Episode Transcript
[00:00:02] Speaker A: Welcome to your Cases on Hold, the JVGS podcast hosted by Andrew Schoenfeld and Aisha Adkeen.
[00:00:08] Speaker B: Here we discuss the best of what each issue of JBJS has to offer with the usual dose of entertainment and pop culture.
[00:00:16] Speaker A: Take us with you in the gym, on the commute, and as ever, whenever your case is on hold.
Welcome back everyone. Your case is on hold. This is episode 113.
If you are listening on the day we Release it is September 1st. Can you believe it's the fall already for our September 2nd issue of JBJS. As always, you are tuning in to hear the most exciting, cutting edge and influential research that orthopedics has to offer.
With that in mind, as always, the opinions and thoughts insights that are provided here are those of myself and the other co host. They are not the opinions of the Editor in Chief or the Deputy editors, the members of the Editorial board, the other constituent editors or the folks who work at JBGS Corporate. This episode of your Cases on Hold is brought to you by the Continuing Medical Education Not Continuing medication, but Continuing Medical Education CME Opportunities at JBJS There is a whole plethora and it takes you from your time as an early learner in orthopedics all the way through to what you may be doing to keep up to date in an advanced stage of the career. It's really delightful. Get credit for listening to us. Get credit for reading the articles, keep up with your CME for maintenance of certification, prepare for web based longitudinal assessment, prepare for board exams. Whatever you need, JBJS CME has it for you.
So who am I to tell you all this? For those who are just tuning in recently, I am Andrew Schoenfeld, professor of Orthopedic Surgery and Vice Chair for Education, Harvard Medical School, and I have with
[00:02:13] Speaker B: me as always, hi everyone, I'm Aisha Abdeen. I'm Chief of the Division of Hip and Knee Arthroplasty at Boston Medical center and Associate professor of Orthopedic Surgery at Boston University.
[00:02:25] Speaker A: If you are listening for the first time or recently, please give us a five star rating. Like subscribe, make sure you get the notifications so that you know when every episode of your case is on hold drops.
That said, it's basically the first and third Tuesdays of every month and sometimes the fifth if the following day is the first of the next month as we've had a couple of times this year I think. But seriously, you can find us on Stitcher, Kastos, Apple Spotify, Amazon Podcasts, YouTube. If you can't find us there, go to JB JS and you can listen through the website.
So I think that we covered all the necessary bases. So let's get into what this issue has to offer.
We'll start with the Top of the Pile. Quite a few articles in the Top of the Pile this month feel like it has like a orthobiologics flavor. We don't have special focus issues in this context, but if we did, I think this would be the I'm going to coin it the Orthobiologics issue. The Next Era of Orthobiologics From Promise to precision by Dr. Pusey, who's on the editorial board here. And this is permanently free and we'll take a step to the side for what's New in Orthopedic Rehabilitation by Riddle and colleagues. Also Permanently free A Precision Medicine Framework to Improve Patient Care using Orthobiologics by De la Huerta Mesa.
Then Orthobiologics at a Crossroads From Biological Promise to Evidence Based Orthopedic Practice by Anzolati Cellular Bone Matrices Reconsidered Immunogenicity Experimental and Clinical Evidence of Enhanced Effectiveness, Safety and Value Proposition by Merino. Permanently Free Orthobiologic Treatment A Patient's Experience with MFAT Injection for Shoulder Osteoarthritis by Oliveira. Permanently free Ethical Challenges in the Clinical Use and Commercialization of Orthobiologics and Global Perspective by Rossi.
Then we have a century of orthopedic experience with global impact.
The Instituto de Ortopedia y Traumatologia Carlos y Ottolenghi at the Hospital Italiano de Buenos Aires. That's by Butaro and colleagues. Then we have Regulatory Frameworks and Clinical Development of Orthobiologics across Asia and Europe by Li, followed by an international expert consensus statement defining the best practices in areas of uncertainty concerning the use of orthobiologics. This is by Koons and colleagues. It is a highlight with an infographic and 30 days free.
