Cell therapy in orthopaedics: where are we in 2019?

Listen to Mr Iain Murray (Associate Editor for Knowledge Translation at the BJJ) interviewing Dr Scott Rodeo (Hospital for Special Surgery, and Head Team Physician for the New York Giants) about his paper "Cell therapy in orthopaedics: where are we in 2019?", published in the April 2019 issue of The Bone and Joint Journal.

Click here to read the article

Transcript

[00:00:00] Hello, BJJ listeners. I am Andrew Duckworth and a warm welcome to what is now our fifth podcast from your team here at The Bone & Joint Journal. But firstly, I'd like to, again, thank all of our readers and listeners for the continuing feedback that we have received so far regarding our podcasts, as well as the authors who have agreed to take part over the past few months. 

As many of you know, we've already covered a range of topics so far in the series, including the management of open fractures with Professor Matt Costa. The role of robotic unicompartmental knee replacement with Professor Fares Haddad, as well as last month's podcast on DDH screening with Dan Perry and Alex Arbolt. We do hope the podcasts are improving the accessibility and visibility of the work we publish here at the journal, for both you as the readers and listeners, as well as for our authors. 

So over the next 15 or 20 minutes or so, we will cover a range of aspects of the chosen paper or topic emphasizing the important points and the key findings from the work and how these could fit into your everyday clinical practices. We also hope [00:01:00] to give you a behind the scenes insight into how the authors have developed the study or work to give them an opportunity to put forward the important conclusions from their study.

So as part of our podcast series, we plan to utilize the invaluable insight of guest interviewers for select papers as we did recently for our February podcast on giant cell tumours with Sam Patterson and AJ Purey. So today I have the pleasure of welcoming our second guest interviewer, Ian Murray, who is my colleague here at Edinburgh, and also our Associate Editor for Knowledge Translation here at the BJJ. Welcome Ian and thank you so much for joining us. 

Thank you, Andrew.

 Ian and I have a real privilege today of being joined by Dr. Scott Rodeo all the way from the hospital for special surgery in New York to discuss the topic of his instructional review paper, entitled Cell therapy in orthopaedics: where are we in 2019? Which will be published in the April edition of The Bone & Joint Journal. Welcome Dr. Rodeo and a big thank you for taking the time to join us. 

Oh, thank you. It's a pleasure to come on and try to share [00:02:00] some information. 

Great. So without further ado, I will hand you over to Ian and Scott. 

Thanks Andrew. So in this podcast we're going to discuss biologics and cell therapy, specifically touching on some of the controverties highlighted by Scott in his excellent review. So to set the scene, Scott, can you tell us what is meant by the term orthobiologics? Cause it's something we're hearing more and more about. 

Yeah, it's a bit of a catch all term, but it generally refers to the use of techniques and, you know, things like blood-based products and cell therapy to augment the biology of tissue healing. A lot of this relates to connected soft tissue to soft tissue, such as tendons, ligaments, cartilage, meniscus, all these tissues that have inherently poor healing capacity based on either poor vascularity, deficiencies in cells or cell functions. So all these types of tissues that we take care of in a lot of orthopaedic injuries that have inherently poor healing potential. So the use of this [00:03:00] so-called orthobiologics really refers largely right now to blood-based products, such as platelet rich plasma, or various types of cell therapy. 

Great. And why do you think we are having so much interest in these approaches? 

You know, as mentioned, we have a lot of the tissues, a lot of the injuries we take care of have inherently poor healing potential, whether that's bone with nonunions or delayed unions, or certainly connective tissue such as tendon ligament, meniscus, cartilage, these tissues have an inherently important human capacity. And a lot of these injuries occur in young active patients who desire to get back to an active lifestyle. So tremendous attraction as far as the ability to augment the biology. We can optimize the mechanical environment as far as our sutures and our implants and the biomechanics, but the whole other part of the equation is the biology of human. How do we augment the biology? And a lot of these tissues have inherently poor human capacity. Now that poor human capacity may be due to [00:04:00] deficiencies in cell number and cell function, deficiencies in vascular supply. These are often in harsh environments, mechanically, you know, inside the joint, where does tissue see high load? So this combination of factors leads to tissues that have an inherently poor capacity. Furthermore, these are tissues that accrue progressive degenerative changes over time, tendinopathy, osteoarthritis. So these suddenly provide a very attractive environment for the ability to augment the biology of tissue healing.

