An educated consumer is a good consumer, and that applies to doctors as well. I was recently asked by an academic colleague who is increasingly being accosted by amniotic- and cord-stem-cell vendors selling live “stem cells” to put together a list of questions to ask them. My list below has questions and answers, and at the bottom of the page is a list of questions to copy and paste and send to your favorite orthopedic sales rep or “stem cell” vendor.
The big problem is that we physicians don’t get cell-based treatment experience or training in medical school or residency, and most of the weekend courses you can take are heavily weighted toward pushing one technology or another. Also the sales reps for these companies are getting increasingly aggressive. My list focuses on what I call the “birth-tissues stem cell industry.” These are vendors hawking amniotic, placental, chorionic, or cord-tissue products and claiming that their vial of magic has viable stem cells. While this stuff may or may not work clinically, the focus of this post is to teach you to be a good consumer of these products so that you and your patients get value. After all, these tissues are very expensive compared to a cheap platelet rich plasma (PRP) shot.
So this is my list of questions you should ask these companies:
- What’s the viability of the stem cells in your product? While this one is simple, this is perhaps the area where companies deceive the most physicians. Live/dead staining is a mainstay of viability testing that’s usually based on a stain that enters the cell to change its color when the cell’s membrane has been disrupted or becomes dysfunctional. For instance, DNA stains, like DAPI, bind to the DNA when the dead cell membrane allows it to pass through. The stain generally can’t make it through the membrane of a live cell. Trypan blue is another standard stain that also won’t be allowed through a cell membrane when it’s fully functional, but it will get through when the cell is dead. Hence, the number of colored cells is a rough metric of how many cells are dead, but they say little about whether the unstained cells can still function. Also realize that these stains aren’t foolproof, as we’ve seen clearly dead amniotic tissues exclude the dye and be erroneously counted as “alive”.
- What testing have you done beyond simple live/dead viability testing? This is a key question, as all the live/dead stain tells you is that the cell is alive, like a patient dying in the ICU is alive. Hence, any company that only shows you simple live/dead stain info isn’t providing enough information to see if its tissue contains functional stem cells. The easiest way to see if the stem cells are alive and functional is to grow them in culture. Hence, the company should report CFU tests that were performed using its tissue, thawed the way the manufacturer recommends. These numbers indicate the number of cells that can survive to form colonies. Also the number of mesenchymal stem cells (MSCs) that survive after a period of time in culture should be reported. For example, if 500,000 viable cells were capable of replicating and the cells double every 2–4 days after a period of 5–7 days to attach and settle in, then you would expect several millions of cells by ten days in culture.
- Is the research on stem cells on your website performed on live birth tissues or your frozen product? One of my favorite bait-and-switch methods used by the “stem cell” birth tissues industry is the fact that they sell frozen material but will often hand doctors literature support that used fresh birth tissues. This switcheroo usually happens when a doctor asks to see data that the product sold by the company contains MSCs. So if you get a paper like this, make sure that you look to see if the product they’re selling was studied or if it was some fresh tissue walked down from the OB ward.
- How do you know that the cells in your product are in fact stem cells? These companies are famous for handing out white papers or brochures listing or comparing the number of cells in their products. However, realize that even in the best circumstances, only a small fraction of the total cells in the product will be mesenchymal stem cells. So total cell numbers don’t equal stem cell numbers. If the company is sophisticated, they’ll provide a flow-cytometry report to quantify stem cells. The issue here is that most of these reports we’ve seen are junk science. Why? To identify an MSC, you need at least six cell-surface markers (CD105, CD90, and CD73 must be present, and CD45, CD34, and CD14 should be absent). Also we’ve seen reports out of universities that are just as invalid as they only tested four markers. Why is this an issue? Many different cell types share these markers, and without this pattern of markers that are present and absent, the numbers being given to you are as likely to represent white blood cells as they are stem cells.
- Is your product gamma terminally sterilized? Gamma irradiation kills cells, and that’s why it’s used in medical products. However, some of these birth-tissue products are gamma irradiated to allow the manufacturer to skip costly sterility testing per donor. Obviously, if the product was gamma terminally sterilized, there are no living cells.
