Section: CME Category: Wound Care

Mesenchymal Stem Cells Bone Graft Infusion or Defect: Experimental and Clinical Use

Sheldon Lin, MD

Sheldon S Lin, MD discusses the rate of nonunion with arthrodesis and how the use of bone grafting has significantly reduced these rates. Several papers are discussed that support its use.

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Goals and Objectives
  1. Understand the clinical challenge of foot and ankle arthrodesis
  2. Explain the risk factors and morbidity of autologous bone graft
  3. Discuss the clinical options available for foot and ankle arthrodesis including PRP, MSC, autograft and allograft
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  • CPME (Credits: 0.75)

    PRESENT eLearning Systems, LLC is approved by the Council on Podiatric Medical Education as a provider of continuing education in podiatric medicine.

    PRESENT eLearning Systems, LLC has approved this activity for a maximum of 0.75 continuing education contact hours.

    Release Date: 03/16/2018 Expiration Date: 12/31/2020

  • Author
  • Sheldon Lin, MD

    Chief of Foot & Ankle Division and Associate Professor of the Department of Orthopedics

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    Sheldon Lin has disclosed that he is a consultant for BMTI of Wright for rhPDGF and is on the advisory board for Tissuegene.

  • Lecture Transcript
  • TAPE STARTS – [00:00]


    Male Speaker: I’m pleased to welcome Dr. Sheldon Lin back to the podium to speak about Mesenchymal Stem Cells Bone Graft Infusion for Defects. So, let’s welcome Dr. Lyn.

    Sheldon Lin: Thank you, thank you very much.

    Male Speaker: Okay.

    Sheldon Lin: Appreciate it.

    Male Speaker: Okay.

    Sheldon Lin: I want to first thank the audience it’s three o’clock. If we were in Spain this would be siesta time and be like bye, you know, it’s time to go get some rest. But on the other series, there is another alternative if you can’t get Gentian Violet, it’s Kat Alanis paint, a purple stuff. It’s same idea, antifungal, antibacterial.

    Today, we’d like to talk about is bone and I’d like to give my disclosure. The agenda really is to understand the clinical challenges for arthrodesis and basically some of the risk factors obtaining the bone autografted and what alternatives we have in the clinical arena. I mean when patients come in, they basically provide us an interesting challenge. When I first made this talk, I said, that’s my wife, what do you think. We talked about osteoconductive, osteoinductive and my wife says, my god, you’re going to bore me to death. I go, you’re right, let’s go to Google instead and let’s just type in the words, I mean this is what Google, this is what our generation, the kids there will get. Osteoconductive, a material that facilitates the formation of bone. I thought that’s interesting. And if you think about it there are many agents out there that really conduct bone, calcium phosphates, sulfates, these various collagen composites DBMs and many commercial name, I’m not going to bore you.

    In addition, if you type into the almighty Google and you say, okay, what is osteoinductive instead. Well, actually it’s any substance that stimulates bone formation. I go, wait a minute, I know what that is. This is autologous bone, allogeneic bone, blood concentrates or bone marrow. So, these are agents. So, with that in mind, I’d like to go and start off with this agenda.

    What’s the clinical challenge, what’s the awareness of the risk factors while obtaining autografted and subsequently what are the options. If you’re looking for an ankle surgery, arthrodesis of the hind foot but it remains the gold standard because unlike let’s say, a hip or knee due to the gait and mechanical role, it’s really critical.

    Here’s an example. My chairman always said to me, Sheldon, there’s nothing worse than a complication but seeing your own complication. This is a picture of my own social worker. I see her every day on the floor, diabetic, sustained a subtalar fracture dislocation due to Charcot. I said, let’s do a triple and stabilize it. So, we reduced it, the diffusion, and over time it does not heal. And every time I see her go, how you doing? Oh, it still hurts. It never healed. It still hurts. Thanks doctor. And I smile and I walk away going oh, my god, I got to change hospitals.

