YouTube Webinar Transcription
“Stem Cells and Growth Factors For Osteoarthritis: Hope or Hype”
Regenerative Medicine for Osteoarthritis
Jonathan Finnoff, D.O.
Jake Sellon, M.D.
JONATHAN FINNOFF: Welcome. Thank you for joining us today for the Mayo Clinic Regenerative Medicine For Osteoarthritis webinar. We’re really excited about this topic. You know, a lot of the different diseases that we take care of we treat symptomatically so we’re really just trying to make people feel better and a lot of these things we just can’t cure. But with regenerative medicine, it’s opening up new doors to be able to treat and potentially cure previously uncurable diseases and so we’re very, very excited about this topic and thank you very much for joining us.
Please use the chat box on the side of your page to ask any questions that you may have throughout the presentation. My name is Jonathan Finnoff. I’m a Professor in the Department of Physical Medicine and Rehabilitation at Mayo Clinic. I’m the Medical Director for the Mayo Clinic Sports Medicine Center in Minneapolis, Minnesota, and I’m a Team Physician for the U.S. Ski Team, the Minnesota Timberwolves and Minnesota Lynx. And joining me today for this presentation is my colleague Dr. Jake Sellon. He is an Assistant Professor in the Department of Physical Medicine and Rehabilitation at Mayo Clinic in Rochester, Minnesota. He is the Program Director for the Mayo Clinic PM&R Sports Medicine Fellowship located in Rochester. He’s also the Medical Director for Athletics at Rochester Community and Technical College, as well as the Medical Director for the Med City Marathon.
I have a disclosure to make. I receive royalties from Demo’s Publishing for a book I edited; however, this book and its contents are not relevant to this presentation and so there’s no specific conflict of interest. Dr. Sellon has no financial disclosures.
We will be talking about the off-label usage of platelet rich plasma and bone marrow aspirate concentrate injections.
So the objectives of this presentation are to discuss regenerative injection options for osteoarthritis. So who is a candidate for this treatment and how do we perform these procedures? What kind of benefits can people expect to receive from these types of procedures? And is there any research that supports these treatments? And so with that background and that introduction, I’m going to turn it over to Dr. Jake Sellon to talk to you about regenerative medicine.
JAKE SELLON: Thanks for the introduction, John. Thanks to all the viewers joining us. Very happy to have this chance to talk with you about this subject, especially in this interactive webinar format. It's great to share some of the exciting things that we are doing here in Mayo Clinic Sports Medicine and the Department of Physical Medicine and Rehabilitation. Hopefully, also, clarify some of the misconceptions about regenerative medicine. We spend a lot of our time during our consultations educating patients about things that we know and don’t know about this yet, but it’s certainly a very promising and very exciting area.
Also, just want to take a quick moment to thank Dr. Jay Smith, our colleague in the Regenerative Sports Medicine Practice. He’s the Director of Regenerative Sports Medicine here at Mayo Clinic and he has given this -- and talked on this subject on multiple occasions and was kind enough to share some of his slides for the presentation today.
So we’re going to start off just talking about osteoarthritis. You know, what is osteoarthritis and why is that an important treatment or thing to treat with regenerative medicine?
So osteoarthritis is the most common type of arthritis and it affects a huge proportion of the population. We think of it as more of a condition that affects the elderly, but actually 15% says everyone older than 25 years old in the United States is affected by osteoarthritis, and as you get -- the older [inaudible] more than 65 years, 35% are affected. This costs the United States more than $100 billion per year so it’s very costly and, you know, if we can find solutions for it, it would save a lot of money and also [inaudible].
So what exactly is osteoarthritis? Well, it’s a degenerative joint condition that involves wearing down of the cartilage. Also, with the cartilage wearing down, you also get extra growth of the bone and formation of bone spurs. This is due to a complex mixture of genetic predisposition, mechanical forces, inflammation and also various cellular processes. It's something that we’re learning more about and that will hopefully help target future treatments in some of the regenerative medicine [inaudible] I’ll talk about.
It commonly affects the knees, hips, hands and spine. It usually manifests in joint pain, swelling and loss of motion or stiffness [inaudible]. The reason why this is relevant [inaudible] is that a lot of athletes struggle with osteoarthritis, even some of our younger athletes, and that can be due to various injuries that they might sustain such as anterior cruciate ligament tears or shoulder dislocations. And so we oftentimes will see athletes that are maybe only in their thirties that are already dealing with fairly advanced osteoarthritis, which, as John said, doesn’t have a cure at this point. A lot of -- most of the treatments are focused on exercise, supporting the joint and essentially treatments for pain control. So the regenerative medicine options are -- you know, the thought that we might be able to start to slow down the disease process or even reverse it are, you know, very exciting.
So these are just a few examples I’ll show you of what osteoarthritis might look like in the knee on the left side and on the hip and so you can see where I’ve got the arrow pointed that some of the typical things we see on X-rays are that the joint space narrows as the cartilage wears down, such as in this case, in the knee, and then as the disease progresses, you can start to develop bone spurs like in this hip and you can see in this case the joint space is pretty much gone so you may have heard of the term bone-on-bone and that’s a laymen’s term for advanced osteoarthritis. So this would again typically manifest as pain and stiffness in the joint.
So then what is regenerative medicine? Well, it’s a little bit difficult to define because there’s not quite a consensus at this point, but probably the simplest definition is it’s an approach that tries to enhance the body’s ability to heal itself to restore tissue structure and function. And the National Institutes of Health has a little bit more of a technical definition that is below here and it talks about developing functional cell tissue and organ substitutes to repair, replace and enhance biologic function that has been lost due to congenital abnormalities, injury, disease or aging.
