Welcome, everyone, who is on time to the National Fellows Online Lecture Series. Today we have Tendinopathy Management Using Hard Science. We are very fortunate to have Dr. Kentaro Onishi, who is an expert in his field. Let's see here. I'm going to start with the first slide. This is sponsored by AMSSM Online Fellows Education Subcommittee, the AMSSM Education Committee, and the AMSSM Fellowship Committee. Next week, please join us on May 11 for the Aging Athlete, which Dr. Nathan Fitton will be speaking and Nate Nye will be moderating. So we are very fortunate to have Dr. Kentaro Onishi. He is going to speak to us on Tendinopathy Management Using Hard Science. For those of you who were on before we started recording, he has written and edited a book on tendinopathy, and I'm sure he'll be using some of those slides and pictures and images to educate us today. I'm going to stop sharing. So Dr. Kentaro Onishi is a physiatrist and is board certified in sports medicine and physical medicine and rehabilitation by the American Board of Physical Medicine and Rehabilitation. He is the director of the PM&R Sports Medicine Fellowship and is an assistant professor at the University of Pittsburgh School of Medicine. He received his medical degree from the Western University of Health Sciences and completed his residency at the University of California, Irvine Medical Center, followed by a fellowship at the Mayo Clinic. Dr. Onishi focuses on non-operative treatment of sports injuries and his clinical interests include diagnostic ultrasound, advanced ultrasound guided procedures, and orthobiologics. He has over 40 peer-reviewed publications focusing on tendon and plantar fascia overuse injuries and is frequently invited to national and international meetings for presentations on his expertise in ultrasound and sports medicine. In addition to his involvement in the 2018 Winter Olympic Games, Dr. Onishi played a vital role in preparing the International Olympic Committee ultrasound program at the 2021 Tokyo Summer Olympic Games in his hometown. This presentation should serve as an adjunct to your individual program's educational programming. It should provide the fellows with direct access to educational experiences with experienced AMSSM members and assist in your CAQ exam preparation. Please mute your device's microphone and turn off your video. Submit questions through the chat function and include your name and program if you wish. And I will ask the questions during Q&A based on the questions you submit. And if you see somebody ask a question that you're interested in, definitely second that so I know that it's something of interest to the audience. And then please complete the evaluation which will be sent at the end of the lecture. Dr. Onishi, if you'll start sharing your slides. Can you see my slide, Melody? Let's see. I can. Yes. So we'll let you take over. I do have to say that I met Dr. Onishi when he was still a resident and he was interviewing around and I was unable to interview him when he came to our program so he was gracious enough to meet me at a coffee shop not far from either of the places we were staying so that we could hang out. And even though he ended up not choosing our program because he wanted to hang out with John Finnoff, which who can blame him? I was very pleased to get to know him and I'm excited for how much he's contributed to AMSSM and we're very fortunate to have him today. Yeah. Thank you, Melody. I remember that vividly about the interview day and you were gracious enough to be available to talk about your fellowship experience as you are the current fellow that back then. Well, good evening, everyone. Thank you again, Melody, for a kind introduction. Robby, Andy, as well as the AMSSM staff for the invitation to speak this evening. My name is Kentaro Onishi from the University of Pittsburgh Medical Center and today I'll be speaking to you about tendon biology and about studies we have performed here at the University of Pittsburgh in order to hopefully inform our clinical practice in managing tendinopathy. Here's my conflict of interest. Perhaps the biggest conflict of interest I have here is that I have written a book, as Melody said, on tendon injuries and I'm very interested in this disease. Before I get started, I wanted to give a special thanks to Dr. James H. C. Wang. He has conducted numerous tendon researches and I believe he's the only researcher that had received multiple R01 grants to study the effect of platelet-rich plasma, or PRP, on tendons. His insight has been very helpful to understand evolving tendon science and I'm very fortunate to have him as my research collaborator here at the University of Pittsburgh. As many of you know, tendinopathy is a painful, debilitating tendon injury that affects us throughout our lives, especially in our most productive professional lifetimes. Tendinopathy refers to a spectrum of tendon disorders, including tendonitis, tendinosis, and various degree of tendon tears. Tendinopathy tends to be chronic and recurrent and it results in a prolonged time away from activities or work. Importantly, such pain could result in compensatory movement patterns, increasing the risks for other musculoskeletal or non-musculoskeletal conditions, such as the ones listed here on the slide. With increased longevity, we live long now, the aggregate total expenditure for musculoskeletal diseases had more than doubled over a recent decade. According to another report, tendinopathy comprises as much as 30% of musculoskeletal injury visits to primary care physicians in the United States and accounts for up to 50% of sporting injuries resulting in estimated 16.5 million cases per year in the United States alone. Today's standard of care for tendinopathy is largely palliative. Both surgical and also biologic interventions lack high level of clinical