look at this, we'll have to borrow from other joints. Specifically, we'll look at Taylor OCD lesions and possibly cartilage lesions at the knee. As you know, most OCD lesions in the elbow are in younger athletes for mostly baseball players and possibly gymnasts. We can say that there's very different mechanisms of overload which may be responsible in these two groups. So obviously, this needs to be taken with a little bit of a grain of salt. When looking at Taylor OCD lesions, there's a randomized controlled study looking at PRP versus hyaluronic acid. It was a very small study of 30 patients who either had three injections of PRP or three injections of uflexa. Both groups did have improvements, but they found that PRP was significantly better. The next study looks at PRP versus prolotherapy in Taylor OCD lesions. This was a retrospective study which showed improvements in both groups, but didn't find any statistically significant difference between the two. And so what can we say for PRP versus prolotherapy in OCD lesions of the elbow? Well, there were two small studies for the ankle OCD of the talus. PRP and prolo and hyaluronic acid all showed some improvements, but PRP potentially was better than hyaluronic acid. But in a very small study, similar seemed to be similar to the prolotherapy. Again, it's really hard to generalize as these were lower quality studies. They looked at the talus, so it's really hard to see if we can even generalize it to the elbow given the different mechanisms of these lesions and potentially different loading patterns. In regards to the use of MSCs for OCD lesions, there's really very little evidence to extrapolate from. Most of the studies actually look for more osteochondral lesions rather than true OCD lesions, and most of them are looking at the chondral lesions within the knee. Again, this may have a different pathophysiology than elbow OCD lesions. Sorry. The existing literature is sparse. It mostly looks at bone marrow aspirate concentrate to augment grafts. These studies show improvement with the bone marrow aspirate, but with more of a hyaline-like cartilage fill. When looking at the few studies with adipose, most of them are combined with either microfracture or combine it with things like fibrin glue, and it does show that it led to better coverage of these grafts when compared to microfracture alone, but again, not really sure if you can extrapolate this out to the elbow, especially in a non-surgical setting. Most of these patients with lesions in the knee will likely go for autologous concentrate grafting procedures like a MACI, and patients with elbow OCD lesions will likely have osteochondral autografts, which is why we're probably not seeing too much orthobiologic use in these patients. So let's move on to orthobiologics for the elbow joint, and this patient basically says, you said the pain in my legs are caused by old age, but my right leg is just as old as my left. As you know, osteoarthritis in the simplest terms is thought to occur from repetitive microtrauma or injury to the hyaline cartilage. This is thought to be the target of most of our regenerative treatments. However, we know it's not this simple. With age, the cartilage itself can wear out with changes to the extracellular matrix or change in cartilage composition, and the cellular components within cartilage will become less responsive over time. Repetitive microtrauma can be the result of mechanical dysfunctions, alignment issues, crystalline joint disease. We also know that joint homeostasis and healing is a function of general health, systemic metabolic processes. These may be disrupted with any systemic condition, like metabolic dysfunction, obesity, neuropathies. So this slide is purposefully a little bit busy. Your goal is not to read all of it, but it's looking at the pathophysiology of osteoarthritis, and we really see it's like a fractal pattern. You really think you have a good overall overview, but the closer you look, the more questions you have, and the more your head hurts. Each of these changes can be theoretically targeted by treatments. So what we see clinically is joint diffusion, synovitis, decreased range of motion, and crepitus. Underneath that histologically, we'll see synovial changes, recruitment of immune cells, alterations of cellular expression, and angiogenesis. This, in part, is due to changes at the molecular level with both pro-inflammatory cytokines, some of which are very familiar, and anti-inflammatory cytokines. We still have an incomplete understanding of the role of some of these and the complex downstream effects. So now that we've established how simple this is, let's throw in some orthobiologics. Again, the literature doesn't have much to say about orthobiologics in the ELBO specifically, so we are going to have to extrapolate some from other joints. Personally, I would note I've done a few, but much less than for elbow tendons, ligaments, or other joints, as it doesn't come