Now, when we’re talking about regenerative medicine, there are essentially three different components to tissue regeneration. So you obviously need cells to create new tissue. Those cells need to have a scaffold or some sort of foundation to work in and then you need to have growth factors, which can either be chemical or physical, and those basically stimulate the cells to grow and proliferate. So that may be things like -- on the physical side like exercise stimulus or on the chemical side it could mean various growth factors such as some of the ones we’ll talk about today.
And the way that we often explain it to the patients -- this is a model that I borrowed from my colleague Jay Smith and the way we often describe this to some of our patients here in the Midwest who, you know, a lot of them are familiar with farming and so you can think of the cells like the seeds in the process and the scaffold or the foundation is sort of like the soil and then you’ve got -- of course, you need the different stimuli for growth. So you may fertilize the seeds or they need a certain amount of water or a certain amount of sunlight and so those are kind of representative of the growth factor. So if you have any one of those that’s not ideal or not good, you know, you may not have the result that you want and at the same time these are all areas that we can potentially target with some of our regenerative medicine treatments. We can, you know, create better cells to use or better scaffold to use such as in the case in orthopedic surgeries where they’re implanting certain devices that cells can grow on. Or in the case of growth factors, these again might be some of the regenerative medicine injection options that we’ll talk about.
So I think we’ll be able to illustrate the regenerative medicine options that we have with a case here and so this is just a sample of a typical case that we might see in our sports medicine practice. This is a 32-year-old professional free skier who had a history of a right ACL reconstruction, two different times, as well as a medial meniscus tear that was debrided or basically had the torn part trimmed away on two different occasions. And we know from studies that the athletes that have these injuries, which are extremely common, are at higher risk for osteoarthritis happening early on in their lives. And so he comes in with right knee pain and aching and stiffness and this pain is worse with impact activities like running and jumping and is better with rest and so that’s a typical -- those are typical symptoms that we would see with osteoarthritis.
His X-rays show evidence of some joint space narrowing and bone spur formation like we might expect with osteoarthritis, and he’s really tried a lot of the nonoperative treatment options out there, including physical therapy, bracing, nutritional supplements, anti-inflammatory medications, cortisone injections and viscosupplement injections. And really beyond that, up until a few years ago, the only option was either to manage the pain or to have surgery, which, in this case, we have a 32-year-old. You know, he’s really not a good candidate for a knee replacement at this point and he’s still interested in being very active. So he’s interested in other options. So what could we potentially offer him from a regenerative medicine standpoint?
Well, we have -- currently we have two different options, two main options here that we commonly use in these situations. One of them is called platelet rich plasma and you may be familiar with this from the term PRP is how we usually refer to it. It has lots of other names as well, but that’s the most common. And then the other option is something called bone marrow concentrate or BMAC, bone marrow aspirate concentrate, and that is the treatment that we are currently using that contains stem cells. So that’s our stem cell treatment, and it contains a particular type of stem cell. It's called mesenchymal stem cells, and those are the stem cells that have the ability to form into the tissues that really we’re dealing with in osteoarthritis, cartilage and bone, tendon, ligament and so on. So you know, there’s hope that those can provide the seeds, so to speak, we talked about earlier as part of these treatments.
Now, PRP and BMC are both used for a variety of musculoskeletal conditions. We’re focusing on osteoarthritis today because that, first of all, is extremely common, but also it’s where probably the majority of the research is at this point as far as the studies that have shown good benefit. But there’s certainly a lot of research in some of these other areas, as well, including tendinopathy that we won’t cover formally today, but certainly, if people have questions about it, we can answer in the question and answer session.
So we’ll talk a little bit more about platelet rich plasma. Platelet rich plasma has some other names. Like I mentioned, you might read about autologous conditioned plasma, platelet rich fibrin or plasma rich in growth factors. It's one of the things that makes it confusing for patients and even for doctors when we’re going through the research is these have a lot of different names so it can be difficult sometimes to sort out the research that’s been done on this.
The thing that defines platelet rich plasma is that it is plasma with a higher than baseline level of platelet. So in other words, if you took your normal concentration of platelets in your blood, if we take your blood and process it into platelet rich plasma, we’re going to have a concentration many times more than the typical concentration of your platelets and that because it’s coming from your own blood, that’s what the term autologous means. And so when we do these treatments, we -- I kind of have a sequence of pictures here at the bottom. We start off in the bottom left with a blood draw and this would be similar to, you know, if you were giving a blood sample for a lab test. We take that blood sample and then we process it right there in the office in the centrifuge, and the centrifuge is what creates the PRP.
So if you look over here on the right, it’s on the right, you can see how the layers -- the centrifuge separates your blood into layers and you have a top layer that’s kind of the pure plasma, the bottom layer that’s the red blood cells, and this middle layer contains most of the platelets along with some white blood cells and that’s really where we get the PRP.
So just in a little more detail, if we look at those three layers, the top layer is what’s called acellular plasma and so that is essentially the part of your blood if you separate it out that doesn’t have any cells in it, and the bottom layer, as we said, is mostly red blood cells, which we don’t want to include in the PRP. And then this middle layer, sometimes you’ll hear the term buffy coat, and that’s in reference to this layer that has a very concentrated amount of platelets and then also some white blood cells.
So that’s what happens during the first spin, and then in the second spin the machine takes that middle layer and it further concentrates the platelets and then, depending on the device that you’re using, separates out certain types of the white blood cells.