evidences, and mechanistic information is still evolving. Today, I'll first talk about tendon as a biological structure. Then I will talk about the effect of mechanical loading on tendon. That's what we do when we send a patient to rehabilitation. We essentially load the tendon mechanically, so we want to know what it's doing on the cellular level. I will then share some of the important literatures to inform the true indication for platelet-rich plasma, as well as office-based tenotomy, followed by a final remark on new tendon injury prevention strategy. Tendon is a viscoelastic and neurovascular structure whose primary function is to transmit mechanical forces to muscle contraction to bones to create movements. Until the recent decade or so, surprisingly, tendon was actually believed to be metabolically inactive once it was formed in embryo and was thought to be comprised of tenocytes alone. However, a cell population with stemness known as TSC or tendon-specific stem cell, or also known as tendon progenitor cells, that can differentiate into tenocytes are recently identified, and this discovery led us to a renewed view of the tendon as a biologically active structure that is capable of self-renewal. Non-cellular part of the tendon tissue occupies the bulk of the tendon tissue, and this non-cellular part is collectively known as ECM or extracellular matrix. Collagens and non-collagenous proteins, such as proteoglycans, make up ECM. Our recent work at University of Pittsburgh has shown that the tendon appears to exhibit functional division. In this study, we had performed a meticulous micro-dissection of porciniaculus tendon to isolate paratenon, endotenon, fascicles. We then performed a tissue analysis, which showed that the paratenon and the endotenon had highly concentrated vascular tissue and substance P. Furthermore, TSCs were found in abundance in these areas. Fascicles, on contrary, were avascular and metabolically inactive and expressed very low stemness with abundance of type 1 collagen expression, suggesting that paratenon and endotenon are the foci of the tendon pain generation, while fascicles may contribute to the structural support but may have little to do with the tendon pain. Knowing tendon's functional division helps to explain current clinical evidences as it relates to platelet-rich plasma and tendinopathy. If you read our recently published review, we were able to point out that the animal investigation had always shown promising responses in regards to tendon regeneration when PRP was injected. However, the clinical trials have truly been 50-50. The knowledge of functional division may help explain this discrepancy. Animal investigations traditionally focused on improving tendon fascicle integrity. PRP seems to do a great job at this, but clinical studies will also need to concern PRP's effect on pain modulation, and this may require a special formula. Let's review the literature on mechanical loading on tendons. Once again, mechanical loading in clinical sense equates to be sending patient to OT or PT to load the tendon. That's what happens in PT and OTs. The effect of mechanical loading was first studied in 1967 by Dr. Videk, who was a Swedish anatomist. He put rabbit through a treadmill running program for several weeks and documented increased tendon strength relative to the control. Unfortunately, histologic and immunostaining experiments were very primitive at that time, and he was actually unable to provide the mechanistic information as to why tendon became stronger. Dr. Savio Wu from University of Pittsburgh in 1980 was the first to repeat a similar experiment using swine model to document increased collagen concentration with a 12-month exercise program. Numerous publications followed Dr. Savio Wu's experiment. Although there are some inconsistencies in these studies, overall, exercise seems to increase tendon strength and makes tendon resilient to injuries. Being a center for excellence for ACL operations, our team had an opportunity to study human tendons. In this experiment, we harvested healthy patella tendon stem cells from young active human patients at the time of BTV graft for ACL operation. We cultured these TSCs and plated on the silicon cell loader, which looks like this device in the center. This allows us to stretch the tendon to a certain stretching length. We treated these tendons with IL-1 beta in order to cause inflammation to mimic tendonitis first, then loaded the tendon at either 4% or 8% stretching. That 4% stretching resulted in reduced Cox2, MMP1, and prostaglandin 2 production, whereas that 8% stretching resulted in further increasing inflammatory markers, suggesting that repetitive small magnitude stretching is in fact anti-inflammatory, while large magnitude stretching is pro-inflammatory. This is something I actually tell my patients once I confirm the absence of severe injuries in order to encourage their compliance with physical therapy program. As you know, some of the patients presenting with pain might be a little bit timid about loading the tendon in presence of pain. Then you can kind of reference these kinds of scientific evidence to tell them that certain small magnitude repetitive stretching is in fact getting rid of inflammation to get their buy-in to participate in physical therapy. Of course, injuries do exist that might warrant an intervention like plated-rich plasma, shockwave, percutaneous tenotomy, or even a surgical repair. So I typically use 4 out of 10 pain as a threshold to decide to go aggressive on diagnostic imaging, which at this point is mostly diagnostic ultrasound. Let's now discuss what we know about plated-rich plasma on tendon since we just talked about it. In this particular study, we had conducted an in vitro experiment using patella tendon TSCs harvested from New Zealand white rabbits. They're really cute if