Yes. And more and more of our patients are asking about biologics and much of the media hype that surrounds it has come from celebrity athlete endorsements in fact. You clearly have significant experience treating professional athletes, particularly as head team position for the New York Giants. 

In your centre of biology therapies, frequently being used to treat these elite athletes. And are the approaches you're using different to your regular clinical practice? 

[00:05:00] Yeah, that's a great question. It does certainly does come up a lot from right from our pro athletes to our everyday, you know, so-called, weekend warriors. We use this therapy sparingly. Not, not on a regular basis by any means. There is, you can look at the, you know, the evidence we have. There are some early emerging data for the use of say platelet rich plasma, as an example for treating symptoms of knee arthritis. There was a little early data on the use of PRP for treating chronic tendinopathy. So most settings we have used these, you know, these biologic approaches in a sparing fashion, but I think we need to really educate our patients as to what we know. And importantly, what we don't know. 

A lot of these treatments have great potential, but the data is often mixed at best or incomplete. But so we said we do use these, but sparingly and PRP is probably the most commonly used cell-based approach, whether that's a cell formulation from bone marrow or adipose is used much less commonly that's a little harder to do in the clinical. I have in my own [00:06:00] practice have used itself only right now in clinical trials and at the time of surgery. So it's an area that continues to be of interest to our patients. It's asked about all the time. I think we need to kind of jump in carefully and really rigorously and educate our patients about, you know, what we know, what we don't know. I think it's okay to use, these therapies are autologous. They're safe. It's important to really have an informed decision in the discussion with your patient, educate your patient about risks, risks, and benefits and what is known and what is not known about lot of these therapies.

No, I agree. It's very important. So if we turn specifically to cell therapies, the terminology is extremely confusing and many of our readers will have noticed a vogue moving away from the use of the term stem cell, because that has a very specific definition. Are you able to guide us through this confusing terminology a bit Scott? 

Yeah, that's a great question. It is. It's almost more confusing each year. You're right. We're learning that [00:07:00] there are a number of different very heterogeneous cell populations that are all kind of lumped together as stem cells. And these are very heterogeneous at the most basic level, a stem cell would be defined by a cell that both has the ability for self-renewal number one, number two, multi-lineage differentiation - that cell can differentiate into all the different cells in a given tissue.

So that's the most simple definition, but the cell formulations used from bone marrow, from fat tissue,  from amnion, placental. They're all very, very different, very heterogeneous. And so clearly the field needs much more refined detailed ways to characterize your cell populations. Ultimately we'll use proteomics and  we'll look at gene expression or expression of certain proteins or how cells act in a functional acid to really characterize these very heterogeneous cell populations because they are all [00:08:00] quite different and it is confusing and it's confusing to us as physicians, you know, it's confusing to our patients. So I think as clinicians, we need to try to understand these nuances and don't love all these cell formulations, as quote on quote stem cells. Just understand that there's a lot of variability. We're still trying to learn about this variability. Ultimately you understand what cell formulation is optimal for a given tissue? There's no way that one size fits all. You know, the optimal formulation for treating arthritis is likely different than the optimal formulation for tendinopathy as an example. So you really need to look at these definitions and further refine these definitions and have a much more detailed way to characterize these cell populations.

Absolutely. And unfortunately it seems that this ambiguous nomenclature is being exploited somewhat by many of the companies that are seeking to sell their product and using the term stem cell often misrepresents the [00:09:00] formulation. So I absolutely agree. It's very important that any user or whether that be our reader really tries themselves to interrogate what the preparation actually is from the information that's given.

Yes. So in which settings, you touched upon osteoarthritis and tendinopathy, is there any particular settings that you feel cell therapies are most likely to make a difference to our patients in future Scott? 