Then we have Osteochondral Autograph Transfer for Focal Osteochondral Defects of the knee Indications, Technique, Outcomes and Future Directions by Stroney and colleagues. Then the lead article for this issue, Peptide Therapeutics and Orthopedics Current Evidence and Future Directions by Urush and colleagues with an infographic 30 days free that's covered. What's in the Top of the pile. We'll then move into the headlines.
My headline is the Timing of Vascular Endothelial Growth Factor Inhibitor reinitiation and risk of wound complications in spinal metastasis surgery. This is by sue and colleagues with a comment.
This is a study in an area in which I do a fair amount of research, including actively, currently, not exactly in this space, but certainly adjacent to it.
We have done some work recently regarding advancements in immunotherapy and other types of tech treatment techniques that are not surgical. In terms of how those might impact surgical outcomes, this article was definitely very interesting for me. The vascular endothelial growth factor inhibitors are widely known in the literature to potentially increase complications if they are reinitiated too soon after surgery.
The complications in this patient population are already quite high. First off, it's a frail population with medical comorbidities and other treatments, radiation, chemotherapy that at baseline increase the risk of complications.
Then you add to that the cancer itself, which in this case is a metastatic involvement. High intensity surgeries meaning long operative time, use of instrumentation, quite common.
So these also are sort of combining in this perfect storm of a Venn diagram to increase complications. So then to add to that the patients who are taking the VEGF inhibitors that also is known to compromise wound healing. The prototypical recommendation per the authors is 28 day postoperative cessation, with others recommending a longer delay before resuming these medications out to 40 days.
They wanted to evaluate this within the context of spinal metastasis surgery. They do preface this by saying there is evidence in other surgical areas in the oncologic field where restarting the VEGF inhibitors too soon following surgery does increase the risk of complications.
They looked at retrospectively over 1,200 patients from their center who underwent surgery for spinal metastases between January 2010 and December 2022.
So a full kind of 13 calendar years inclusive.
And right up front they're talking about that there is some indication bias here where patients were indicated if they had a favorable prognosis and what that is is kind of open to question.
Who exhibited neurologic deficits or spinal instability?
Very common indications for surgery in this population.
While there were numerous VEGF inhibitor agents that were used across the population, these were analyzed as a single class for the purposes of the study.
The outcome, they are using a little bit of causal language here, which I think we should take note of. Independent predictors of wound complications and their approach is a multi variable logistic regression with a forced entry approach that could be described a little bit better in this context. I didn't love the brevity through which they approached their statistical analysis in that arena because forced entry is kind of ambiguous, it's a little bit vague and it's up to the interpretation of the end user what that means exactly.
For me, forced entry would mean that they have the idea of the factors that are important to consider as confounders and it doesn't matter to them how those factors may have performed in a bivariate comparison. They're going to include them as covariates in the adjusted analysis.
In which case I would just say you should present it as just a conceptual model and you're sort of agnostic to. It doesn't really matter to us, for example how biologic sex or BMI or diabetes or smoking play into this. We want to look at their adjusted effect in this population which is quite large. Again, at the end of the day after exclusions, they're at about 1160 patients of which 301 had complications. So you do have quite a bit of leeway in terms of what factors you want to consider.
But what the approach also could mean, and I think this second approach is less favored, is they went through everything and they looked at a bivariate comparison, kind of a head to head, and then they said is it significant or not? And if it was significant they included it. If it wasn't significant, they said was it important to us to include it? And if it was, they said yes. And if it wasn't then they were like no, we can leave it out. And that is less ideal.
What is also less ideal in this context is how they present their table one. You know, we've touched on this going back years now.
We probably say it once every six months or something like that. But I think it is good to recenter the audience on the fact that all of these studies are. All studies are supposed to be at their foundational element. They are an experiment. And if we're doing an experiment here, the experiment is we have one group that's getting the VEGF inhibitors restarted or restarted early and then we have the other group that is not getting VEGF inhibitors or is getting them and they're getting started later.