you have a chance to see them. We treated the TSCs with PRP at concentration that is 3.5 times higher than the baseline of what rabbits gave us. The study showed an accelerated tenocyte turnover from TSCs. We saw the reduced nucleostemming expression, which is the tendon stem cell marker, with simultaneous increase in tenocyte-related gene expression indicating PRP's effect on accelerated tendon regeneration. This study was published in 2010 in American Journal of Sports Medicine, and it was referenced 258 times, becoming one of the most referenced studies on PRP on tendons. As you can see from the numbers of references, there was an initial excitement amongst clinicians that PRP may be a promising tendinopathy treatment option. Not so fast. Our 2014 study is also important. This has, however, only been referenced 48 times, and this is why I wanted to highlight this study. In this study, we isolated TSCs using the same method as our American Journal of Sports Medicine paper from 2010, and treated TSCs using culture media that would promote non-tenogenic stem cell differentiation. Specifically, we based TSCs in adipogenic, chondrogenic, and osteogenic media, and infiltrated TSCs with platelet-rich plasma at two different time points. When TSCs were treated with PRP early on, PRP promoted TSC differentiation into tendon tissue regardless of what media TSCs were bathing in. However, when PRP treatment was delayed by just mere one week, PRP did nothing to reverse non-tenogenic environment. This is an important finding. Because the study result indicated that PRP may be ineffective for already degenerated scarred tendon tissue, we believe PRP may be most effective in treating a freshly injured tendon, such as an acute partial tendon tear. I'm curious to hear what other experts think about this statement, but I just wanted to share this less-referenced studies that might be equally important as the 2010 AJSM paper. The clinical strategy to treat degenerated scarred tendons should then be to either remove or at least mobilize the degenerated tissue for optimal regeneration. Percutaneous needle tenotomy, or PNT, is one of such interventions where a tendon is cut, usually incompletely, using a needle. Dry needling is sometimes used interchangeably with percutaneous needle tenotomy, but dry needling is usually in reference to myofascial pain, and therefore tenotomy is a preferred term when targeting the tendon. Let's quickly review PNT clinical evidences. This is where a needle is used to poke the tendon. I find this recent narrative review by Stoichov's group to be informative. In this review, authors identified three systematic reviews, seven RCTs, and six cohort studies. Elbow tendinopathy was most commonly studied. Other tendons studied included rotator cuff tendon, Achilles tendon, patella tendon, and gluteal tendons. Most of these studies reported meaningful clinical improvement. Timing of the intervention in RCTs were as early as six weeks after the onset of symptoms to six months. Only two studies reported complications, and they included local hemorrhage, increased pain following the procedure. Two studies demonstrated improving tendon quality on ultrasound. Only two studies mentioned a post-procedure rehab program explicitly. Notably, there was a considerable heterogeneity in needling protocol with the needle size ranging from 18 gauge to 23 gauge and numbers of passes ranging from as few as just three passages to as many as 50 passages. Overall, Stoichef group concluded that the current research shows early promises as PNT is low risk and inexpensive, I guess relative to other options similar to this like platelet-rich plasma or even shockwave. However, they suggested future studies that compare PNT to a sham procedure in order to elucidate its true efficacy. As some of the previous speaker in this series might have discussed, there are now new several devices that enable tendon scar removal. These are some of the such devices. This one on top is called TENJET and this uses ventric suction mechanisms to remove scar tissue. This one on the left bottom corner is known as TENDENOVA device which is newest addition to tendon debridement device. And as far as I know, this is the only one that is essentially wireless. However, the most original one is the one on the right bottom corner called TENEX which was first approved by FDA in 2012 for degenerative tendinopathy. Here's the animation of how TENEX or percutaneous ultrasonic tenotomy or PUT procedure removes degenerated scar tendon for those of you who have not seen this device before. As you can see, this handheld piece has two lumens. The internal part vibrates at 16.5 kilohertz to mobilize the scar tissue much quicker than your manual tenotomy. Then the outer lumen circulates saline fluid to complete the aspiration, which then helps with the scar removal out of patient's body. This is a sample video percutaneous ultrasonic tenotomy performed with a foetal tendon where the tendon is viewed in long axis view and needle is coming from distal to proximal. The second video in the middle is going to be that actual PUT procedure where TENEX device is advanced into the anechoic region of the patella tendon. Again, for percutaneous ultrasonic tenotomy, not PNT, but PUT, most commonly studied tendon was forearm tendon or elbow tendons. Of the 236 forearm tendons treated or indexed and published, there was a four point average reduction in pain in one week following the intervention with an ultimate decrease in six to seven points over a study period, which was most commonly 12 months. Magichilian's study in 2021 was interesting study because it showed a PUT combined with PT resulted in a better clinical outcome compared to PUT alone advocating the possible necessity of post-PUT rehabilitation program. Bowden's study, and of course, Dr. Kim Mott was co-author