And so that’s one of the things that I, you know, want you to understand today is that, you know, right now we’re still learning more about what is the optimal type of PRP for specific conditions and so there are different devices that make different kinds and that’s one of the things that we’re studying here at Mayo is looking at, you know, what sort of PRP specific devices are making and then how will that ultimately affect the outcome for patients.
So once we have the PRP, we then inject it into the joint and so here at Mayo we use ultrasound guidance for all of our procedures to make hundred percent sure they are on target. And I just have an example of a couple injections under ultrasound. This first one is a knee joint injection and this actually is, if you can imagine your knee, if we took it like a slice of bread through just above the kneecap. This is the needle coming in after we’ve numbed up the skin and we deposit the PRP into this little pocket above the joint and then it flows down under the kneecap into the joint. So it’s very reassuring that, you know, we know that it’s on target and the patients often enjoy watching the procedure. We keep things very comfortable during the procedure.
And then this is just another example of a hip joint injection and if you can imagine here, this would be like the ball of the ball and socket part of the hip. This would be the skin up at the top of the screen. The needle is a little bit more difficult to visualize here, but it’s running down here to this part of the joint and I’ll play this and you’ll be able to see the PRP going in throughout the joint here, this dark area. So this is really, you know, what we say is the easy part of the procedure and it’s very similar to what you might have with a cortisone injection or some other type of injection once we have the PRP or the bone marrow produced.
So how does PRP actually work? That’s one of the things that we’re still trying to understand completely. We know certain things about it, and part of that has to do with how osteoarthritis affects the joint. We know that within an osteoarthritic joint there are a lot of inflammatory chemicals and chemicals that break down cartilage and not only that, they decrease the amount of something called hyaluronic acid, which is an important building block of cartilage that helps with joint lubrication as well.
So the platelets help optimize that environment and potentially slow down the process. So first of all, we all know that platelets are the first cells that go to the site of any injury that we have that kind of kick off the healing process by signaling other cells in the area. So in the case of osteoarthritis, we know these platelets are similar. They’re essentially little packets of growth factors and when they reach the inside of the joint, they release these growth factors into the joint, kind of like the fertilizer analogy that we talked about earlier.
Now, these growth factors modulate inflammation. So what does that mean? Well, if you have a very inflamed joint, they can change that inflammation to a more appropriate level. The body needs some inflammation for healing, but too much, we know, is a bad thing. So in that way, it sort of acts like a natural cortisone and so we know we get an anti-inflammatory effect.
Another way that PRP might help is by stimulating the lining of the joint, which are called the synoviocytes, to produce more of this hyaluronic acid or this substance that helps fortify the cartilage and helps with lubrication.
Another thing that platelets can do is potentially attract and activate mesenchymal stem cells that are already in your joint. We all have stem cells throughout our body that help -- any time we have an injury, they are activated and can help rebuild the tissue. Well, we know that in osteoarthritis, these cells, you know, are not able to keep up with the amount of destruction that’s happening and so the platelets help the stem cells that already exist in your joint active. So that’s another potential way that they may be helping.
Now, as far as regrowth of cartilage, that’s one thing that has not been shown at this point with platelet rich plasma, at least by itself. But it certainly sets the joint up into a more healthy environment.
So I mentioned that different types of PRP are different devices -- or produce different types of PRP. So what are the things that we look at? Well, at this point we feel that probably the most important part of PRP are the platelets themselves and so we generally know from basic science studies that the more platelets that you have, the more of an anabolic or a growth-promoting effect you can have. And so what we don’t know is what is that optimal dose of platelets and so the PRP that we are producing typically, you know, has around 10 times, but even up to 20 times the amount of platelets that you may have in your blood. So it really ramps up that potential growth-promoting process.
We know that red blood cells are not good to have in a joint and so I just brought up this picture here on the lower right. This is a patient with hemophilia. Hemophilia, you may know, is a condition where patients have a problem with their blood where it doesn’t clot very easily and one of the issues with that condition is patients can bleed into their joints and over time we know that that can actually cause destruction of the joint. So this is a patient, unfortunately, a patient with hemophilia that has sort of end-stage destructive changes in their joint from just bleeding over and over again in the joint and we think that’s because of the red blood cells, which have a toxic effect on cartilage cells. So we use PRP that has essentially no red blood cells.
Now, the final part of blood that is within PRP or that we have a decision to make as far as whether we want it in PRP is white blood cells and so white blood cells, there are many different types. We know that inflammatory white blood cells, or neutrophils, are probably not good to have in a joint and so we remove those from our PRP before injecting. Now, the jury is still out to some degree on, you know, regarding how much of the other types of white blood cells are optimal to have there, but the literature, you know, points us in the direction that the neutrophils are not good and so we don’t include those.
So because there is such a difference in different types of PRP, we feel it’s important to monitor this and so we can be confident and have our patients confident that we’re using the -- they’re getting a good treatment here and that we intend and so we feel that a quality control program is very important and we have that running with all of our cases where we analyze the types of cells and cell counts that are going into the joint. And, you know, at the same time we think that this is very important in future studies for researchers to report exactly what types of PRP they’re using because that probably makes a big difference in the outcomes.
So mentioning research, what is the research out there for PRP? And I’ve just kind of summarized it here. Now, this is the literature for platelet rich plasma, or PRP, for knee osteoarthritis or actually for different types of osteoarthritis. There are lots of what we call [inaudible] series out there where researchers reported on a series of patients that they treated and essentially all of them report very good results with little to no side effects.