    If you look at the articles out there, Carol Fry’s a series of ankle arthrodesis had one of the highest nonunion rates, 41%, the worst in the literature. Again, majority were posttraumatic and specifically plafonds and talus fractures. Dr. Mark Easley, my good friend down at Duke looked at Lou Shawn and Mark Myerson series, 184 consecutive subtalar fusions. Well, even these in these expert hands, a 16% nonunion rate, higher other than [indecipherable] [00:03:07] smokers and higher in redo cases.

    If you look at diabetics, and folks say something. This is hard to do. You got to take a picture in the subway getting the light perfect and then explaining to the young lady why you’re taking her picture. But basically Papa [indecipherable] [00:03:24] 15% to 30% nonunion rate in diabetic elective arthrodesis. Nathan Artisan [phonetic] at Cedar tried to understand this and using DBMs specifically 63 cases using graft, putty and orthoblast, got this rate down to 11%. So, let’s sort of step back.

    We know we’re trying to achieve an ankle fusion. The nonunion rate is around 15%. It’s going to be higher in certain subsets we mentioned them before, smokers, redo’s, AVN’s, diabetics and despite your best technique, nonunion remain a common postoperative complication.

    So, if you think about it, what do we have as alternatives? Autograft, allograft, we’re going to talk about this? If you step back you think about it, you can try to prepare the fusion site. Do the best job you can. You can try to minimize soft tissue stripping to minimize the devasterization, get adequate exposure to get all the cartilage at cap to get raw bare bony bed and perforated to promote bleeding and hopefully with rigid internal fixation compression, you try to achieve that picture on the far right. But, you know, there are smokers, redo’s complications like AVN, diabetics. This is the challenge. So, the question I would throw at you, I want this, can I use the triad, triad of cells, the triad of a scaffold, the triad of time with the appropriate growth factors to achieve a successful tissue regeneration and bone healing.

    [00:05:00]

    So, I want to do is really go over this and see what we can do to help our clinical practices. First thing, the gold standard, we all know is autograft, but it comes with a price. Where do you get it, from the hip, the shin, the heel? There is this price. It does provide your stem cells. It does provide matrix growth factors over 300,000 plus undergo iliac crest harvesting annually throughout the United States. But with it comes pain, scarring over time, blood loss, infections, hernias, surgical complications. There’s nothing worse than a complication, but then your own. Let me show you some of my own. May be a little too aggressive here. I took her iliac crest, required a mesh, got infected. Here’s some cases. I’ll tell you, it’s pretty humbling when you see your own complications.

    Gupta looked at a series and the copy he showed is as high as 31% and what really makes it worse is this. Patients will come in after a triple ankle fusion and says doctor "my foot feels great, thank you so much, but my hip hurts so much." Twenty-seven percent of the patients still reported pain even at the two-year mark at the donor site. It tells you we need an alternative and I want to really go over this with you, what are the alternatives we can do.

    So, we know there is this complex cascade involving a bone formation. So, I asked myself, I like to step back and say what are common questions? First, what are the growth factors commercially available to an orthopedic surgeon or any surgeon? Autologous platelet concentrates, the various growth factors. If you type in platelet-rich plasma and I just say hey, what did Google say, that’s always interesting. I apologize, little here we go. It shows that this is a practical application for tissue engineering, that’s not good enough. And what you really look at is a concentration of growth factors from the blood. I say that’s interesting. Well, to me is simply a system designed to separate platelets from the patient’s own blood at the point of care. And whether you centrifuge or let’s say a filtration method, these are techniques that really allow you to generate and obtain a concentration platelets 5x, 7x and these various growth factors about 70% is PDGF and we’ll talk about PDGF tomorrow. And by activating it, these release these critical growth factors at the wound whether you cut yourself, whether you have an Achilles tendon rupture, whether you have a fracture or a fusion site. There’s no low folks. There’s data. So let’s look at the data.