I think, you know, broadly speaking, we start by just, any of our connective tissues have inherently poor human potential. There's a little data right now, as far as treating symptoms of arthritis. So I always tell patients, they know at least formulations as some early data to suggest that they are symptom modifying, whether they are structure modifying is more of a leap and less now. So that is to say we can treat symptoms say for knee arthritis, but do we really regenerate tissue? Well, there's some early emerging data that maybe we can with the laboratory purified stem cell [00:10:00] populations. So symptoms of arthritis would be one area. Number two is a little bit of data on use of cell therapy to augment a healing of the rotator cuff, the rotator cuff repair. Again, it's a lot of this data is early and we clearly need more data in this area, but certainly broadly tremendous potential, for tissue repair. But again, we need more data. We need to really understand, you know, what is the biologic target we're trying to treat? Are we trying to improve cell proliferation or matrix synthesis or vascularity. Those are all very different goals and the appropriate formulations type of cells and dose of cells is likely going to be different based on what we're trying to treat. So, you know, different biologic targets, different treatments. Again, this one size does not fit all. And that's where we need a much more refined understanding of what we're treating or putting into the patient. You know, ideally we can match the desired biologic, target the tissue we're treating with the optimal cell formulation. Until we know that we're kind of flying [00:11:00] blindly here but so that's where we need more research, but I think I'd say currently right now, a little data for using cells in arthritis and tendon repair.

Absolutely. That's a great call to action that we need more quality data.  It's a very difficult area to study, isn't it? Because of this heterogeneity and so comparison between studies is often difficult. Is there anything that you think we can do as a group to try and move the field forward in terms of research?

Yeah, that is what we need and I think the single biggest challenge in this whole area is heterogeneity. You know, when you study any other therapy, any drug, you know, you get drug X at concentration Y, or the patient did this particular exercise. Whereas the treatment with biologics it's all different. You know, my PRP is different than your PRP. In fact, my PRP made today is different than my PRP made tomorrow. So we need to characterize what are we putting in the patient  we need, [00:12:00] ideally right now, what I encourage clinicians to do is optimally we take a small sample of what we put in the patient and bank it, you know, send it to keep in the laboratory where we could ultimately look at the composition, the biologic activity now that's, by now, we don't know what to look at. You want to do a host of very expensive tests. And so right now we in our practice, we're just banking these specimens. Optimally, we need to identify one or two sentinel markers of quality, of potency. So we can eventually measure what we're putting in the patient and relate that back to the outcome. You know, the clinical outcome, the imaging outcome. Only in that way, we start to understand what works, what doesn't, what is the optimal formulation or cell type for a given condition. So I encourage clinicians if you're using these therapies, which is very reasonable again, they're used commonly, they're generally safe and there is great potential, but if you're using these therapies, at least put your patient in a registry, if possible, follow that patient's outcome and optimally, again, if we can record [00:13:00] what we're putting in the patients at the very least identify what cell formulation you're using, what's the sources and then that's how we'll move this field forward. 

Absolutely. Yes. It's hard to imagine a medical trial where the researchers or the patients don't know the dose of the drug they're being given in that trial. But certainly it seems that some of the studies we've had in biologics, although well meaning, because of that heterogeneity, it's difficult to go back and even see what the patients have received. 

Exactly. At the most fundamental level, it's the most basic question you want, you know, you need to understand whats the patient's treatment. And if we don't even know that it makes it hard to determine outcomes and then make conclusions. 

Yeah. I like your points there about the responsible use of biologics by individual users. As a research community, what's your thought on whether we should try and encourage standardized protocols say for [00:14:00] PRP or for cell therapies so that we can compare outcomes between studies or do you think that's too much of a barrier putting these limitations on individual groups on what they can study or what they should study? How do you feel about standardizing preparation protocols?

 Yeah, I think I understand it is challenging. That's the challenge of clinical medicine. You know, any given practitioner, you know, can kind of do what they want to do and that's fine, but I'd say is at the very least have a clinic practitioner try to, you know, put patients in some type of registry, you know, your points well taken. We also do need to standardize. I think, to be able to standardize, we need data. We need to understand, okay, what works, what doesnt, and I think it ultimately does go back to well done clinical and translational research. If we can learn those things, that is, you know what formulations are optimal for different tissues. We've promised that data. Then we have evidence. So at the end of the day we should expect our practitioner to all practice in an evidence-based fashion. If we can provide that [00:15:00] evidence of what works and what doesn't, then they get the ability to sort of push clinicians, as far as what formulation to use and start to have some standardization in the field.