So potentially, you know, there's, there's three groups in, in this cohort and that's the experiment. The study is built around VEGF initiator reinitiation really that's in the title. And I suppose that you can use the patients that aren't on VEGF at all as kind of an independent control, but they only have 81 patients that are on the VEGF inhibitors and they probably don't have that much clinical variation around resuming the VEGF inhibitors because they kind of had a protocol that they were adhering to and if they deviated from that protocol, there was probably a pretty good reason. And it was just a handful of patients where there were these deviations.
So the table one, if you look at it, they're presenting by wound complications as if the wound complication is the main point of the study. So you get this table that's showing the total population and then the number that had no complications and major complications and minor complications. But that's not the purpose of the study. The purpose of the study was about the VEG S inhibitor. So I would have wanted to see the, at the top row, the total population, the population with VEGF maybe. And again, I think this would probably be so small as to not really be useful or informative. But in a perfect world, those that started it early, those that adhered to the 40 day restriction or whatever it may have been, and then, then you have it broken down later by who sustained complications and who didn't, but at baseline you want to see the foundational characteristics of the experimental population, if you will. And that's just really missing here. That's one of like my biggest issues is that we started with a premise and then there's kind of a, there's a little bit of a side quest sort of, or you're on a service road and you're going to rejoin the highway at a later time and they'll resume telling you about what their recommendations are for VEGF inhibitor reinitiation. But you're not really seeing that in this setting.
When they present in Table 2 the results of the multivariable analysis.
Yes, you see that VEGF initiation or VEGF inhibitor initiation at any point really, because they're not giving you that delineation about early, late or whatever it may be. It's just across the board, all comers, much higher risk of complications overall and major as well as minor complications.
The study then also takes another abrupt left turn to where they start talking about the other risk factors for complications and they didn't say they were going to do a risk factor analysis. So it really, we're not getting into the Brandt dude here. But they just went ahead and did it without telling you and then they're saying, oh, and diabetes is a risk for this and obesity is a risk for that. And you know, that really just gets into. There are so many comparisons here. And when you look at the 95% confidence interval across almost all their point estimates, they really are quite wide. That just speaks to, There are not that many patients with these combinations of factors. They have some restricted clinical variation and probably inadequate representation across so many variables that they're considering. And when you do these kinds of things and why it's not really recommended to do them as a best practice, you find statistical findings that are present just due to chance or artifacts from the model or just unique to this population and hence parochial and not translatable elsewhere. The focus was on the VEGF inhibitors. Everything else that you're including, yes, you should present all the odds ratios for transparency and just for due diligence to see how the model is performing. And if people want to do logic checks, you know, for example, if you look at something like it isn't really present here, but you know, say for example, that brain metastasis in this population shows as a survival advantage or something like that, that would be like. Well, that doesn't quite, that doesn't really add up, right? Yes, it's just unique to this population. But then you could say like, well, I'm not sure how trans. Like these are all things that you have to include for due diligence and logic checks and proof of concept transparency. But your real focus is just on the, what the VEGF inhibitors are doing.
And even then I think it's a little bit less robust because their real premise, the motivational narrative is around starting it early, starting it late and the amount of time that you have the patients off. And that's just really kind of glossed over in the results. It doesn't, it doesn't hold up really exceptionally well until you get to the very end of the results where they say that their discrimination test ROC analysis, they call it modest discriminatory power. I think that that's a little bit of an over optimistic spin. The AUC is 0.65 essentially and we generally say if it's under 0.6, if it's in the 0.5 range, keeping in mind that 0.5 is a coin flip.
So 50 to 60%, that's just considered not really that useful in the 60s is really considered poor. Modest is in the 70s, good is in the 80s and, and that's really kind of the standard outlook for the auc. So when they're saying it was modest, I, I think they're just, they're, they're, it's their spin and it's a little bit more optimistic about the outlook. Performance isn't really that good.
And they said that patients reinitiating VEGF I within 40 days had a higher rate of wound complications. And then patients reinitioning after 40 days but within 60 days had no difference in the risk compared with non users. But if you look at their point estimates, they say no difference.
It's no statistical difference, but it's 37% versus 25%.