of this paper from Emory was interesting because PUT and PRP were both equally effective. Finally, Ang's Singaporean study had an impressive 90 month average follow-up following percutaneous ultrasonic tenotomy for elbow tendinopathy with sustained improvement over a 90 month period of time. Achilles tendon and gluteal tendons also have published data showing some successes, although it seems the satisfaction rate tended to be lower overall compared to that of the elbow. Some case series size less than N of 10 or subject size of 10 are available for following fascia tendons. And surprisingly, some people have used 10X or percutaneous ultrasonic tenotomy for ligaments such as coracohumeral ligament and MC of the knee. Our team here at University of Pittsburgh has recently submitted a sub-federal grant and received a very good score mostly based on these observations in order to collect both animal and human data on combining percutaneous tenotomy with platelet-rich plasma for degenerative tendinopathy compared to PRP as monotherapy. Our goal is to see if microinvasively moving non-tenogenic scar tendon tissues followed by PRP infiltration would result in a better animal and clinical outcomes compared to PRP alone. Has anyone in this room heard about HMGV-1 or high immobility group box one? If I show of hands or just clicking the buttons. Well, let me know if you do chat in the box. HMGV-1 is normally an intracellular protein that is involved in regulation transcription. However, the same molecule can be released extracellularly. And this extracellular form has been implicated in various medical conditions such as lupus, sepsis, thromboembolic disease such as stroke and heart attack, arthritis, or even COVID-19 because of its ability to modulate inflammation. Our team recently published a paper that showed that the tendon is a source of HMGV-1, that HMGV-1 is released in response to tendon overloading or overuse, and that the glycerosine which is a naturally existing sweetener and metformin which is commonly used diabetic drug both inhibit HMGV-1 related changes in tendon, concluding that HMGV-1 is the main causative agent for tendon inflammation and degeneration in response to tendon overloading or overuse. A subsequent study published two years ago now actually received the best paper award from American Foot and Ankle Orthopedic Society. The study showed that the metformin completely halted overuse tendinopathy in mouse ocular tendon. We used cage-controlled animal as the control and subjected mice to intense treadmill running or ITR. Based on our previous studies, we know that ITR results in severe tendinopathy in mouse ocular tendon, just as shown here in the third picture. It's really red, swollen, but with the metformin injection, ocular tendon remained morphologically and histologically normal without any signs of degeneration even after ITR treadmill program. So thinking ahead, we have formulated a topical lotion that can achieve the same tissue concentration in tendon as the injectable form to see if we can use this lotion to prevent tendon overuse. I'm partially hoping this works, but I'm also partially hoping it doesn't work completely. So maybe I can maintain my job treating tendinopathy. And I look at the clock and right now it's nine and we have still 30 minutes and I'm not gonna use all of the 30 minutes, but since we have some time to spare, maybe we'll go into discussing some interesting case series. This first case, it's about a 52-year-old skier and a hiker who presented with one year history of slowly worsening medial dorsal foot pain. Pain is described as burning and radiates from the center of the anterior ankle joint toward dorsal medial cuneiform area. Pain is worse with going down the hill. Pain has episodic sharpness to it when descending the hill. Position of comfort is terminal dorsiflexion. Pain increases with terminal pontiflexion while asleep. She has not had a previous trauma to this area. Physical examination was unremarkable except for a nodular sensation at the dorsal medial cuneiform area. Notably, ankle squeeze test and external rotation stress test were both negative. This is more for the residents and fellows, but just as a reminder, both of these tests, ankle squeeze and external rotation stress test are used to test for syndesmotic sprain or high ankle sprain. We then proceeded with diagnostic ultrasound. After appreciating all of this differential diagnosis, there's numerous differential diagnosis to explain anterior ankle and foot pain. Here's a sort of diagnostic ultrasound image and video. And as I start the video, we found a thickened tibialis anterior insertional tendon. As you can see in the video, this is the short axis view where the left side is lateral and the right side is medial. And we are scanning toward a medial cuneiform. And this entire tendon is actually that of the tibialis anterior tendon, which is abnormally large. In addition, we performed microvascular imaging called the spur microvascular imaging and this showed intra-tendinous vascularity. Here's the side to side comparison for your sake of the tibialis anterior tendon. You can appreciate the increased size of the tendon with relative hypoechoic signal on the affected tendon on the left compared to the unaffected tendon, which is to the right at the level of medial cuneiform. For treatment, we first tried dextrose injection, our prolotherapy, given that she was in the middle of skiing season. And this results typically in much less downtime compared to platelet-rich plasma or percutaneous ultrasonic tenotomy or regular tenotomy. The prototherapy had resulted in a definitive partial relief, allowing her to complete her skiing season. We ultimately, however, needed to resolve to percutaneous ultrasonic tenotomy or 10X for resolution during the off season for this particular case. This