New Knee Arthritis BMC Study Adds More Confusion
POSTED ON IN Research BY Christopher Centeno
It's hard for patients to understand that in some fields, academics are way behind their private-practice counterparts. One of those fields used to be interventional spine care, but the academic system eventually caught up. One of those right now is regenerative medicine, where academics are, for the most part, just figuring out which end is up. This can cause some problems, like issues that I've found with a recently published paper on the use of a same-day bone marrow stem cell procedure (BMC) for knee arthritis. So let's review this recent paper.
All Stem Cell Procedures Are Not the Same
Before we get into this recent paper, let me go over the different components of a stem cell procedure that separate a novice from an expert. Why? Regrettably, most of my academic counterparts are still novices. Here goes:
- Drawing stem cells. How you get your stem cells is critically important so that you get the maximum dose of cells. The most common type of procedure used to get bone marrow stem cells is a single-site draw, and more than 90% of physicians who perform same-day stem cell procedures use that method. However, we've known since the 1990s that this reduces stem cell yield. Below is my video on all of the things you need to know to perform these procedures like an expert.
- Concentrating stem cells. More than 95% of physicians practicing today use a simple, automated bedside centrifuge to concentrate bone marrow stem cells. However, as we've seen, this reduces the number of cells available over what we can do in the lab using our proprietary methods.
- Dosing. Ninety-nine percent of the practicing physicians don't count the number of cells, so they have no idea if they have enough cells, which leads to errors in judgment, like treating both knees when there is only enough cells to treat one knee.
- Stem cell injection techniques. Most physicians just blindly inject somewhere inside the knee joint with or without guidance, unaware that placing cells in specific spots (based on the animal modelling) would likely work better.
- Not understanding how a stem cell injection should work. Many physicians using stem cells don't understand basic concepts, like using certain common anesthetics around cells will kill them or using common steroid medications around cells will harm them. They also make mistakes, like not understanding that the concentration of cells in the joint is important, which we'll discuss below.
- Patient selection. Our registry data shows that patients who have arthritis in many different joints may have a stem cell problem, so treating these patients may be harder than treating patients with arthritis due to an old injury.
The New Same-Day Stem Cell Knee Arthritis Study
First, it's always great to see more research on stem cells and knee arthritis, so it was great to see this new one. In this small study, published in the American Journal of Sports Medicine, the authors treated 25 patients with bilateral knee arthritis with bone marrow concentrate (BMC, or a "same day" stem cell procedure) in one knee or a saline placebo injection in the other. The patients were only followed for six months, but the BMC-treated patients didn't report any more relief than the saline-treated patients? Hmmm...Given that this isn't consistent with our experience over the last decade-plus, let's dissect what was done in the study. Here are the issues I see:
- While the authors claim that they used BMAC (same as BMC), what they actually used was a different animal, BMC plus large volumes of PPP (platelet poor plasma).
- The total cell count of the concentrated bone marrow was very low, and the authors diluted this still further. As an example, after placing the bone marrow in a machine, they ended up with 6 ml to inject, which is about triple the size of the actual stem cell layer (which means they had lots of red-blood-cell contamination). More concerning is that they then added a whopping 10 cc of PPP. So if the concentration of stem cells per cc was X to begin with, it was three-eighths X once they injected. Why is this an issue? Multiple studies show that the concentration of stem cells in the knee or on a cartilage lesion is likely related directly to outcome, so by diluting the number of cells per cc, the authors may have reduced the efficacy of an otherwise helpful procedure.
- The concentration of cells injected was very low. The paper lists a mean of 16 million "total MNC" count (which is a subpopulation of the total nucleated cells [TNC]) in the final product injected. They don't list TNC, which is the only metric reported in the literature right now that's been associated with a dose-response in knee arthritis (see our paper on stem cell dosing in knee arthritis). How do we convert "total MNC" to TNC? One paper discusses a conversion factor of about 50% (total MNC + approximately 50% = TNC). Hence, if we take their 16 M cells per ml and add 50%, we get a TNC of about 24 M cells per ml. If we multiply that times 6 (because on average 6 ml was injected), then we get a TNC of 144 M. Even if we round up, this paper used significantly less than the 400 M TNC per knee that we defined as the lower limit for a positive pain outcome in our paper.
- The bone marrow aspirate technique was not the best for maximizing yield. Near as I can tell, they used a single puncture site and withdrew 26 ml of bone marrow and redirected the trocar three times. So through a single cortex site, they drew three X 8–9 ml. We know based on multiple papers that lower volumes from multiple cortex sites produces more cells (see video above).
- They used the wrong anticoagulant for bone marrow. In our experience the ACD they used is a poor anticoagulant for bone marrow as it often produces clots. Since they used a machine to process the bone marrow, they would have no idea if they had clots in the marrow. However, clots rob cells, so this may be one of many reasons the number of re-injected cells was low.
- The choice of treating bilateral-knee-arthritis patients was not ideal, as our registry research has shown that patients who have three or more joints involved don't fare as well with these procedures, likely due to a systemic stem cell problem. While they don't report any info on other joints, it's likely a safe bet that a significant portion of patients with bilateral knee arthritis have arthritis in other joints as well.
- The authors didn't rule in or out other causes of knee pain. Given the recent research on the number of patients undergoing knee replacement who do more poorly because they have a low-back problem, this could be a problem.
- The fact that one side was used as a treatment and the other as a control is a big "no no". Let's think about this practically. If I have one knee that got treated and swells after a stem cell injection (common) and the other doesn't after a saline injection, the test subject will know which knee likely got the placebo. This then invalidates the "blind" part of the study. In addition, any positive or negative changes in one knee impacts the other with regard to activity. Suffice it to say that while this study deign was likely chosen because it made recruitment of the study faster, it's a bizarre and problematic way to perform knee arthritis research.
There are other issues with the study, but those are the big ones. Again, one of the problems that we see is that we have many physicians who learned their craft from a weekend course and thus make basic errors. In their push to expand kit sales, manufacturers of bedside units have tried to distill procedural education to a few hours, which only reduces the likelihood that these procedures will be effective.
The upshot? I'm not sure that this study tells us much other than a strange variation of a low-cell-count, same-day stem cell procedure where the cells are combined with 10 cc of PPP when used in patients with bilateral knee osteoarthritis (OA) didn't seem to work. I look forward to other studies!
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