[00:18:03] Speaker B: Yeah,
[00:18:05] Speaker A: that's still a big difference. Clinically meaningful. And if it was a larger population, it would have held up then they say the preoperative cessation interval demonstrated no predictive utility for postoperative wound complications with an AUC of 0.48.
So sometimes people get confused. They think 0.5 is the bottom. No, because the converse is actually like 0 of an AUC would say that it perfectly predicts the opposite of right. So now we're headed in the wrong direction for even there to be any kind of clinical utility.
Then they get into, you know, that there's an additional analysis for patients, insufficient washout. The numbers are just getting smaller and smaller as you go along here and are not really providing robust clinical details that can be invested in. I would say ultimately they come back to the 28 day or the 40 day cessation. And they say that their results indicate a minimum 40 day postoperative cessation interval, which has been shown in other disciplines, including colorectal cancer.
And then they say if the oncologic urgency necessitates earlier we reinitiation, then you have to assess concurrent risk factors such as nutritional status, interoperative blood loss.
Well, I mean, it's not like you wouldn't consider those things in any, like you should be considering those in every context. So it kind of goes without saying their conclusions emphasize first their other risk factors, diabetes and performance status and nutritional compromise.
And then they say perioperative VEGF inhibitor use, not the timing, just its use increased the risk of both major and minor wound complications.
So you know, at the end of the day, it's like this study didn't tell us anything that we didn't already know about VEGF initiation.
The premise for me, it's like, if you know this happens in colorectal cancer and you know it happens in other cancers, why would you think it wouldn't happen in spinal metastasis? The signals are the same.
It's sort of like, you know, do we need a randomized trial to show that parachutes save lives? Like no, we, we objectively not. And there's just, there's just so many non sequiturs here. And you know, at the End of the day, it. It really just is the author's fairly large experience, but also collected over 13 years and they didn't adjust for secular trends in their analyses.
So, you know, their statements at the end are true statements. There's nothing about what they're saying that needs to be put on hold. But the utility of this work, I'm pretty lukewarm on, I have to say.
[00:20:57] Speaker B: Got it. Yeah. These are all really insightful points that you made. I thought it was a really important article. You know, in 2007, believe it or not, I was working in a lab at Sloan Kettering and looking at VEGF and its characterization in osteogenic sarcoma. And since then there have been multiple anti angiogenic agents being used increasingly for metastatic carcinomas, like in this case. I think it's really important for us as orthopedic surgeons to be on alert when patients are on these medications and studies like this kind of draw our attention to that and to sort of begin the concept of when is it safe to restart these medications? I envision that many years from now it'll almost be like using DMARDs in rheumatoid and having a list of which ones we can start when after a 12 joint replacement. Similar to that when we have a patient that has had metastatic treatment, whether it's for the appendicular skeleton or the spine, we have an algorithm and this is the beginnings of that data. I had a different take on the risk factors. I think one of the main limitations in the setting of this being a retrospective study was that there were not sufficient patients to be able to account for important confounders for wound healing in patients with cancer. Specifically the effect of radiation. I think they only had 4% of patients had radiation. So you couldn't make any meaningful sort of assessments of these risk factors. I think they made an attempt. You know, corticosteroids were not assessed. Other chemotherapeutics were not assessed, although they were pretty comprehensive in their therapeutic, you know, classes. They used alkylating agents, antimetabolites, I think plant alkaloids. But it wasn't clear that it was an exhaustive list of all chemotherapeutics and those effects on wound healing. But that would I think be impossible to do based on the numbers that they had and sort of plants to see for a prospect of sort of multi centered study on this in the future. But I think it's very important data and it sort of sets the stage for those ensuing papers.
[00:22:43] Speaker A: Yeah, all. All good thoughts and reasonable points.
So let's, let's move into your headline. We'll see if what's new and interesting in orthopedics this week on your side is going on hold as well. Lower trapezius transfer at the time of reverse shoulder arthroplasty with an allograft prosthetic composite can restore external rotation by Sanchez Sotelo and colleagues in a multi center effort and this does come with Comet
[00:23:14] Speaker B: yeah, so this paper was a retrospective descriptive study from three major tertiary care centers including the Mayo Clinic, Emory and MGH at Massachusetts General Hospital to collectively report on their outcomes of a very complex shoulder reconstructive technique that combines reverse shouldered arthroplasty using an allograft prosthetic composite or an APC with a lower trapezius transfer or an LTT to the infraspinatus of the allograft extended with the inferior capsule.