up quite as frequently. This is pretty hard to generalize outcomes across different individuals, and I would say there's a significant need in those with elbow arthritis, as there are limited surgical options for these patients. Again, no specific larger studies regarding prolotherapy for elbow arthritis. There is some better evidence for knee osteoarthritis and for CMC osteoarthritis. So, barring from the knee literature, we see that there are three randomized controlled studies, all with some risk of bias, which seem to indicate a beneficial effect over exercise alone, with relatively few minor adverse Here's a smaller study looking at PRP versus prolotherapy, showing that both did have some improvement, but PRP seemed to be a little bit more effective within the knee. This is a busy slide, which is available for your perusal later, but it illustrates the current level of evidence for PRP and knee OA. Out of all the orthobiologics, the most robust literature we've seen so far is but it illustrates the current level of evidence for PRP and knee OA. Out of all the orthobiologics, the most robust literature we have is likely for PRP in the knee. There are several recent large systematic reviews showing some potential benefit of PRP over hyaluronic acid, corticosteroid, and saline, for a period up to six months to a year. And so we move on to MSCs. Again, there are no studies pertaining specifically to the elbow. Here are a few looking at some upper extremities, shoulder joint, but these are really just two smaller retrospective case studies looking at micronized fat aspirage. They show relatively good outcomes with pain and function, with minimal adverse events. The second one is our own data, which we included with, which we actually included severe osteoarthritis as well, and patients had generally good global outcome and improvement in pain and function. If we move down to the knee there is perhaps a little bit more literature regarding the use of MSCs. There have been two recent systematic reviews looking at the summary of data for MSCs in knee OA. Most studies seem to show some improvement in pain and function with little significant adverse effects but overall the quality of the literature is poor with few randomized control trials and there's a large heterogeneity in the type of treatment, the preparation, the protocols and some were even combined with surgical procedures. Lastly this is a study looking at review of all MSCs in all joints and again most were from the knee. Most had reported improvements but the major takeaway from this is that there were no significant adverse events. And so what can we take away? In regards to the use of MSCs for osteoarthritis there's a promising trend in studies but few good studies. Most are poor in quality with a high risk of bias. There's minimal adverse effects and these procedures are relatively likely safe. Most of them are pertaining to the knee so it may be a little bit harder to generalize to the elbow. These procedures are more invasive than PRP and there is the potential for regulatory concerns but potentially there's a more promising mechanism of action and better in vitro evidence. So in summary orthobiologics like prolotherapy, PRP and minimally manipulated MSCs for orthopedic purposes are very likely safe. I dare any of you to say that three times fast, minimally manipulated MSCs. Okay promising evidence, there's promising evidence for UCL injuries but more studies are needed. There's very little evidence for the use of these orthobiologics and OCD lesions of the elbow. Will we be able to extrapolate from other joints where there's minimal data and different loading patterns? It's hard to tell and there's much more evidence for the knee and not for the elbow specifically. Prolotherapy and PRP may be less invasive with less regulatory concerns. Overall more evidence is needed for the use of sports injuries and orthopedic conditions particularly when it pertains to the elbow. And I know we're gonna get on a little bit of a soapbox but it's important to be responsible clinicians first. There is a lot of hype out there and as really good physiatrists and all members of the AAPMNR, we really need to have transparent and clear conversations with our patients, be truthful about the current level of evidence and not kind of fall into the promises or propaganda that are out there. And I know that we are all, by being in this room, we're all on the same page. Thank you for attending the lecture series today. On one last uplifting note, I will leave you with some stem cell parental advice noting that this stem cell will be what anything it wants to be when it grows up. I will pass the baton on to Josh for a discussion of orthobiologic protocols and rehab. Hello, my name is Joshua Rothenberg and I'm doing the presentation on elbow biologics, patient selection, treatment, and rehabilitation. I would like to thank Dr. Joanne Borgstein for inviting me to be a part of this lecture. I