There are several trials or even randomized controlled trials and these are the highest level of evidence within medicine where you have randomized, blinded trial where you are comparing two different types of treatments and so these are much more meaningful as far as their outcomes and there have been several with PRP and knee osteoarthritis and I’ve listed them here. We have about 16 trials at this point comparing PRP with hyaluronic acid and all 16 of them have shown that the PRP worked well, at least as well as hyaluronic acid, and many times or in many cases, better and with longer duration. There have been 13 of those in the knee, a couple in the hip and one in the ankle at this point.
There’s also been a couple trials looking at PRP versus a placebo, which is a placebo is basically a treatment that we don’t expect to cause any positive or negative effects and so it’s been compared against saline and also a local anesthetic and PRP performed better than those in each case.
There is one trial so far looking at PRP versus cortisone and the PRP did better than the cortisone. And then finally, there was one trial looking at PRP with physical therapy versus just physical therapy by itself and PRP with the physical outperformed the physical therapy alone group. But you can see I have listed here the references. There are lots of studies at this point, so we’re getting increasing confidence that this is an effective treatment that seems to be safe. Really no serious side effects in any of these studies.
But just to wrap up, you know, I guess going back to the question is PRP effective for knee osteoarthritis or for osteoarthritis, in general, and I think at this point the answer is yes, it seems to be effective for pain and function specifically, which is really what they looked at in these studies. Now, the jury is still out regarding whether or not it can slow the disease process and those are things that we should learn more about in the coming years with more research.
It seems to work better with younger patients, in patients with lower grade osteoarthritis. However, we still see good effects in patients with advanced osteoarthritis, not in all cases, but it certainly seems to be worth a try.
The onset is a little bit different than cortisone and more like hyaluronic acid in that it takes a few weeks, oftentimes four to eight weeks, for the effects to be noticed, but the good part is that it often lasts for a long time, even up to a year or more.
People often ask can it be repeated and the studies that are out there have looked at repeat injections or single injections. Right now, the jury is still out on that. We typically start with a single injection and then make an assessment from there, and occasionally we’ll repeat injections if patients want to try to get some incremental benefit. Most of the research has been done in the knee, as I showed, but it seems reasonable to extrapolate this, as there have been some studies in the hip and ankle that have also shown very good benefit.
How about safety? Well, as I said, there have not been any serious side effects reported with PRP, so it seems to be a very safe treatment and certainly compared to some of the other treatments that we’re currently using like corticosteroid.
The one side effect that has been noted occasionally is a flare in pain and swelling for a few days after the injection. This is rare and when it happens, it’s typically just for a few days and doesn’t ultimately affect the outcome of the procedure.
Finally, while we -- it’s difficult to say if there are any absolute contraindications or reasons not to do -- use PRP, but one situation where we are currently and typically not doing it is in patients that have had a recent cancer history, perhaps in the last five years, in remission, or certainly if someone has active cancer. And there haven’t been any studies looking at that, but we do know that after you inject PRP, there is a temporary elevation in some growth-promoting hormones within the body and so at this point we think that we feel more comfortable not doing that, but certainly as more research comes out that that may be subject to change.
So with that, I’m going to turn it over to John. I think that PRP is a great option for a lot of patients, and we can chat more about it on the Q and A session. So John, go ahead.
JONATHAN FINNOFF: Thank you very much, Jake. Nice presentation. I’m going to be talking to you about mesenchymal stem cells and as Jake had mentioned previously, mesenchymal stem cells are pluripotent stromal cells that can form a variety of different tissues. So they can become muscle cells or cartilage cells, they can help form tendons and they can also help form bone. The way that they work when we’re talking about regenerative medicine is threefold. The most obvious is that they go to the area of damaged tissue, they stick to that damaged tissue, they differentiate into the right cell type and form new tissue in that area. But they also secrete different hormones and little regulators called cytokines and chemokines that attract other cells to the area and stimulate them to help with the reparative process, and they also have an immunomodulation response where they decrease inflammation and some of the destructive factors that are happening in the arthritic joint.
For regenerative medicine specific to osteoarthritis, we obtain the mesenchymal stem cells typically from bone marrow, but another source where they can be obtained is fat, although there are some issues with FDA regulations and using fat in clinical practice. So I’ll talk to you about bone marrow derived stem cells.
So the way we get these is we’ll the patients lay down on their stomach and we’ll feel the prominent bones on the back of their hips and then we’ll scrub off that area with some soap, we’ll look at it with an ultrasound, and if you look in the lower right-hand corner, you will see there is a white outline of a bone and then there is a drill coming down and entering the bone in that area. But we’ll anesthetize the skin and the tissues down to the bone with some local anesthetic, usually lidocaine and possibly a longer-acting local anesthetic called ropivacaine. Then we’ll do a little poke hole with a scalpel and then introduce a bigger needle down to the bone and then drill into the bone and aspirate bone marrow from inside of the bone, and we do it from multiple different locations so that we can try to maximize the number of stem cells that we get.
Then, very similar to PRP, we take those stem cells and we -- or that -- we take that bone marrow aspirate and we put into a centrifuge and spin it and just like the buffy coat has platelets, it also contains these stem cells and so we extract this buffy coat after the centrifugation and we inject this concentrate of stem cells into the area of damaged tissue. Now, unfortunately, even when we do this and try to concentrate those stem cells, it’s still a very, very low concentration of stem cells, just because we don’t have that many in our bone marrow. And so ideally, it would be nice to have more stem cells in the injections.