Once the RSA APC reconstruction had been performed, a cuff capsule allograft tissue was passed posterior to the glenosphere and secured to the harvested lower trapezius. The technique was described for use in revision shoulder arthroplasty to contend with severe proximal humeral bone loss and whereby fixation of the humeral component can be challenging and the attachment sites of the rotator cuff are compromised.
Two surgeons performed 28 of these reconstructions between 2019 and 2023. One of the shoulders was treated with a whole humeral allograph with the use of the reverse shoulder arthroplasty and a total elbow arthroplasty and the LTT transfer. This case was excluded presumably because the total humeral allograph with elbow arthroplasty was such more complex, but they didn't quite state specifically while they excluded this one.
There was one case of PJI that was treated with resection arthroplasty and for this case the authors reported on the complications and reoperations but excluded it when reporting other clinical outcomes. I think this is reasonable since that patient no longer had the original reconstruction, but it would have been interesting to see all patients functional outcomes as well.
The authors detail how they perform the procedure, including the delto pectoral approach and a separate posterior approach, and how they prepare the humeral allograft and address the fixation at the allograft host junction. They describe how they address the host allograft capsular and tendinous attachments and how they do the lower trapezius tendon harvest and transfer they have some really beautiful illustrations on how the technique is done.
In the Supplemental Material, the authors describe the indication for surgery. There were 12 revision shoulder arthroplasties, 13 second stage reimplantation, one reconstruction for oncologic resection and one proximal humerus nonunion that adds up to 27. They originally had 28 after excluding the total humeral allograf with TEA and that left 27. But it would have been interesting again to know the indication for the surgery in that patient. I would have liked to see more information on the indications for this operation. So for instance, what was the reason for the revision? The 12 revised total shoulder arthroplasty? Was it bone loss? Was it loss of fixation of the implant?
Were all these total shoulder revisions? Were there any reverse revisions or hemiarthoplasty revisions?
Was the proximal humerus non union a periprosthetic fracture or was it a native humeral fracture? Some more detail on the indications on where this technique is most useful.
The outcomes included the range of motion, the single assessment, numeric evaluation or the SANE score.
The American Shoulder and Elbow Surgeon's ASES scores, complications and reoperations. Range of motion and patient reported outcomes are reported only for patients with a minimum of two year follow up.
The range of follow up was 2.5years with a mean of 2.7 years and range of motion was not available for two patients who had undergone resection for either infection or bone grafting. One of the most significant functional outcomes finding was that there was an improvement in active elevation of the shoulder and as well as improvement in external rotation. Preoperatively only 14% had active external rotation past neutral. But as most recent follow up 80% of the shoulders had active external rotation past neutral. I think that's pretty significant.
Preoperatively pseudoparalysis was present in 11 shoulders and postoperatively at most recent follow up only 3 patients had pseudoparalysis. In the discussion, the authors later used the statement true pseudoparalysis, which I think is a funny oxymoron as you can't have something that's both true and fake.
But I guess I know what they meant by that, but I think it was a significant decrease in patients that had this weakness post op. So regarding the proms, the SANE and the ASES scores were not done for four shoulders, one for resection, arthroplasty for infection, one for bone grafting, and one patient had died that did not add up to four so there might be one missing on that.
The mean SANE score was 56 and the mean ASES score was also 56.
The authors start the section on complications by stating, quote, one shoulder underwent successful iliac crest bone grafting for delayed union at the host allograft junction and another underwent iliac crest bone grafting with revision plating for non union of the host graft junction, unquote. I think this is more of a stylistic things, but I would have preferred them to just state what their complications were rather than saying they underwent a successful treatment of their complication. But that's again, stylistic and I think it would have been a little bit more transparent to just list the complications and how they were dealt with afterwards.