So again, it all goes back to research, getting clinical data, good translational research to start to provide the evidence that we can in fact arrive at standardized protocols. 

Yes. And a big challenge that we often hear about is the regulatory issues, particularly with you guys over the pond, in the States with the FDA, we have perhaps slightly easier ways of getting through the regulation here in Europe. Is there anything that you feel is a big barrier in terms of regulation to you get into trials? Or do you think that things are moving in the right direction? Because ultimately moving this field, moving this field forward is going to have to involve the regulators industry and the researchers all working together.

Absolutely. [00:16:00] I couldn't agree more. I think we're moving in the right direction. The head of the FDA now in US and new individual last two, three years, I think he's taken a very responsible approach here where kind of a two-pronged approach. At one time, we were trying to really, kind of crack down a bit, if you will, on unscrupulous use, on the indiscriminate use of a lot of these therapies, because there is unfortunately some indiscriminate use, you know, the marketing is way ahead of the science. So on one hand, they're trying to crack down on those with indisciminate use but at the same time paved the way for legitimate therapies to come to trial. So actually to kind of make it a bit easier for legitimate companies and centres to proceed to FDA approved trials. So I think we are going in the right direction. I think, you know, the regulatory environment continues to evolve. I think that the scientists need to work with the clinicians and the regulators in those used, you framed it very nicely. It needs to be a team approach. You need the clinician, the scientists, the industry representatives, and the regulatory [00:17:00] individuals to work together. And I think we have an environment of all of them in here.

I think there's, I would say we have tremendous potential, tremendous interest. I mean, it's not just orthopaedics. In all fields of medicine it's a huge growth area. I think no doubt our regulatory bodies and individuals understand that. And I think they are trying to put their arms around this problem. How do we use this in a responsible fashion? How do we limit indiscriminate use, but at the same time, encourage legitimate therapies and let them move forward? So that's our challenge. 

Great. So Scott, I think many of our listeners will be very excited by the use of biologics, but will be keen to move things forward as much as they can in a responsible fashion. Do you have any advice for people who might be looking to use biologics in their practice in the first instance of how they can use it responsibly and any particular resources where they can get trustworthy information without being intimidated by the literature as a whole? 

I think we, as practitioners, need to [00:18:00] simply practice evidence-based medicine. Read the literature. I think we need to read literature that is, you know, peer-reviewed in journals such as Bone & Joint Journal and, you know, our other major journals. We need to pay attention to where the evidence is. There's lots and lots of marketing. I think we need to follow rigorous data. Again, use these therapies. Put your patients into some type of clinical registeries as possible.  And that's hard to do admittedly, but even at the simplest level, follow your patient's outcome, collect imaging and clinical outcomes data. If you had the ability to bank, a small specimen, fine, or at least record what type of cell formulation you use, you're using or some blood derived products such as PRP, you know, collect data on which to put in the patient also characterized patient.

So again, just goes back to collecting data on a patient, on our treatment, on our outcomes. Patching evidence-based medicine. I think it's incumbent upon us also to be honest with our patients too. You know, we need to inform patients and just [00:19:00] let the patients understand what we know, what we don't know, where the data is, and we need to let our patients know, so that they can make informed decisions as far as using these different types of therapies and I think that's the best way to move forward with responsible use in this area.

Scott, I think that's fantastic advice, not just for the researchers, but also very useful information for very everyday users of biologics who may not be contributing to papers themselves. So thank you so much for sharing your insights with us. And it's been a pleasure speaking with you. 

Thank you so much.

And thank you, Ian and Scott. Thank you so much for a really excellent and informative discussion and congratulations Scott on a really excellent paper. I would encourage all of our readers and listeners to not only obviously listen to the podcast, but to read the paper itself. It's very informative, about the field itself and the challenges that it faces.

So [00:20:00] to our listeners, we do hope you've enjoyed joining us, and we encourage you to share your thoughts and comments through Twitter, Facebook and a like about what we've discussed here today. And thanks again for listening.