    Marks, down in Miami Florida looked at 88 patients with mandibular discontinuity. And what made something really interesting for this oral and maxilla surgeons, they come back to put in the artificial teeth. They get to do a punch biopsy of the bone. So, here we are. He looked at two groups; patients with graft alone, no PRP; patients with bone graft and PRP, wait six months, do the punch biopsy, put in the artificial teeth, interesting. The amount of bone in the punch biopsy was significantly greater than those who got PRP. When he showed these two methods, very interesting. Let’s look at the literature. So, I try to do a study looking at the effect of PRP. We looked at 62 patients, 123 operative procedures. These are patients having fusion, 69% were high risks, smokers, diabetics, mean age is 51.

    And we looked at in combination with various agents and then when we were done with the study, we got it published. I said that’s interesting, but I realized it wasn’t scientific. So then, my good friend Chris Cozzia [phonetics] out in Minnesota says, Sheldon, I got a better study for you. This is a phase-three study, a comparative cohort looking at the agility total ankle. Now the agility total ankle is now passé, but it required a tib-fib arthrodesis in order to maintain a stable bed. And by doing this, they compared bone grafting alone between the tib and the fib versus PRP with the bone graft, 66 versus 114. And the data is interesting at 8, 12 and 16, you can see patients that got PRP with bone grafting who are statistically higher at 8 or 12 weeks. Even more interesting, the ultimate nonunion rate was 15% bone graft alone, 15 doesn’t shock me, 3% in their series. If you really tease it out, it even gets even more interesting for those who are smokers.

    Now, there’s been articles out there looking at platelet gels or platelet-rich plasma. This is the article by Delarie and Zia Ijaz [phonetics] on High Tibial Osteotomies or HTOs. Three groups; platelet gels with bone chips; platelet gels, bone marrow aspirate and bone chips; and finally bone chips alone. I think a picture’s worth a thousand words. You could see here, bone chips alone is that bottom row looking at radiographic scoring at 3 months, 6 months and 12 months. The group above, PRP with bone chip or PRP with bone marrow aspirate and bone chip statistically better. You’ve seen a picture on the far right there, that’s bone chip alone. You still see that HTO, it did not heal.

    [00:10:00]

    But other than that the record is somewhat limited and recently at the AAOS, they had this meeting looking at what is the role of PRP and they could not come to really a consensus. The track record is poor. We don’t have enough studies. There’s recently been transferring increasing use for soft tissue and, you know, osteochondral lesions, but the data is still not conclusive. Here’s an article from JOT looking at platelet gels supplementation in long bones treated with X-fixes, no effect.

    Let us switch gears. If you look at bone marrow aspirate and we’re here for regenerative medicine and you look at what is Mesenchymal Stem Cells? Just type it at the almighty Google. Oh, typo there. And what they say is a Multipotent Stem Cell that can be utilized to generate a variety of tissues or cell types. The classic article should be from Hernigou, in which he looked at patients having percutaneous autologous bone marrow aspirate with concentration for tibial nonunions. These patients have a tibial nonunions, all they did was to inject bone marrow at the site. And out of the 60 patients, success was achieved in 53 out of 60 just with a single injection. The key word is concentration. They are able to get the cells concentrated to about 19,000 osteoprogenitor cells CFU/mL. And what’s fascinating, there is a critical number because the seven patients that did not heal and these are the people out of the 60 something had healed, their bone marrow concentration level was only about, I think was like, 600. So, therefore it demonstrated there’s a critical value that’s needed in order to have an effect. The question I would, basically from this literature say, is there a critical role? What is the critical size of the graft?

    And I’ve had the honor of working with Chris DiGiovanni, we’re trying to answer this question over in Mass General. Showed a piggyback off of the augment trial or rhPDGF trial, we looked at really 573 joints, 383 managed with rhPDGF-BB/TCP and 190 with autograft. What’s interesting with this study, we took a CT scan at 9 weeks and then a CT scan at 24 weeks. So, we asked ourselves, at nine weeks, if the surgeon did an inadequate job, in other words, it wasn’t adequately filled, will that have an impact. We defined adequate fill, if it fits over 50% of the fusion site. So, CT scan at nine weeks wait, wait, wait, wait, wait, decide here’s two groups; adequate fill, inadequate fill, what is the result? That was the basic question.