do have a disclosure. I do serve as a consultant for Mineray North American Ultrasound Company. I have no further disclosures. So why the interest in regenerative medicine elbow conditions? It's because of articles like this out of American Journal of Sports Medicine. In 2018, this is a prospective randomized double-blind placebo-controlled trial. This particular study failed to show any additional benefit of the surgical excision of the ECRB over placebo surgery for the management of chronic tennis elbow. We also have articles like this out of the Journal of Bone and Joint Surgery looking at steroids. And in this particular article, they concluded that the local of injection of steroids only provided a short-term benefit for medial epicondylitis. So steroids were only beneficial for short-term pain relief only. We have medications like non-steroidal anti-inflammatories. Are these simply masking symptoms? Are they actually treating pathology? Are there any side effects long-term? So particularly for our epicondylosis of the elbow, we typically don't think of these as inflammatory conditions. So are non-steroidal anti-inflammatories appropriate for these conditions? We have other articles particularly addressing more steroid injections. The IOWA Orthopedic Journal concluded that there was significant tenotoxicity following a single injection of combination local anesthetic and corticosteroid. The Journal of Bone and Joint Research looked at dose and time-dependent effects of steroids and found that a 0.1 milligram per milliliter dose of corticosteroid temporarily decreased cell viability and increased cell apoptosis. We also have national news such as CNN Health that are publishing articles that say steroid injections may lead to more long-term health than previously thought, new study says. So when it comes to patient selection, I sort of divide this into three phases. We're looking at all common elbow diagnoses such as lateral epicondylosis, medial epicondylosis, UCL partial tear, RCL partial tear, and pronator syndrome. But, you know, we're going to divide these into three phases. The first phase is the conservative treatment group and this is what we are most familiar with. And then phase two, the interventional treatment group, and phase three, the surgical treatment group. So for phase one, or group one, the conservative treatment group is for any irreparable or any asymptomatic tear. or tendinopathy, for chronic common extensor or chronic or common flexor pronator tendinopathies, or even for partial thickness tears. What are our objectives here? Number one is to decrease pain, increase function or range of motion, correct postural adaptations, enhance activities of daily living, minimize long-term adverse events, and overall to restore joint mobility, motion, motor control, strength, dynamic stability, and neuromuscular control. So when looking at this, we should know what some of the negative predictors for conservative management are. And in this particular study, they looked at factors associated with failure of non-operative treatment and lateral epicondylitis. And these things that ended up progressing the surgery were more associated with a symptom duration greater than 12 months, a presence of concomitant ipsilateral radial tunnel syndrome, a worker's compensation claim, and a prior history of surgery. And in this study, 16% actually went through a surgical treatment. But really, amongst other studies, there was 3.2%, 7.2%, and 11.5% that ended up in surgery for lateral epicondylosis. Another negative predictor can be imaging. And in this particular study, they looked at MRI imaging as a predictor of failure in non-operative management of ulnar collateral ligament injuries. And what they found was the MRI factors that associated with those that progressed the surgery were distal UCL tears. In fact, they found that distal UCL tears were found in approximately 90% that actually failed non-operative management. So what are some of the conservative options or phase one treatments? The first option that many providers entertain are non-steroidal anti-inflammatories, whether this be oral anti-inflammatories or topical gels such as diclofenac. There is some controversy over as to whether this is appropriate, especially for our epicondylosis, as appropriate management treatment options. However, some providers across the country do provide this as a phase one typical treatment option. Another treatment option are therapeutic modalities, particularly ice, iontophoresis, or laser therapy. These are oftentimes in conjunction with another phase one therapy, which is physical therapy. We also have counterforce straps and kinesio taping, oftentimes done for our epicondylosis or UCL injuries. Kinesio taping is something that is a newer option that is often used in elbow pathology. And lastly, we have physical therapy, which is particularly the gold standard of phase one treatment options. Physical therapy for appropriately