Now, from a basic science standpoint, our stem cells, when they’re circulating in our blood, when an area of tissue damage occurs, then our stem cells will go to that area and it’s typically because of local factors that are secreted by cells and receptors that are expressed on those cell surfaces and so the mesenchymal stem cells are signaled to go to that spot of damaged tissue. When they get there, they release a bunch of growth factors to help stimulate new tissue growth, it stimulates other mesenchymal stem cells to migrate to the area and local juvenile cells that are in that area, it causes them to differentiate and become more mature cells to help create new tissue.
They also inhibit some of the inflammatory cells from differentiating and starting to damage localized tissue. And in fact, they can stop some of the secretion of these inflammatory cells, of inflammatory chemicals that would damage the tissue, and it promotes them to start actually secreting different chemicals that promote regeneration of the tissues. And so they really have a lot of different effects localized to the area.
Now, if you do intra-articular injections, so inside of a joint, of mesenchymal stem cells with hyaluronic acid -- and hyaluronic acid was mentioned previously by Dr. Sellon. Essentially that’s the lubricant injection that a lot of people talk about and so it’s kind of like a gel. So if you inject this gel with mesenchymal stem cells into rabbit knees with osteoarthritis, then it actually slows the degeneration of their knees, it decreases the abnormal bone formation and the bone spur formation and it starts to generate new cartilage and particularly new cartilage that’s more normal. So it has the normal water content and the normal chemical contents in it so it works better than some of the abnormal cartilage that we see a lot of times and it suppresses pro-inflammatory mediators so things that break down your knee.
If you do intra-articular injections with stem cells in rat knees with osteoarthritis, then it causes the rat to have less pain and it slows their progression of osteoarthritis. And if you do the same thing in sheep knees with osteoarthritis, then it actually causes significant hyaline cartilage regeneration -- so that’s normal cartilage regeneration and that’s what we want -- it improves the muscle contraction around the joint so your muscles function better and that helps you to absorb shock and reduce the stress on the joint, it slows their degeneration of the knee and, most importantly, it doesn’t cause any significant adverse effects on their knee, which is super important because any treatments that we use, we don’t want it to harm the area that we’re actually trying to treat.
We have found that the closer that the stem cell is to the origin of the target tissue, the better it becomes that target tissue. So for instance, bone marrow derived mesenchymal stem cells can become cartilage much better than the stem cells that we get from fat, and stem cells that you get from the lining of the joint, the synovial tissue, are even better than the ones we get from bone marrow. So over time as we get the right type of stem cell and we get the right concentration of stem cells and then we mix it with the right fertilizer and hopefully you have a good scaffold in that area, we’re going to get better and better and better at regenerating new tissue for osteoarthritis.
And what about humans? You know, we’ve talked about basic science with rats and sheep and, you know, that doesn’t necessarily mean that it’s going to work in humans. So for starters, you know, mesenchymal stem cells have been used for years in a surgical setting and many of you have probably had knee surgery and one of the things that’s commonly used to treat osteoarthritis is a surgery called microfracture, and microfracture uses a little pointy, hard instrument that they nail up through the bone right where the cartilage is needed to grow and then they pull that little, pointy part out and the bone marrow leaks out through that hole that you created and it starts to form new cartilage on the surface of the bone in the area off that defect and that is a stem cell procedure. It's almost identical to what we’re doing except for we’re not poking a hole in your knee. We’re getting the bone marrow -- we’re getting the stem cells from your bone marrow and your hip and then we’re concentrating those stem cells and then just doing a simple injection into the knee without doing a surgery. But from a surgical standpoint, microfracture has been used since the late ‘80s.
A lot of the studies that are currently clinically based though do combine stem cell injections with some type of surgical procedure. From a strictly injection standpoint, there have been a few studies in that area, but frequently they use non-bone marrow derived mesenchymal stem cells -- so ones from fat -- or from the synovial lining -- so the lining of the joint -- or they are expanded cultured stem cells. So they get the stem cells out of the bone marrow and then they culture them for a prolonged period of time to produce more stem cells and then they inject that concentrate into the knee.
So the first study that I’m aware of was a case study by Centeno and he took two bone marrow derived mesenchymal stem cells and then he expanded them and injected them back into the knee and he found that not only did it reduce people’s pain, but based on MRI findings, it increased their cartilage volume. So cultured expanded stem cells in these two patients seems to cause a reversal of osteoarthritis. Again, we’ve always tried to treat it symptomatically. Even a knee replacement is just a symptomatic treatment. It's just a very, very fancy pill. This is the first thing that’s actually trying to change the underlying course of the disease.
Hauser took unconcentrated bone marrow aspirate -- so just aspirating the bone marrow, he didn’t centrifuge it -- and he injected into the hip, knee and ankle in seven patients and found that all of them had improved function, pain and quality of life. Hauser injected unconcentrated bone marrow aspirate -- oh, excuse me.
Emadedin did two different studies where they did cultured expanded bone marrow aspirate concentrates. So this is the one where they cultured them and got a lot more stem cells and then injected them. The first study was in six patients with knee osteoarthritis and it increased their cartilage thickness, decreased the amount of swelling in their bones from the bones banging together and not having a cushion and improved their functional outcomes. And in patients that he did this into their knee, ankle, and hip, he found that their improvements lasted for the 30-month duration of the study. So he stopped the study at 30 months, but they were all still doing well. So it seems to last actually a long time.