    Here’s the answer. Out of this 573 joints with adequate fill, 81% went on to union. But if you had inadequate fill, only 21% achieve union. Odds ratio was 16.4. That to me was very interesting. Again, fill does matter. I mean here’s the Table 2 that really shows it very well and you can see there, top row, if you had an adequate amount of graft material, our study show it didn’t matter with this TCP allograft, autograft. If you had adequate fill, 81% success. If you had inadequate fill, you’re down to 21% with an odds ratio of 16.4, fill matter. Actually, I showed that to my misses and she goes "hmm, so size does matter, I don’t know."

    So, the question comes out is what are the types you could fill. We know there are orthocomposites. We know autograft exists. We know allograft exists. But in reality, there are differences. Chris Chiodo at Boston, he actually looked at this, my good friend Chris. He says, is there a difference and they looked at an iliac crest versus tibia and sure enough you see the top is iliac crest, the bottom is the distal tibia and really the iliac crest has lots of active hematopoietic marrow, in contrast the tibia was merely just fat.

    And Chris Hyer working with Greg Berlet and Tom Lee over in Columbus also answered this question. And they wanted to measure specifically the number of osteoblasts connective tissue progenitor cells. In other words, look at the ones that actually make the bone. If you look at this picture, you see the top row when the shock is iliac crest, the bottom is a distal tibia. So, you can see that how this is an L zone red staining for mineral. If you have bone marrow from the iliac crest, there are a lot more osteoprogenitor cells compared to other sites, whether it be the distal tibia or whether it be the calcaneus. So, let us step back, think about this.

    [00:15:00]

    Fill does matter for the fusion. Number two, it doesn’t matter what type material you place at the site. There is a difference that exists with iliac crests and other sites in regards to osteoprogenitor cells. We’ve seen from the article by Hernigou that bone marrow does seem to be able to be effective in treating nonunion, although it was injected, 53 out of 60, but the keyword is they concentrated to achieve a critical value. And with this, you know, I think that this shows you that this is the power of what’s available in the clinic arena for your patients who may have nonunion or the challenge.

    Now, let’s sort of switch gears a little bit more and say, let’s say you’re not an autograft person. I don’t want to deal with that patient complaining of pain, pain, pain for two years. Can you use allogeneic stem cells? Recently, there’s been several articles showing the role of allogeneic matrix, allogeneic stem cells. We recently-- I had the honor of being asked to be an editor for foot and ankle clinics in December of 2016. And in this article we had the clinical series from Sam Adams working at Duke as well as Chris Cozzia looking at allo-stem and they achieve the success of 83% and 86% in subtalar arthrodesis using allogeneic bone graft for elective arthrodesis. So, again these are products that are commercially available, you get it off the shelf, you place it aside, this is allergenic bone graft that can help your patient.

    I’d like to show you some cases. A 30-year old lady, sickle-cell had talar dome AVN with increasing pain and arthritis as shown here. The question is, you know that she has AVN, you know there are problems, she has sickle cell. What can we do to heal this? I say well, bone marrow’s supposed to help. Let’s give it a try with graft. I’d like to do a transfibular approach. I like to do the iliac crest aspiration. We obtained the graft that we soaked it and subsequently we placed the bone marrow on to the graft. And then sort of you know, let it sit there for 20 minutes or so and then we use it to pack it into the site. And you can see here packing fill matters, packed more bone graft in there and then I used to do a homerun screw with an onlay fibular technique.

    I’d like to show you another example. A 19-year old patient came from AI DuPont. He had triple arthrodesis previously when he was a young child for clubfoot. His talus collapsed, it’s gone, I mean he’s got a successful trip, but but look at that ankle joint it’s gone. I said, you know you’re young, you’re 19, shall we do a total ankle kind of young. I don’t know, I don’t have an experience at that young age. I go, why don’t we do a fusion. So, I thought previous surgical site, he’s already had changes and don’t want to do a total ankle, let’s do a fusion. So again, allograft, bone stimulator, put the screws in, just saw him. He’s at a 10-year mark, no pain, feeling great.