[00:28:08] Speaker A: That adheres to the old maxim, it's not a true complication if it's successfully treated right.
[00:28:15] Speaker B: I love that an analysis of the results based upon indication for this technique would be helpful. These papers that have expert surgeons describing very unique, complex reconstructive techniques are tremendously helpful, particularly when adding such really beautiful detailed diagrams and surgical interoperative photos as they had.
However, I think it could have been a little bit more instructive on indications of when this technique works best.
The description of the indication was very broad to encompass humeral bone loss and revision surgery, and there was a wide range of indications for the operation in their series. I would have liked a little more detail on the reason for operation so that the readers can get a real sense for the ideal cases and the ones that didn't do so well with this technique. But overall I thought it was a really important study to have out there. I think it's going to be very helpful for surgeons that do these complex reconstructions, particularly with some of the diagrams that they show. So it's a sort of a proof of concept. I think they did a very nice job of that. What was your take, Andrew?
[00:29:10] Speaker A: So as I was reading this, we talk about, you know, in passing at the beginning of almost every episode. The other editors in the JBGs family of journals, we have a journal that's called JBJs Essential Surgical Techniques. The whole journal is dedicated to surgical techniques. And as I'm reading this, I. The whole time I'm like, why wasn't this published in JBJS Essential Surgical Techniques? Because that's. This is a technique article. It is beautifully illustrated. It really has some rich detail around the procedure and great exhibits for sure.
All lovely. And I may be. And I recognize that I'm a bit of a methodologic purist. That's. That's part of the reason that I'm here.
And so you might say, well, how do you differentiate what belongs in Essential Surgical Techniques versus what should be published in jbjs?
And I want research to be hypothesis driven. If it's just here's our 27 patients, and I get it, it's rare cases, it's complex cases. It's stuff that people aren't doing other places. Is it stuff that people should know about unequivocally, Is this a research study? Unequivocally, no.
It's. There's 27 cases with, just as you amply illustrated in your presentation, broad heterogeneity, a lot of grittiness in terms of what it like the procedure was not uniquely the same across the board. These are complex cases. Patients don't come to the need for this just sort of, you know, de novo. They've already been through a lot of. And none of that diminishes from the value of this work. For everything that you said as a proof of concept, as an ability to illustrate what can be done in the hands of two surgeons. That's. The other point is that there's huge potential for expertise bias. I'm not 100% sure how the proverbial coaching tree works here, but I do believe that the person who is doing these at Mass General trained at Emory. I don't know if he trained with Dr. Sanchez Sotello or they trained with the same antecedent and they learned this technique or find this technique kind of together. I don't know how Emory fits in exactly, but that's beside. Doesn't seem like. Like any of the surgeries were done there, but. Yeah, so, I mean, at the end of the day, they're saying this is therapeutic. Level four evidence. I think this is really, in the current outlook, more closer to level five evidence. It's kind of an expert case series with just their sort of narrative presentation about this. There isn't any evidence other than that these two individuals can do these procedures and have. This is their body of work in terms of the results.
It doesn't inform what someone else can do.
So I really wouldn't say that this is a. It's a fairly large case series. If it was just three, you wouldn't call it a study. The fact that it's 27, I don't think makes it necessarily more of a study. And the things that they're saying where they say it has the potential to restore active external rotation and shoulders with proximal hurricane bone loss and posterior superior cuff deficiency is True in their practice, but not necessarily someone else's practice or in different hands. And that's why I'm still at the end kind of scratching my head around.
This is an Essential Surgical techniques article that happened to be published in the main journal.
[00:32:50] Speaker B: Yeah, that's a really good point. In fact, if it were published in Essential Surgical Techniques, we could potentially see more of it as a case series in some of the pre and post op X rays. And that crazy case they had where they had the entire humeral allograph with
[00:33:03] Speaker A: a total they can do a video for it.
If you haven't checked out Essential Surgical Techniques and you're listening to this, like, give it a look because those papers are especially. Well, the production quality on them is really exceptional. Yeah, it's an overlooked area in the JBGS publication family where I think that jbg, for obvious reasons and open access get the the highest level of attention and then you probably get reviews and then it's like essential surgical techniques. But don't sleep on essential surgical techniques. If anything good comes out of this, let it be that people are going to go over there and look at what that journal has to offer.