- Has your tissue been tested with human stem cells to see if it helps them? An interesting claim of some birth-tissue “stem cell” manufacturers is that their young tissue will help old stem cells work better. You’ll want to see some data on this using their product as when a 501c3 performed these tests with many different amniotic products, this wasn’t observed in culture. In fact, a stress marker known as ROS (reactive oxygen species) increased in the old stem cells exposed to young amniotic products.
- How do you know your tissue works any better than a much cheaper PRP shot? This is, of course, a fundamental question as PRP is inexpensive and these products are expensive. Hence, simple lab tests comparing the birth-tissue product with PRP and measuring how both stimulate human MSCs are helpful. These lab-based tests were run by a 501c3 nonprofit, and the evidence suggested that the amniotic products tested were no better, and likely less effective, at stimulating MSCs than a low concentration PRP.
- If you’re claiming this stuff has live cells from birth tissues, isn’t that a 351 drug that needs FDA trials and not a simple 361 tissue registration? Yes, it’s all about the regulations. If the company is claiming that their product has live stem cells that could help a patient, then by law it’s a 351 drug and not a 361 tissue. What’s the difference? A 351 cell drug requires full FDA drug-style clinical trials (animal testing, phase 1, 2, and 3). A 361 tissue is a quick registration that happens online without any clinical trials. There is no birth tissue sold today with an orthopedic indication that has a 351 cell drug approval; hence, if the manufacturer or its sales-rep surrogate is making the claim of live cells, then that company is violating existing FDA law.
- If your product has growth factors and no cells, how do those growth-factor levels compare to PRP? When a corporation or provider finally admits that their birth products contain no live cells, the retort is that it’s growth-factor rich and as such is a healing biologic. However, ask them if they have studied the growth-factor levels of their product versus PRP. After all, you have experience with PRP, and you know how that works. So if the GF levels are lower or higher, you likely have a good reference point. When a 501c3 tested growth factor levels in many commercially available amniotic products, they were all lower than PRP.
- If this product is as good as you claim, are you willing to have a nonprofit test it using very rigorous testing that will compare it to other birth-tissue products? It all comes down to put your money where your mouth is, right? While a few of these manufacturers will send their product out for independent testing in highly controlled settings, few will allow them to be compared to other products by an independent group.
The upshot? Just copy and paste these questions (I have them below with more detail and without the answers) into an e-mail and fire it off. If the vendor can answer all of them with ease, you may have found the proverbial holy grail of the birth-tissue “stem cell” industry, a supplier who may have live stem cells to sell. If they choke on these questions like a high school senior asking a girl to the prom, then move on to the next vendor or just keep injecting PRP!
The 10 questions—please feel free to copy and paste:
- What’s the viability of the stem cells in your product? If you have viability testing performed by an independent company or your lab, please send it.
- What testing have you done beyond simple live/dead viability testing? For example, have you grown these cells in the lab after your product has been thawed per your package instructions? If so, please provide that data.
- Is the research on stem cells on your website performed on live birth tissues or your frozen product?
- How do you know that the cells in your product are in fact stem cells? For example, do you have flow-cytometry data that follows the ISCT standards to identify mesenchymal stem cells (MSCs)?
- Is your product gamma terminally sterilized? Is your product sterilized using any method before it leaves its place of manufacture?
- Has your tissue been tested with human stem cells to see if it helps them? For example, has your product been tested as a “stimulant” or adjuvant with older human MSCs in culture? If so, please provide these results.
- How do you know your tissue works any better than a much cheaper PRP shot? For example, has your product been tested versus PRP to stimulate human MSCs in culture, and if so, what are the results?
- If you’re claiming your product has live cells from birth tissues, isn’t that a 351 drug that needs FDA trials and not a simple 361 tissue registration?
- If your product has growth factors (GFs) and no cells, how do those growth-factor levels compare to PRP? For example, have these GF levels been assayed and compared to those found in PRP?
- If this product is as good as you claim, are you willing to have a nonprofit test it using very rigorous testing that will compare it to other birth tissue products? For example, the IOF (a 501c3 nonprofit) has tested many birth-tissue products and compares them to each other as well as to PRP.