    So, let me step back and summarize. One, we could show that there is a critical amount you need to fill at your fusion site. And you had to have adequate fill and with adequate fill, you will achieve success with an odds ratio of 16:4 compared to patients who you do an inadequate fill. It doesn’t matter what type of material you place in there, what type of ortho biocomposite, whether it be allograft, autograft or any other material, but you just got to have something that the body can work with to bridge the site. This is what the data says. There are differences that do exist in regards to osteoprogenitor cell, you’ve seen from Chiodos’s article, from Chris Hyer’s article in regards to the osteoprogenitor cell that if you can obtain from the richer sites up by the iliac crest that’s better. And finally that these are options that are available in the clinic arena for those patients that will challenge you. Thank you very much.

    Any questions in the audience?

    Male Speaker: I have one.

    Sheldon Lin: Okay.

    Male Speaker: Excuse me, I have one. How much is, how much is adequate?

    Sheldon Lin: So, you can see here based upon our study, we had defined it as on a sagittal cut over 50% being filled is defined as adequate. And by having 50% or more filled, it led to 80 plus percent success rate at 24 weeks out, compared to having inadequate fill, it was down to 21. When I work with my team, I sit there and I will debride the site, I’ll take a liber or a pick and just perforate that. Let’s say the subtalar fusion, the talus, the calcaneus, 10, 12 holes. I’ll then say to them let’s just stuff the site, we will stuff some stuff. Then I take a bone tap and really pack it again. I go, let’s stuff it again twice.

    [00:20:00]

    You want to have more matrix to fill the site than what you think is adequate.

    Now, someone said to me, what is the amount you should put in? So, I’m going to step back from data, the rhPDGF trial had demonstrated that the average amount for a single joint was around 3 cc. So, I usually have this little metal shot glasses, that’s about 3 cc folks. If you pack in there 3 cc per joint then it’s about appropriate, but clearly somebody who is 6 foot 8 inches, like Elijah one versus somebody who’s like my size, I mean there’s relative difference. There’s going to be a relative amount of difference, but average joint is around 3 cc. One of those metal shot glasses.

    Male Speaker: Do you ever spin your BMI at all with this highfalutin centrifuges?

    Sheldon Lin: Do I ever spin the bone marrow?

    Male Speaker: The BMI, do you ever spin at the centrifuges with this highfalutin ones that they’re advocating now to get like a higher concentration at the--

    Sheldon Lin: Right, so what you’re asking is there are the ability through increasing time, through higher spin speeds to get 7x, 9x concentration of, for example, PRP. And I don’t have any experience. I know Steve Arnosky had talked about has a potential role getting to that level 7x and it actually looks like a matt when it’s spun that thick that high. And because I’ve worked with the veterinarian and he uses it in his dogs, but I don’t know of any data showing a major difference of like the current 5x, 6x versus 9x concentration, to tell you the truth. So, I mean I just don’t know of any major difference. See the PRP area is actually very controversial because there are three major problems or they were questions I should say, is that leukocyte rich or poor, should use it with or without fibrin, how much you should concentrate, what is considered too much. So, those are the three questions that comes with the PRP application.

    Male Speaker: And we’re trying to get it from the heel not the hip because of the pathology there in the hip. So, you know, you want to get the most bang for your buck. So, the saying uses like high-energy centrifuge and you’ll get a richer BMI, so.

    Sheldon Lin: I think the better question is how many osteoprogenitor cells, CFUs will you get at the site that you obtain your bone marrow sample. That’s because if you think about it, if I go to the desert and I try to extract water from the sand and there’s not much water to begin with versus let’s say, go to Jersey here at Teaneck and I suck water from the soil, there’s a lot more water. So, I think that ultimately the better question is how many CFUs are at the site that you can obtain for harvesting CFUs.