[00:33:45] Speaker B: Agree.
[00:33:46] Speaker A: So if you're like, is this dude going to put all three papers on hold this episode? The answer is no.
So let's get into your case on hold featurette. Spoiler alert. It's not going on hold. I really like this one. It's a basic science study, so we're not used to having these in the ear cases on hold featurette. It's primarily our hand was a little bit forced because there are no honorable mentions in this issue. So we're kind of going a little bit off the standard practice here and presenting a basic science study. We'll see how it goes. Prevascularized Bone marrow derived Mesenchymal Stem Cell sheets Promote Tendon Bone integration and Rotator Cuff repair by Lee and colleagues with a comment visual summary that going back to 2007, you were working in a lab on VEGF. I will preface this to 2002.
I was working in a lab on tissue engineering.
[00:34:44] Speaker B: Oh wow.
[00:34:45] Speaker A: I was tissue engineering.
My mentor was tissue engineering the distal phalanx. And I was interested in tissue engineering. Meniscus. Actually before I was a spine researcher, I was still interested in spine at the time clinically, but I really liked the idea of meniscus tissue engineering because I thought it was very feasible.
I thought that there might be corollaries to tissue engineering the disc because of a lot of shared similarities as it turns out as I'm reading this, I'm getting all of these trips down memory lane and positive reminiscences about my experience saying like all this stuff for the tendon bone interface for the rotator cuff is, you see that in the meniscus too. So there's, it's all still there. Where how did things end up? Well, I came here to the Harvard Combined program for my fellowship and they were like, we don't do basic science. You're going to be a clinical researcher.
It was over from then.
So this study is looking at, it's a tissue engineering study with a lot of corollaries to the work that we were doing 24 years ago in Ohio on tissue engineering meniscus, or distal phalanges for that matter.
So they had 20 female New Zealand rabbits who underwent bilateral infraspinatus tendon repair randomized to receive either bone marrow derived mesenchymal stem cell sheets or pre vascularized sheets generated by co culture with endothelial cells implanted at the tenon bone interface.
Then they looked at healing at six weeks, assessed by observation, histology, immunohistochemistry, gene expression and biomechanical testing, the gene expression included.
They also did pcr, which is the same exact way that we were looking at our miniscule constructs.
So that work, by the way, was published in Connective tissue research in 2009. And I'm sure everyone is going to run to look at it at this point.
So, you know, the problem here is the same problem that you see in the meniscus.
The tendons are hypovascular. They rely primarily on synovial diffusion for nutrition.
And the avascular zone is proximal to the supraspinatus insertion. And postoperative blood flow remains lowest at the suture anchor site. That environment is hypoxic and there's oxidative stress in that area which results in excessive autophagy and ultimately that can.
People who are in the know, of course, know that a lot of times, even in the best of circumstances, the rotator cuffs don't exactly heal completely.
And so they're looking to improve vascularization as a role to promote the TBI healing and regeneration.
Prevascularization is the tissue engineering strategy to overcome the oxygen and nutrient diffusion limitations in these 3D constructs supporting the survival and function of tissues after implantation.
Cell sheet technology is a scaffold free platform where they harvest cultured cells along with the native extracellular matrix and then co culturing Sheets with endothelial cells can establish a capillary like network facilitating rapid vascular integration. In vivo, this has shown benefits in myocardial repair, spinal cord injury and skin wound healing. In the meniscus, we were using PGA and PLLA and poly epsilon caprolactone and I'm just pulling that from 25 years ago.
It's still on the tip of my tongue.
No, those were scaffold heavy constructs. This is scaffold free, so it's a little bit different.
Great graphics. Love the graphics here. Lots of great basic science pictures. Some people hear basic science and their eyes start glazing over.