is for board review purposes. Just to review, tibialis anterior tendinopathy is bare and it usually affects overweight female between 50 to 70 years of age. Most typical complaint is burning of the medial midfoot. Plantar flexion position is typically uncomfortable due to tension on the tendon. So consequently, these individuals almost always complain of nocturnal increase in pain, whether they are sleeping, supine, and gravity pulling the patient into that sort of plantar flex position, or sleeping on the stomach prone position, because, you know, you really can't sleep prone without putting the foot in the plantar flexion position. I've never seen anyone sleeping prone with dorsiflexed foot. That would be uncomfortable. Importantly, we don't have enough cases regarding the tibialis anterior tendinopathy to understand the natural history. So as a collective mass, as a sports medicine physician, we must be diligent about publishing these cases in order to better understand this pathology. Second case is about a 62-year-old avid golfer who presents with a focal lateral shoulder pain. This gentleman presented with 1.5-year history of gradually worsening atraumatic lateral shoulder pain. It started as a stiffness for about a year, but this has become debilitatingly painful. He had to try months of physical therapy, steroid injection targeted to subocomial space, and even hydrodissection targeted to axillary nerve based on workup that was done prior to presentation, which included X-ray, MRI, and an electromyogram without any improvement. Physical examination was most consistent for, most significant for focal pain tenderness at the deltoid insertion. Pain was also exacerbated by both resisted AB induction and terminal adduction range of motion. Diagnostic ultrasounds performed in our clinic, and it was only notable for very focal cortical irregularities with somal palpation tenderness relative to the same location at the deltoid insertion on the contralateral side. So our working diagnosis at this point was pseudotumor deltoidus. This diagnosis is rare, and only eight cases have been reported or published in literature. The name was coined in 2001, so it's relatively recent in the case series, and the patients in these case series all presented with acute worsening of the shoulder pain that showed a cortical irregularities at the deltoid insertion. The name is derived because the diagnosis is diagnosis to exclusion, diagnosed while working up patients for neoplasms. We don't really understand this diagnosis well, just like the TBS anterior tendinopathy diagnosis is usually made by clinical history and imaging. Though all previous reports, eight cases that has been published were all done so using MRI X-ray or CT scan and not with an ultrasound. Treatment is usually conservative. Interestingly, upon revisiting our patients upper arm or humerus X-ray, we do see an ill-defined area of cortical thickening and a scoliosis at the deltoid insertion that since 2020 paper described in describing a case of pseudotumor deltoidus. So in this case, ultrasound was kind of cluing in to revisit this imaging and then look at this. So in terms of treatment for this particular case, we proceeded first with a lidocaine injection to deltoid tendon insertion with a diagnostic response. We proceeded with platelet-rich plasma then, but without an improvement. Percutaneous ultrasonic tenotomy ultimately gave him a resolution in 12 weeks time following the procedure, ultimately returning this golfer to back to golfing play. So what's the take home? It is that pseudotumor deltoidus is a rare diagnosis, but should be in a differential diagnosis. They are mostly diagnosed with conventional imaging such as X-ray, CT or MRI, but ultrasound may be assistive. We do not fully understand this disease, but in this particular case, it's important to remember that the patient responded to an intervention targeted to deltoid insertional tendon. We must be once again diligent publishing these cases, sharing cases to begin to understand this disease pathologies better. The final case this evening is about this 13 year old lacrosse player. She reported a six months history of left medial knee pain after getting kicked in the area. She reported initial swelling and akimosis. She was initially diagnosed with MCO sprain by outside physician, but physical therapy targeted to MCO did not help. MRI was non-diagnostic and she was planned for a diagnostic arthroscopy when her parents sought a second opinion. She reported a focal area of pain indicated, hopefully you can see the little asterisks in the red. Otherwise, ligamentous examination and meniscal examinations were all negative. We proceeded with diagnostic ultrasound given the elusive nature of the presentation. And this is a patient's longitudinal view of the medial knee where the left side of the screen is distal. Right side of the screen is proximal and MCL traverses over the medial joint line. Medial meniscus is sitting like an wedge shaped triangular structure between two bones that makes up the medial joint. AESMT stands for anterior expansion of semi-membrane or suspended. It's one with a five distal expansion semi-membrane or suspended. Note that there is a thin and a quick area surrounding anterior expansion the distal semi-membrane or suspended. And this area was also tender to sonopalpation. Here's the long axis view of the same tendon to the right side of the image with the side to side comparison image of the contralateral healthy side in long axis view to the left of the image. While there are some visible fibular pattern the anterior expansion of semi-membrane or suspended was certainly thickened on the affected side compared to the normal side indicating subacute tendinopathy is a diagnosis. I had an opportunity to publish this paper while I was at Mayo as a fellow with Dr. Jake