Davatchi did a similar bone marrow aspirate concentrate injection that was culture expanded into four patients with knee osteoarthritis and over a six-month follow-up, they found that three of the four had significant improvement and one patient didn’t have any significant improvements. And when he followed them up five years later, the three that had improvement were still doing well.
So are bone marrow derived mesenchymal stem cell injections an effective treatment for osteoarthritis? Now, really at this point we can’t say that it absolutely is. It is definitely unknown. The basic science is very promising, and the limited clinical research suggests that it’s going to improve pain and function and possibly even reverse some of the osteoarthritis. But this is very, very preliminary research and, in general, it’s done through a different manner than we do in the office.
But it does seem to be safe. So it doesn’t seem to cause cancer in anybody, and the side effects seem to be pretty minor. So localized pain where you’re aspirating the bone marrow, maybe a little bit of pain and swelling in the knee for a day or two afterwards, similar to the platelet rich plasma injections. And looking at nearly 20,000 bone marrow aspirates in Great Britain, they found only a .08% risk of an adverse event and those adverse events were typically bruising and pain in the area. So really these procedures seem to be quite safe.
So in the case of our patient, who was the professional free skier, obviously this patient was young, fit, healthy, had tried everything they could and wasn’t doing as well as they wanted to and they were making their living doing impact types of activities. So the patient opted for a platelet rich plasma procedure because of the amount of research behind it and the fact that it seemed to not only help but possibly, based on the mechanism of action, maybe it’ll slow the progression of osteoarthritis or maybe even potentially reverse it to some degree.
And so before the procedure for about seven days they were told to avoid anti-inflammatories because it prevents platelets from functioning, and then the procedure was performed and you can see the needle being introduced into the knee on the picture in the right-hand side of the screen. They rested for a couple of days after the procedure, then resumed their normal activities. They were told to avoid anti-inflammatory medications like aspirin and ibuprofen and Aleve for a couple of weeks, again, because it inhibits platelet function -- and we’re depending on platelet function for this to work -- and at four weeks this patient had dramatic pain relief. And when they followed up with me a year later, they still had significant pain relief and opted to just continue with the current treatment and if they had any resumption of their pain in the future, then they would seek me out and have another platelet rich plasma injection. So they’re very happy with their treatment.
So in summary, regenerative medicine harnesses the body’s ability to heal itself by delivering growth factors or stem cells to areas of degenerative or injured tissue. The two most common types of regenerative therapies for nonoperative sports medicine are platelet rich plasma and mesenchymal stem cells. The evidence currently suggests that PRP is an effective treatment for improving pain and function in osteoarthritis and bone marrow derived stem cells are an exciting new frontier and while the basic science research is promising, the clinical evidence at this time is limited and it really should be reserved for those who have failed other nonoperative treatment measures.
So thank you very much. We will now start taking questions and remember that to continue this conversation you can use the chat box and click on that chat box and enter any questions that you may have and we’ll try to answer as many questions as you have.
All right. So would this -- the first question is: Would this procedure be useful to eliminate or reduce pain coming from multiple herniations in the disc deformation in the lower back? Jake, do you have an answer for that?
JAKE SELLON: Well, I’m sorry, did you say PRP specifically?
JONATHAN FINNOFF: PRP or stem cells.
JAKE SELLON: Sure. Well, that’s a great question and that’s an area that we are looking at here at Mayo Clinic. One of my colleagues, Dr. Wenchun Qu, is one of our spine experts here who is involved with our Regenerative Medicine Program and the Department of Physical Medicine and Rehab and he is initiating several trials, one of them looking at bone marrow concentrate for degenerative disc disease.
As far as platelet rich plasma, I am aware of a trial that was published a few months ago where they did show some benefit in patients that had disc related pain, and I think it was -- again, showed improvements in essentially back pain and function afterward. But really not much literature out there, say, compared to knee osteoarthritis and I’m not aware of the literature for bone marrow concentrate. I don’t know, John, if you have any -- know anything about that.
JONATHAN FINNOFF: No, I would agree. I would agree with you, Jake. Essentially, at this point it’s very preliminary. There has been some data on PRP more so than stem cells. It's not as much as for osteoarthritis or tendinopathy as far as the volume of literature, but the initial studies seem to be promising, but it certainly would be very experimental in those areas. You’d want to do this type of procedure with somebody who was very experienced and also was doing research in the area.
So does this procedure help with stenosis of the spine? And unfortunately, stenosis is more of a proliferative disorder where as you get arthritis, you’ll start to get bone spurs, you’d start to get thickening of the ligaments in the spine, and all of those start to make the area where your nerves are narrower so you just don’t have as much room. And so injecting stem cells or platelet rich plasma into that area won’t help widen and increase the room where your nerves are getting compressed. So unfortunately, it’s probably not going to be an ideal treatment for spinal stenosis.
The next question, it says, I have a knee infarct and my doctor says knee replacement is my only option. Could stem cells help me? What do you think, Jake?
JAKE SELLON: Well, I guess I’m not sure exactly what they mean by knee infarct. If they’re talking about avascular necrosis, that’s something that one of our colleagues here in orthopedic surgery, Dr. Rafael Sierra, is currently using bone marrow concentrate to treat that condition in the hip at least. I’m not sure about the knee. But there are some studies out there supporting that and they basically decompress that area where the infarct is or the avascular necrosis and then inject under X-ray guidance into the area of bone and seems to be getting good results. I don’t know, John, if you have anything else to add on that?