But this was really a great read for me. And at the end of the day the the sheet implantation was found to improve histological healing as compared with the baseline sheets. Better collagen fiber arrangement, more spindle shaped nuclei and fibrocartilage formation with mature chondrocytes. So all the positive things that you look to see, there was greater density of alpha smooth muscle actin positive vessels. The immunohistochemistry demonstrated greater areas positive for collagen type 2 and interleukin 10. Biomechanically, prevascularization yielded greater ultimate failure load and stiffness. So across the board there wasn't any area in which the prevascularization didn't outperform.
They do note several limitations, including the acute repair model does not fully recapitulate chronic degenerative tears.
That's probably the biggest limitation in this concept. And six weeks observation only really looks at early remodeling. But the findings are definitely encouraging.
The prevascularization sheets led to superior histological and mechanical outcomes at the tenon bone interface. And they believe these benefits really stem from the synergistic interaction between the the endothelial co culture and the cells that are there in the sheets.
They hope it represents a promising strategy for advancing tendon bone repair. Of course there is many a slip between the cup and the lip and a lot of other studies need to come in terms of getting this from bench to bedside, so to speak. That goes for all basic science studies. Their clinical relevance statement. The equivalent of what the level of evidence is supposed to be for the basic science pie is that they represent a biologic adjunct to enhance tendon bone healing and rotator cuff repair across the board. And probably in some degree due to my once upon a time affinity for basic science research and the analogies to my previous work from two decades ago.
I think this was great.
[00:41:35] Speaker B: I agree.
I think it was really fascinating. Concept in orthopedics, we've gotten really adept at addressing mechanical problems. We can fix things with more metal and more synthetic stuff. And it's become relatively easy in comparison to dealing with the biology and the soft tissues. But in any aspect of orthopedics, there's always the soft tissue conundrum. In the shoulder, it's the rotator cuff. In the hip, it's the abductors. In the knee, it's the extensor mechanism and, and the collaterals. And the notion that we could enhance vascularity and soft tissue healing with this type of technology, I think is pretty mind blowing.
I think the use of a rabbit model is great. It's a start to evaluate this technology, but there are some definite shortcomings that need to be addressed with future studies. You know, the authors briefly allude to this, but they tested this in healthy rabbits with a fresh rotator cuff tear and repair. And so the model doesn't replicate, you know, the hypovascularity and soft tissue degenerative changes in the aged human. Right.
So we don't know if the difference in outcome between the pre vascularized BMSC and the BMSC vascularity would persist if the baseline substrate was as hypovascular as it typically is in actual rotator cuffs. I was almost thinking myself, it's been 18 years reaming acetabuli and hammering in implants and playing mom tennis clinics. My rotator cuff tinnitus that's coming on, I was picturing the forever youthful Bugs Bunny with his shoulder abducted, you know, chopping on his, his carrot. What's up, doc? You know, mimicking, you know, me. And so, I don't know, like, would he do better with this technology than me, or would the delta be that different between the hypo, the prevascularized tissue, versus the, the standard non prevascularized graft. We don't know. But, you know, I think it was, it's fascinating technology and I think it's going to really change orthopedics. So I really like how the, the whole issue this month was about orthobiologics. It really is going to revolutionize things. I think this is just the start of it all.
[00:43:32] Speaker A: Yeah, for sure.
There may be broader applications for some of this, as you said, into repairs of the extensor mechanism, potentially.
The issues with the tendons around the hip, certainly not as common. Rotator cuff is going to be the most common application across the board. But there are definitely other areas where this same problem persists and this may have smaller applications, but still clinically relevant, potentially impactful?
[00:44:06] Speaker B: Most definitely.
[00:44:07] Speaker A: So that's all we have. Normally I say we're about out of time. I'm not sure that we're about out of time, but maybe for once, we've run out of stuff to talk about.
There will be honorable mentions in the next episode. If you like what you heard, like, subscribe, tune in in two weeks where we'll have honorable mentions that Dr. Abdi will present.
If you didn't like what you heard, you know, thanks for sticking with us this long. And check it out next time where we will have honorable mentions, and maybe that'll change your opinion for, for right now. You know, we went 2 for 3 on hold. But even though the basic science study was a positive here in our universe, no matter what, your case is on hold.