Sullen and Jay Smith where we described the injection technique for semi-membrane or subversive. We used 10-cataveric knees and injected three CC of latex dye. While 100% of injections were accurate eight out of 10 cases resulted in latex extravasation suggesting a lower volume may be needed if we are looking for a localization ability such as if you're using the injection for diagnostic injection purposes. For this last cross-player we first proceeded with a diagnostic injection to semi-membranosis bursa using two CC less than three CC of 1% of lidocaine. She reported an immediate diagnostic benefit. So we then discussed the treatment option, which included the discussion of platelet-rich plasma and this injection platelet-rich plasma resulted in ultimate resolution. So in summary, tendinopathy is a prevalent condition. Current standard treatment is mostly palliative. Tendon loading or PTOT, whatever you want to call it, in moderation is in fact anti-inflammatory. PRP may be most effective for acute or subacute tendon injuries without severe degeneration. Advanced tendinosis or advanced scar formation from a tendon may require scar removal before a definitive improvement. Finally, HMGB1 can be a future therapeutic target for tendinopathy. Well, that completes my presentation for this evening. Here's my contact information for those of you who want to email me. Thank you so much for your attention and I'm happy to answer any questions you may have. Thank you, Dr. Onishi. That was super helpful and very interesting. And thank you for presenting actual studies that are showing how these are happening in our athletes. There are a few questions and if you guys do have questions from the talk, please put them in the chat and we'll be happy to try to address them. Dr. Onishi was kind enough to leave some time for this. There was a question regarding the study that did not support use of PRP for chronic tendinopathy. Did it differentiate between leukocyte-rich versus leukocyte-poor platelet-rich plasma? This is a special, you know, the animal study dedicated centrifuge that allows us the complete filtration of leukocytes. So it's a leukocyte-poor PRP. Thank you. And how do you think to use metformin in tendon treatment? Yeah, so we are looking for more prevention purposes because this really, you know, our study that won the, you know, Jay Goldner award from American Foot and Ankle Orthopedic Society, we only looked at the preventive effect of the metformin injection to the Achilles tendon on the animals. We haven't studied what happens if we are to use that metformin at the same concentration we used to already degenerated or injured tendon. We assume it will prevent further, you know, formation of degeneration, but of course we have to study that before we can say that, right? So, yeah, so we are right now looking at as a method to perform primary prevention. So the ideal study would be to study large population, half of the people put slap on like, you know, you know, placebo lotion, and the other half puts like a real lotion and follow them for over like five, 10 years. For the last case with the medial knee pain, can you comment on your thoughts of platelet-rich plasma versus corticosteroid injection for that? Sure, I think corticosteroid can be used, but the patient was 13 year old and, you know, you're concerned about, you know, detrimental effect on growing tendons. And we clearly know the cytotoxicity to the stem cell in the tendon using a local anesthetic and or, you know, the cortisone, especially when you mix those two seems to be extremely toxic. So then, you know, had this candid discussion with the mother of the patient, discussed, you know, this is what we know about cortisone, and this is what we know about platelet-rich plasma. And they ultimately chose platelet-rich plasma as a choice. I think that jury's out in terms of what can be used for subacute tendinopathy. And I say subacute tendinopathy based on clinical history of six months, right? And another thing is that fact that the tendon sonographically maintained some of fibular patterns as you are able to see on the slide, but it was increased in thickness. As it gets more advanced and you lose any visible fibular patterns and you start seeing punctate calcification, you start seeing fatty infiltrations or even ossification. And those are what I consider a sonographic advanced tendinopathy. So I said that this was a subacute. So I think you could consider steroid, but, you know, then ultimately patient that is well-educated will make the decision, in this case, the patient's parents. And an interesting case about this is, you know, previously there has never been reported case of traumatic distal semimembranous tendinopathy because she was kicked in the area where the shingles were not quite covering. So I thought this was an interesting case. You can get kicked right on the tendon. In fact, one of the distal expansions, five expansions of the semimembranosus, and, you know, she has this, you know, chronic tendinopathy. So I thought that was an interesting case to present. And also besides the fact that she was about to be subjected to diagnostic arthroscopy. At least to me. Right, and at 13. Right, so being aware of microanatomy helps to think to do diagnostic injection. And with response to your confidence, this is where the injection should be targeted. And, you know, the publication that I quoted, you know, shamelessly about my own study showing that 3cc resulted in extravasation. If you're looking for localization with diagnostic injection, then you should use smaller volume. So, you know, it's a combination of published data and knowledge plus the clinical sort of, you know, acumen that probably helps to guide this treatment to the successful outcome. Can you speak, there are a few questions about how to choose the correct