JONATHAN FINNOFF: No, I would agree. So essentially avascular necrosis is where you lose blood flow to an area of the bone and so the bone dies, and when the bone dies, it gets weak and brittle and collapses. And so traditionally, we’ve treated that with a joint replacement. But the goal of nonoperative treatment is to revascularize that area. So like Dr. Sellon said, pushing a hole into the bone and then injecting it with stem cells or PRP is one potential way of promoting revascularization. Now, it depends on how far progressed the bone -- the avascular necrosis is. If you have collapse already, it’s not going to reform your joint. So it would be best in the early stages. And certainly it is experimental and so it’s hard to say whether it would make a difference or not, but it makes theoretic sense and the preliminary data would suggest that it might work.
So the next question is: Has there been research for osteoarthritis caused from post-arthroscopic glenohumeral chondrolysis and could one of these interventions work? So what happens -- what this is talking about is they used to do an arthroscopic procedure and after the procedure sometimes they would use a pain pump where they would push local anesthetics into the joint to try to reduce the amount of pain that somebody had in the joint, and these local anesthetics can have toxicities and so some people would develop diffuse death of the cartilage inside of their joint and so essentially you turn a joint that had whatever problem you were doing the surgery for into a very arthritic joint and it’s a very, very difficult problem.
Would this type of intervention be a treatment option for it? Absolutely. Would it be able to fully reverse their problem? I think it would be very similar to what we talked about today in terms of osteoarthritis. It would have some anti-inflammatory effects. It might stimulate some new tissue regeneration, but it probably wouldn’t normalize somebody’s X-ray. Dr. Sellon, do you have any comments on that?
JAKE SELLON: Yeah, I mean, I agree, John. I think that it would be worth trying one of the interventions for symptomatic relief, at the very least, but I think that probably at this point based on what we know, it may be unlikely that it would reverse the disease process, which, as you said, is very difficult.
JONATHAN FINNOFF: So this is an interesting question. Do you have to use the marrow from your own bones? What do you think, Dr. Sellon?
JAKE SELLON: Well, I think -- I mean, right now that’s what we’re doing. It's unclear in the future if -- you know, if there may be a move toward using the marrow from other patients or donors, but I think at this point just given the potential safety concerns and that, you know, I would recommend using your own cells because, of course, you know, you have concerns about infectious disease or, you know, potential reaction to someone else’s tissue. So -- but I guess I’m not aware of studies looking at using other people’s bone marrow.
JONATHAN FINNOFF: Yeah. In general, when you’re going to the office and getting this type of thing done in an office, they’re going to use your own bone marrow. You know, I agree with Dr. Sellon that it’s possible that you could aspirate if you had a match, you did matching, you could aspirate from one person and inject into the other, but that’s not something that’s done in the office. It's certainly possible that in the future we’ll be aspirating and then sending things off for culture, but it would have to be done under pharmaceutical grade conditions and that would add a huge amount of cost to it, but it also may end up with better results. And so we have a lot of questions that still need to be answered.
How often, Dr. Sellon, do you think that somebody can have a PRP injection?
JAKE SELLON: Well, that’s a great question. You know, as I mentioned, we typically start with one injection and then assess the results and then if patients get excellent relief like we had in our case presented today, then basically we have them follow up as needed and they can repeat it if they start to have their symptoms return. And in some cases, that may be several years later, if at all. I think that, you know, some of the studies out there have shown benefit [inaudible] more than one. There was one particular study comparing two versus one and there [inaudible] seem to be a big difference. More recently there was a study showing that there may be a little bit of benefit in patients who have lower degrees of osteoarthritis by doing more than one injection. They specifically used three versus one. But I think that we just don’t have enough evidence at this point to kind of set people up right from the start with a repeat injection, but it certainly is very safe to do so. It's just, you know, does it really add more efficacy? The jury is still out on that.
JONATHAN FINNOFF: So I agree. I think it’s safe. You should use it based on how much response you have to the treatment, and you don’t necessarily need to set up a series of injections right off the bat.
Can this regenerative medicine be used for rheumatoid arthritis? So I haven’t seen any studies on this and I’d like to hear Dr. Sellon’s opinion. Certainly, PRP has some anti-inflammatory effects, as do mesenchymal stem cells. But this is a -- rheumatoid arthritis is a very, very different disease process from osteoarthritis. You know, your body is essentially attacking the joint. And so would PRP or stem cells benefit or harm this patient population? I think that the jury is still out, and I would be -- I would be more hesitant to do an injection with either of these in somebody with rheumatoid arthritis. What’s your opinion, Dr. Sellon?
JAKE SELLON: Yeah, I mean, I agree. In our practice, we don’t have as much personal experience with rheumatoid arthritis compared to osteoarthritis, which we, you know, commonly see in either athletes and active people. But I think that -- you know, I know of people that are using platelet rich plasma for rheumatoid arthritis and, you know, right now there’s not much -- any research out there on it so it’s difficult to say. I think it makes sense from a theoretical standpoint that a lot of the anti-inflammatory effects that you can potentially get with platelet rich plasma, we know rheumatoid arthritis is primarily an inflammatory disease, so I think it makes sense. With bone marrow concentrate, I’m not aware of any research. I think it’s a little bit more complicated. I think that we’ll probably see more studies on that coming out. At this point it would be -- PRP might be something I would consider, but it would be a case-by-case basis.