strengthening and tendon loading, particularly in our epicondylosis. So if pathology is refractory for three to six months, then we consider moving on to phase two or interventions. So for patient selection, generally anybody with, you know, a partial tear of the common extensor or common flexor tendon, or even just epicondylosis for the common flexor or common extensor tendons, or a partial UCL tear that don't respond to that phase one treatment option, then, and it has been three to six months, we can consider moving to phase two or interventions. So these are the invasive intervention options. We have corticosteroid injections, and I put a little warning there because oftentimes these can lead to weakening of tendon structures if injected in or around tendons. We have prolotherapy, we have platelet-rich plasma, percutaneous needle tenotomy, and there are a few devices on the market for percutaneous ultrasonic tenotomy. But we're going to focus on really my algorithm with platelet-rich plasma and prolotherapy today, since these are the most common injected in and around the elbow. This is my personal algorithm, and this is if, you know, standard conservative treatment fails. And so if standard conservative treatment fails, then I consider peer-to-peer prolotherapy. If it is a tendon or a ligament problem, and the athlete is an in-season athlete, then I would consider prolotherapy because they have a shorter time for recovery and, you know, shorter length of recovery so that we can get them back to their sport. If I have a longer period of time to play with and a longer recovery period, then I will consider PRP over prolotherapy. And usually with PRP, if it's a tendon problem in the elbow, I will use percutaneous ultrasonic tenotomy if it's available to the provider. Again, there are a few devices on the market. Or if done in the clinic, then you can use percutaneous needle tenotomy while doing this under ultrasound guidance. If this is a simply mild arthritis case, then I will favor PRP over prolotherapy. However, we do not have a lot of evidence, as will be presented by my colleagues, when it comes to arthritis in the elbow. If PRP or prolotherapy fail, then usually, you know, I may consider a surgical consult. However, there are some other biologics that are now available to us, which is bone marrow aspirate concentrate or adipose, microfragmented adipose. And in certain scenarios, I may consider one or both of those. Adipose tissue, I would consider if there was a defect that could be filled. And bone marrow, I would consider if there was a refractory to PRP or prolotherapy and the patient wanted to avoid a surgical solution. So group three is the surgical treatment group. I don't end up sending a lot of my patients down the surgical treatment group for elbow conditions, but the two times that we do consider this are refractory chronic tendinopathies that particularly don't respond to PRP or prolotherapy. And these people do not want to entertain bone marrow aspirate or adipose or UCL tears and throwing athletes. So what are the goals of physical therapy? I usually like a dual program. This is both scapular and elbow program associated with my biologics injections. Researchers, researchers, excuse me, researchers have identified shoulder girdle weakness in patients with lateral epicondylosis. We would like to restore full pain free range of motion, flexibility, muscle strength, scapulothoracic and glenohumeral muscular control and stability. And it's important to identify the muscles which appear tight or short and ensure that flexibility is restored there. So phase one is week one to two status post PRP injection. And the goals of phase one are to improve scapular strength due to association of shoulder girdle weakness, improve range of motion of the wrist and elbow, stretch wrist extensors and flexors, and do isometrics for the wrist, elbow and shoulder. So this is an exercise of isometric scapular retraction. Here the goals are neuromuscular re-education of the proximal muscles or the scapular stabilizing muscles. And the exercise is an unresisted or isometric activation of the serratus anterior and middle and lower trapezius muscles as demonstrated in this picture. I also try to start in weeks one to two some passive wrist extension. This is off of the American Academy of Orthopedic Surgeons website, but this shows what passive wrist extension looks like. Generally recommendation is five reps four times a day and five to seven days per week. And again passive wrist flexion. And this is again five reps four times a day and five to seven days per week. This is just the beginning phase to keep things loose and stretch after PRP injection. And then we do isometric wrist extension. And the goals here are neuromuscular re-education of primarily wrist extensors and radial deviators with the exercise being an unresisted or isometric activation of the wrist musculature. So this is demonstrated in the picture that you can