patient and the correct pathology for PRP versus the ultrasound, you know, 10X and 10JET. And sometimes we combine them depending on the degree of pathology. Can you just discuss briefly how you go about deciding what to approach and what's your first try, even though we know it's a bit of a, it's a bit, there's an art to that science. Absolutely. I think a lot of it is clinical sort of decision, especially in the context of treating active people with competition schedules. In season athletes, unless it's a season ending, you know, painful condition like tendinopathy, I would not elect to use invasive procedure such as percutaneous ultrasonic tenotomies, such as, you know, 10X or even tenotomies for the fear of tendon ruptures. If you can sustain their, you know, function and performances using less invasive options, then my preference is to use that. And, you know, although I didn't get a chance to talk about this injection called dextrose prolotherapy too much, so for one, you know, TVS anterior cases, I frequently use dextrose injection over platelet-rich plasma for tendinopathy. One, my impression is dextrose injection about 10 to 12.5% seems to work quicker than platelet-rich plasma in the scale two to five days. And it's much more affordable compared to platelet-rich plasma. Whereas a PRP, usually you don't see the benefit for like two to six weeks. And that's half the season for some of the collegiate athletes that I mainly treat. So usually my go-to is to, you know, sort of, you know, make them compete through the, you know, allow them to compete through the season using less invasive options, such as prolotherapy. And then during the off season, if the prolotherapy doesn't resolve the symptoms, then we'll have more involved procedures such as percutaneous ultrasonic tendonomy, which requires minimum of six to eight weeks of downtime before returning to play. You know, we're seeing a lot of protocols for particularly platelet-rich plasma, where there's already a plan to do multiple injections. Can you speak on your protocol for when you might do what they call a booster shot or something like that, where you might feel like you've gotten a positive response but not an adequate response? Yeah, so I don't really think I can recall personally where I repeated platelet-rich plasma for the same tendon more than once. I usually use it once and, you know, the booster, or I pretty much can get rid of most of the tendon-related pain using dextrose. And we're actually looking into this, you know, having access to the tendon mechanobiology laboratory here. And it's a simple study to do to look at what happens if you inject dextrose to the tendon and, you know, you basically study this histologically and immunostaining-wise and what happens to it. And we have some ideas of what's going on and we are getting ready to publish it. But dextrose is really my go-to. I would say 90% of tendinopathy actually responds to dextrose. And only a fraction requires something that's more advanced and involves the more costly, like platelet-rich plasma or PR10X. So I didn't talk about it just because I wanted this presentation to be evidence-based, but dextrose is actually my go-to. And I'm sure Dr. John Volkstein will love to hear that, but because she uses this procedure as well, but it really works. And- She is on, so we'll have to ask her not to speak for an hour on this, even though we do like her to talk about dextrose and prolotherapy pretty much at any chance we get. Can you talk a little bit more about the percutaneous needle tenotomy? You mentioned there was significant heterogeneity between protocols such as needle gauge and how many passes, the number of passes that they take. What do you personally use? And do you alter that depending on the patient or the tendon? I'm a little bit leery about sticking needle into the tendon. I consider peritendinous or extratendinous procedure to be entirely different than intratendinous procedure, such as intratendinous platelet-rich plasma, intratendinous dextrose injection versus peritendinous PRP or peritendinous prolotherapy. So when I stick the needle, I better have a good reason to compromise the tendon integrity that's already kind of damaged. So I usually go full core press, go big or go home approach. So I almost do not use percutaneous needle tenotomy. So I'm not probably the best person to actually talk about that. If I feel the need to go into the tendon, then I usually elect to use percutaneous ultrasonic tenotomy. And as I jokingly made a comment, percutaneous ultrasonic tenotomy or Tenex device particular, vibrates 16,000 times per second. And I don't know how fast your needle tenotomy skill is, Melody, but I can't move my finger 16,000 times per second. So I go in there and we don't really exactly know how that percutaneous ultrasonic tenotomy works, but there's some thoughts to that effect of tendinosis being similar to a compartment syndrome of a tendon, where scar tissue increases the intra-tendinous pressure. And as a result of increased intra-tendinous pressure, then the natural blood flow that's normally going into the tendon is unable to go into the tendon. Now, a scar can happen on the surface of the tendon or scar can happen intra-tendinously. And advanced adenosis that we see on an ultrasound where you see the thickening in the center part of the tendon is a case where the scar tissue forms within the tendon. That's when I decide to pull the trigger for usually percutaneous ultrasonic tenotomy as opposed to needle tenotomy, just because of a complete mistake of removal of the scar tissue that might be preventing blood flow that's going into the tendon. And once you can resume that normal blood flow that goes into the tendon, then tendon receives the oxygen and nutrients that then would allow them to use those stem cells locally available to regrow