JONATHAN FINNOFF: How long will it take before I can go back to work or sports after a PRP or stem cell injection? So from a stem cell injection at this time, it’s variable, the post-procedure protocols that people are using. In general, I tell people to take it easy for about a week. It doesn’t mean that they’re not weight bearing. I don’t put them on crutches. And really, I use this as part of a more multifaceted program. So I talk to people about weight loss, appropriate nutrition, making sure that they’ve got good, strong hips and thigh musculature so they absorb shock and reduce the stress on their knees. I talk to them about nutritional supplements, over-the-counter medications, making sure that they’re using appropriate bracing if it would be effective. You know, so a lot of different things and this is just one aspect of it. So with stem cells, I usually have people take it easy for about a week and then I let them go back to their normal activities. Dr. Sellon, what do you think about your stem cell practice, as well as PRP?
JAKE SELLON: Yeah. I mean, first of all, I agree a hundred percent with [inaudible] approach. This is -- these injections are just one part of the treatment program. You know, we kind of think of this as a recipe and the outcomes are much better when we combine things like exercise and weight loss with the procedures.
As far as the activity afterwards, you know, we don’t have a lot of research to tell us what the optimal rehabilitation afterwards is. So right now just to be on the conservative side, we typically have patients take about a week after their bone marrow procedure and not use crutches, not put much weight on that joint, to just let the initial effects take place without a lot of joint stimulation. And then we have them transition back into normal walking and gradually return to normal activity in the weeks after that first week.
As far as platelet rich plasma, right now most of the studies out there, they have not had any restriction on activity afterward and so that’s what we’re doing and we’re seeing good results with a lot of our patients. So really there is no recovery afterward [inaudible] have them participate in a physical therapy program, no modification to their weight bearing or activity after the first day or so.
JONATHAN FINNOFF: So in some of the cited cases, you mentioned age is a factor. Is there a particular age or range beyond which either PRP or mesenchymal stem cells are not effective? And if your knee is bone on bone, so you have no cartilage left between the two bones, is there any cartilage to regenerate?
So you know, with almost any treatment -- and this can go across the board, the worse your disease is, the more difficult it is to treat and that’s just a good blanket statement, whether it’s high blood pressure or heart disease or osteoarthritis. So there’s no doubt if you have bone-on-bone osteoarthritis, it’s more difficult. As you age, you are more likely to have the worse osteoarthritis just because you’ve had more years of wear and tear in the area. So certainly, as you age and you have worse arthritis, you may not have as positive an outcome as somebody who had mild osteoarthritis who is younger in age.
As you age, you also have less concentrations of mesenchymal stem cells in your bone marrow, so when you do the bone marrow aspiration and then centrifuge [inaudible] process to try to concentrate them, you might have less stem cells and with less stem cells, there is some data that would suggest you may not have as good of clinical outcomes.
Now, all of that being said, does severe arthritis and older age mean that this can’t work for you? No. I mean, it does not. There’s not a study that says that there’s an age where you can’t do it or a severity where you can’t do it. All that -- all that you can say is it’s going to have a more difficult time to be as effective the worse things are and in the case of stem cells, in particular, the older you are, but it still can help people and certainly, if you have a contraindication or a reason you can’t have surgery, there’s no reason that these wouldn’t be considerations for treatment. What do you think, Dr. Sellon?
JAKE SELLON: Yeah. I mean, I absolutely agree. I think just one additional point to add is that we know that the X-rays [inaudible] tell the whole story and so we commonly see patients who have, you know, very advanced arthritis whose symptoms really are not that bad and so they may just need a -- you know, it may only take a PRP injection to get them some good symptomatic relief. And so I think just because you have very advanced arthritis, these things are still potentially worth trying.
JONATHAN FINNOFF: Yeah, absolutely. So how long does it take to do a PRP injection and how long does it take to do a stem cell injection?
So from a stem cell standpoint, it depends on how you’re doing the stem cell injections and what machine you’re using to process it. Here at Mayo Clinic, it takes between two and three hours to do a stem cell injection, and that’s mainly because it takes time to harvest the bone marrow and to prepare it. The injection itself only takes a few minutes. It's actually relatively quick. But the whole process takes more time.
Beforehand, we talked about I have people off of anti-inflammatories for a week and afterwards I have them stay off of anti-inflammatories for two weeks, again, to try to prevent any [inaudible] of platelets because we’re going to collect platelets at the same time that we’re collecting the stem cells and we want those platelets to work because they’re our fertilizer to stimulate those stem cells to function.
In addition, I tell people to -- I give them a prescription for a pain medication to take about a half hour before the procedure to reduce their pain during the procedure and then while -- after the procedure, I give them some pain medication they can take if they need it since they can’t take an anti-inflammatory. Jake, what about PRP?
JAKE SELLON: Yeah. PRP is a simpler procedure because obviously we don’t have to do a bone marrow harvest and so it’s -- it’s simply a blood draw which, you know, takes a few minutes. The longest part of the procedure is the spin in the centrifuge which can take maybe 25 minutes or so and then as John said, the actual joint injection is often only just a few minutes. So from start to finish, maybe it takes 45 minutes to an hour. And as far as, you know, John mentioned for the bone marrow procedure, we often prescribe medications to make the procedure more comfortable. The PRP procedure is really just very minimal discomfort during the procedure just from the blood draw and the injection which we anesthetize the skin, but we don’t need to pre-medicate for that procedure.
JONATHAN FINNOFF: So thank you very much for your time and attention. We’re really glad that you joined us for this webinar and we hope that you found it informative. We’ll try to answer additional questions that we did not get to in the following week and so certainly submit your questions and we’ll try to field those after this webinar is over. But that ends our webinar. Thank you very much and have a great day.