see where you place your forearm on a table and use your offhand to provide some resistance so that you can do some isometric wrist extension. Phase two or weeks two to four. When should you progress from phase one? Generally the patient should be able to perform full wrist active range of motion and isometric wrist extension with no pain. So we want full non-painful range of motion. We want no pain or tenderness and we want satisfactory isokinetic testing and clinical examination. So in phase two we're looking at elastic resistance rows with the elbows at the side. The goals here are light to moderate controlled stress for progressive resistive strengthening of the proximal scapular stabilizing muscles. And the exercise is a resisted exercise for serratus anterior middle and lower trap groups. We want to now work on short lever with wrist extension. The goals here is light to moderate controlled stress for progressive wristed strengthening of elbow and wrist musculature. The exercise here is a resisted exercise for the elbow and wrist. So you can use a band attached to the table resting their forearm on the table and then you know go into wrist extension. This is a variation of that another wrist extension strengthening exercise and you you can use a one pound weight rather than a band and progress the weight as tolerated but we want pain-free range of motion and tendon loading in this particular exercise. Same thing for wrist flexion you can use a one pound weight or you can use a band and this is just a variation of that exercise. For forearm pronation and supination you're gonna do the same thing you're gonna rest your forearm on a table use a one pound weight and you're going to rotate your forearm and pronation and supination for resistive strengthening program. Phase three is generally four to eight weeks after a PRP injection. When to progress to phase three the patient usually must demonstrate that they can perform at least 20 repetitions of a concentric or eccentric wrist extension with the elbow flex forearms supported in pronation and wrist over the edge of a supportive surface. So in this phase where we generally have the patient work on prone extension with and without weight the goals here are moderate to heavy loads with a longer lever arm for progressive strengthening of the proximal scapular stabilizing muscles. So again we're working on scapular stabilization in each phase. The exercise is an advanced resisted exercise for the serratus anterior and middle and lower trap groups. As far as wrist extension goes and loading we now want to work with a longer lever arm not just the forearm but the whole arm on the table. The goals here are moderate to heavy loads with longer lever arms for progressive resistive strengthening and the exercise is advanced resisted exercise for elbow and wrist musculature including plyometric exercise. In this phase additionally we have the stress ball squeeze. This can be done at 10 reps one time per day and five to seven days per week also working on strengthening. We have a finger stretch which also puts some more load across the tendons and this can be done with a rubber band or any sort of elastic band around the fingers 10 reps per day and doing that five to seven days per week. And phase four is a return to play phase anywhere from 9 to 12 weeks from a PRP. This is continued daily strengthening endurance and flexibility and progressed a pain free unrestricted play. The length of rehabilitation it's been reported that an exercise intervention should be maintained for at least 6 to 12 weeks in order to demonstrate clinically significant outcomes though uncertainty exists over how long to undertake conservative care before seeking a surgical opinion. So generally my program is around 12 weeks and divided into those four phases. Those are the exercises I like in my in my patient population. Progression to E from phase to phase it's recommended that the exercise be performed and progressed in the complete absence of pain as well as during minor discomfort as recommended by the pain monitoring model. So in summary there are many standard conservative measures that may be effective for elbow pathology. The biologic must commonly be used and most commonly used in the elbow is PRP. I would say for most clinics is plus or minus percutaneous needle tenotomy. Biologics may be effective for chronic or refractory cases and have level 1 evidence to support their use for common extensor tendinopathy of the elbow. Post procedure rehabilitation typically begins 1 to 2 weeks after the biologic injection and should last around 6 to 12 weeks overall. These are some of my references and thank you very much. Thank you again to Dr. Joanne Borgstein and the rest of the team.

orthobiologic injections

elbow conditions

conservative treatment options

elbow tendinopathies

platelet-rich plasma

prolotherapy

corticosteroid injections

mesenchymal stem cells

patient selection

rehabilitation protocols