and regenerate. So that percutaneous needle tenotomy on surface seem like you're removing the scar tissue, but it may be used to decompress the pressure that's increased. And at the same time, creating a more space for that healthy regeneration to take place. So speaking of healthy regeneration, there have been some studies saying anti-inflammatories may be bad. They might counter the treatment for tendinopathies. And what are your thoughts regarding that? Yeah, so I think that anti-inflammatory may be bad because interestingly, you know, HMGB1, as I mentioned in the presentation, is known to be released from the tendon when it's actually undergoing cell death. So tenosyedine. But platelet-rich plasma, the platelet is actually a rich source of HMGB1. And seem like that NSAIDs actually have an effect on oxidation of HMGB1 that is released from the platelets. And then without performing platelet-rich plasma injection to the tendon, on daily basis, you know, tendon is exposed to your own blood, autologous blood, that includes platelets. And platelets, you know, sort of dump this molecule upon activation, including HMGB1. And HMGB1 normally undergoes sort of oxidation process over the 72 hours once it gets released from inside of the platelets to the outside of the platelets. And HMGB1 seems to, you know, affect that sort of oxidation process to make it actually oxidize much quicker than, you know, without the NSAIDs. And seem like NSAIDs is bad news because when the HMGB1 is in the reduced form, it's known to attract stem cell to the area where the HMGB1 is present. So it's actually regenerative. It actually helps recruit the stem cell from the tendon. But then when it becomes oxidized, then it starts destroying the tissue. So it's actually the same molecule that has actually two different, you know, activities. And NSAIDs kind of push it toward oxidized form. So overall, molecularly speaking, I guess that NSAIDs may not be the best option for that reasons. Yeah, and you did mention that you like to use a pain scale of four out of 10 as kind of a gauge. And so when patients are on pain medications, we want to make sure that that's not mitigating or altering their own body's perceptions of that pain scale. So I'm assuming you were meaning that that was without pain medication, but I just want to clarify. Yeah, that's correct, Melody. And there was a great question. You know, you talked about tendons and there's also this issue of teen asinovitis that we see. Do you have any advice or treatment for that? Yeah, teen asinovitis is one of the few indications remaining where I might liberate myself to use a load of steroid peritendinously. I think that depending on the reason for teen asinovitis, it might, you know, just be simply inflammatory condition where tendon is, you know, very upset. And then just as long as it's a peritendinous, I allow myself to use one time cortisone injection maybe around the tendon and see if that improves it. Because, you know, I've gone the wrong way and then I've used dextrose for that kind of purposes and they inflamed it bad. So learned from my own, you know, experiences that teen asinovitis, I tend to use cortisone around the tendon and to see if that controls the symptom and doesn't recur. So that would be in one case where I still use cortisone. That might be a good segue to also discuss peritonitis. Do you ever use hydrodissection for that? Or what do you like to use for peritonitis? Yeah, peritonitis where the, you know, that peritonitis is inflamed. I think that cortisone can be used, but then in the chronic setting where the patient has had a problem and you see the neovascularity, hydrodissection or high volume image guided injection and or where feasible, you could consider mechanical neobasal ablation or tendon ablation or tendon scraping procedures. And I think that we need to understand the tendon scraping a little bit better. The thought is to disrupt the neovessels and your nerves that's growing into the tendon. That might be true, but it might be that you are removing the scar tissue that is on the surface of the tendon that's actually preventing from a normal blood flow into the tendon. So like I said earlier, it may be opening up the channel for the blood flow to finally go into the tendon for the healing to begin. So we don't really know how it helps, but I do use them for limited tendons, such as atlas tendon or proximal patella tendinosis. Yeah, and that's kind of a good plug for the importance of image guided injections around the tendons. Any other thoughts or anything you thought of when we were asking you? These were great questions. Thank you to those of you who are participating. Those are really wonderful thoughts, questions. I think that really added to the discussion. Dr. Onishi, do you have any other thoughts that came up or things you'd like to bring up with those? No, thank you so much, everyone. I know it's late evening hours and family time and everything, but thank you so much for tuning in. And thank you again, Dr. Onishi, we appreciate that. And there is a tendonopathy book that has been published. If you guys have any follow-up questions, you're welcome to email Dr. Onishi. And Dr. Onishi, if you wouldn't mind just typing your email in the chat once more, just so that anybody who's logging in right now is able to see that, and then we'll go ahead and close the official talk. But I do see Dr. Borgstein on if she wants to pop on and chat for a few minutes. I think we've covered it really well. Great job, Kentaro. Thank you, Dr. Borgstein. Yeah. Okay. All right, thank you, everyone. Have a good evening. Thank you.

3rd Edition, CASE 13

3rd Edition

Elbow and Forearm

Tendinopathy

Sports Medicine

Tendon-specific Stem Cells

Platelet-rich Plasma

Percutaneous Needle Tenotomy

Tendon Regeneration

HMGV-1 Protein

Metformin

Tendon Injuries