    Male Speaker: I have a question, you were I guess a co-author, co-investigator for the DiGiovanni trial, the augment trial, which showed that the augment, which is I think beta-tricalcium phosphate and recombinant human PDGF. The fusion rates for ankle and hind foot were equivalent to autogenous bone grafting.

    Sheldon Lin: Correct.

    Male Speaker: Do you think that that’s a reasonable substitute then to engender fusion on these complex fusions or--?

    Sheldon Lin: Well, I mean clearly that’s part of my lecture tomorrow, but I think that, that study, which was looking at 437 patients was powered to demonstrate is rhPDGF/TCP equivalent to autograft. And the data shows that it is, I mean I have used augment many, many cases and the results are about the same as autograft. I mean the data supports the concept that what you have is an equivalent. And I’ll be honest with you, the reason why it’s important to know this is that, I have patients come into me and they’re like, I wear bikini and I don’t want a scar near my hip. I don’t want any other scar, I want something that you can pull off the shelf. I just want a pain at wherever you do the surgery, but I don’t want another donor site pain. And so, now you’re sort of stuck saying I can get something off the shelf, I can allograft oh, that’s somebody else’s bone, I don’t want theirs either. So, now you have an alternative and I’m pleased to say that the FDA reviewed the FDA phase three trial and subsequently gave approval in I think it was October 2016, but yes it’s been a relatively interesting run.

    Male Speaker: Since we have so many veterans who are also worried about bikini scars and due to the result of the augment trial although I was a little perturbed there were no podiatrists listed on that trial. So, I don’t know if you had any. But we’ve incorporated augment into our fusions and we do quite a few ankle and rear foot fusions, but we still get a number of nonunions. Is that because -- we packed them with the augment with bone chips as if we’re not packing enough? Do you think that that might be one thing?

    Sheldon Lin: So, first I would say that…

    [00:25:00]

    I would say that Chris Hyer’s part of Tom Lee and Greg Berlet Center was one of the investigators of the augment trial…

    Male Speaker: Good.

    Sheldon Lin: …who is a podiatrist. So I mean just we pick 37 sites so that had the PI of the site and some their own like secondary investigators to go with the site and just that’s the way it sort of played out, but I’m pleased to answer, yes we have podiatrists there. But in regards to your question, you know, if you look at the nonunion rate of that trial 437 patients, whether you had autograft or rhPDGF/TCP, the nonunion rate ultimately end up being 7% by CT, read by an independent radiologist Peter Evangelista, which is low. And I think that, you know, the one thing is that it is not the panacea. So, the key word is, and you’ll see me talk about this tomorrow, rhPDGF is not a differentiating agent. It does not induce bone. It is an osteoconductive agent, it’s mechanism of action is totally different from a BMP. I mean, so I think that yes, there will be patients that will have a nonunion. But again, the data has shown and I just look at data from the 437 patients, it’s been equivalent and we haven’t really seen a major, you know, what do you call, high value I mean that’s not --

    Male Speaker: Maybe it’s just technique or so or maybe diabetes and smokers which we have a high prevalence for--

    Sheldon Lin: Well, so I’m also going to throw one little thing is that, if your center is predominantly diabetics and smokers, you know you’re already in a high-risk population. In the classic, in this study of 437 patients, I think the amount of diabetics was of down into 3% or 4%. We did not want to analyze this and throw that as a variable and that could be the main reason why you’re seeing in a higher complication rate is that these are high-risk population. But again, what I would entreat to the audience is, it shows you we need more literature or better studies in that high-risk population like a diabetic. And maybe rhPDGF/TCP has maybe, it’s inadequate to kick to resolve this diabetic subset population problem. So, I don’t have a magic answer for you. I’m just sort of theorizing why.

    Male Speaker: Fine, fine, fine. Thank you.

    Male Speaker: Any other questions?

    Sheldon Lin: Any other questions. So, thank you very much for the opportunity. Thank you for staying awake as this is always critical and hard at 3 o’clock.

    Male Speaker: We’ll hear more tomorrow.