The entire “birth tissue in a vial” industry is based off one simple concept. As a doctor, you’re not buying a bottle of amniotic fluid or cord blood; you’re buying a vial of large numbers of young stem cells. This is why 1 cc of this stuff sells for $1,000–$2,000, much more than the current price of gold. However, what if this wasn’t true? What if this whole house of cards came tumbling down? Let’s review how new lab data collected on the new Liveyon PURE product impacts this sales pitch.
Buying Vials of Lots of Young Stem Cells?
The cost of amniotic fluid or umbilical cord blood is about $1,000 per 1 ml. Given that there are 28 ml of liquid on average in an ounce, that’s about $30,000 an ounce. What sells for that much? Not gold, as that’s currently only $1,306 per ounce. It is cheaper than plutonium at $4,000 a gram.
If we had copious data showing that these products are miracle-cure treatments for things like arthritis, then the cost may be justified. However, we don’t have that data. Or maybe if we knew that these products contain a substance that can’t be found elsewhere in the body and that this substance was proven to have miraculous effects on diseases like arthritis. We don’t know that either. Or maybe if the products have very high growth factor levels that can’t be obtained by things like platelet-rich plasma. Nope, also not true. In fact, a simple platelet-rich plasma shot made from your own blood generally contains higher growth factor levels than this stuff. So what drives this ridiculous price? The hype surrounding mesenchymal stem cells.
Different Stem Cell Types
There are a few stem cell types that have been discussed and researched when it comes to treating orthopedic problems. The two big players are mesenchymal stem cells and hematopoietic stem cells. Let’s start with the last one first and work backward.
Hematopoietic stem cells (HSCs) live in our bone marrow and produce blood cells. They can also substitute for muscle satellite cells (read muscle stem cells), so they may be helpful in treating muscle injuries. However, suffice it to say that HSCs, while possibly important in muscle repair, aren’t the “big kahuna.”
Mesenchymal stem cells are the all-star triathlete of stem cells when it comes to orthopedics. Multiple studies have shown that these cells are promising treatments for everything from arthritis to tendon/ligament repair. Other studies have shown that the dose of MSCs in various therapies matters for producing a good treatment outcome. For example, for therapies like bone marrow concentrate that have MSCs, the patients who get a higher dose of their own MSCs (as measured by CFU-f) get better results. So when birth tissue companies are peddling amniotic fluid and umbilical cord blood/tissue as “stem cells,” some of them fall over themselves to claim that these products have lots of mesenchymal stem cells (MSCs).
Liveyon voluntarily recalled its first-version products from the market due to bacterial contamination. Everyone from the FDA to the FTC weighed in on this debacle. Shortly thereafter, it launched a new product called “Liveyon PURE.” For this new product, the company didn’t lay off the idea that the product had stem cells as the generic term is used throughout its marketing. For example, its new white paper says, “The data describes percentages of positive cells for each cell surface marker suggesting that the product contains B cells, endothelial cells, HSCs, MSCs, and a variety of immune cells.”
Hence, Liveyon, like many companies claiming that their products have stem cells, has the term “MSCs” in its marketing. In fact, in one product brochure that Liveyon recently released, the term “stem cell” is used 6 times in the PDF. On the Liveyon PURE website, the term is used 10 times. In fact, Liveyon describes the product as “a clinical trial grade stem cell concentrate derived from umbilical cord blood.”
So if the product has many young MSCs, it may be worth 20–30 times the price of gold. If it doesn’t, that could be a problem. Why? We have no or poor clinical data that umbilical cord blood would be a valid treatment for anything in orthopedics.
Our New Liveyon PURE Series Testing
We decided to run another round of tests on multiple umbilical cord products, all from companies that claim live MSCs. This is a follow-on to the first-of-its-kind research we presented at the IOF meeting in 2015. Since then, other authors have weighed in on the stem cell content of many birth tissue products (Lisa Fortier’s lab at Cornell, UC Irvine Lab). In addition, many new products have entered the market, so it was time to update our tests. In addition, if any of these products actually had many live MSCs, as a medical network focused on regenerative orthopedics, we could potentially be a big customer.
The game plan that we formulated was that we would first test a few vials in our university-equipped lab to dial in the experimental protocols (which tests we thought were needed). Then, we would ship the rest of the vials up to the CSU Orthopedic Research center for the final tests. We began those tests last Thursday.
Does Liveyon Have Live Cells?
Liveyon claims to have viability in the mid-80s. What does that mean? Check out my video below to better understand:
We tested the viability of the Liveyon PURE product, and using both Trypan Blue and a fluorescent stain (Sytox Red/Green), we found that the viability of the product was in the mid-60s. We also plated the cells in culture medium and let it sit for 24 hours in the incubator and were pleasantly surprised to find that the cells were, for the most part, still alive. We didn’t check further after that time point, but that will be done on subsequent vials of Liveyon product that will be tested at CSU.
What are these viable cells? They likely are what the white paper states: “B cells, endothelial cells, HSCs, and a variety of immune cells.” I would likely add in blood progenitors. Note that I deleted MSCs from this list, as that’s something else we tested. More on that below.
The big question here for providers is twofold. First, there is likely not much that survives in Liveyon that can’t be found in the patient’s own bone marrow. Second, unlike the patient’s own bone marrow, these foreign cells can provoke an immune rejection reaction in the host. This is why umbilical cord blood used to treat pediatric cancer is also HLA matched, like a blood transfusion. Hence, with these living cells, there is a real risk of a serious immune response.
How serious is this risk of donor mismatching? This is from a recent paper on the topic:
“the risk factors like the donor/recipient mismatching and cell dose, are probably amplified by the effect of multiple transfusion exposures, that might sensitize the recipient to donor alloantigens.”
Meaning that repeated injections of cord blood can create an immune response to the foreign cells. This is made worse by a higher number of cells (in this case more in the vial and higher viability) as well as multiple treatments. That last part is key, as patients in the real world are often getting exposed to many injections over time to treat their ailments, all from different donors. Finally, the paper above describes cases of pediatric deaths due to graft vs host disease (GVHD) in mismatched donors.
Does Liveyon Have MSCs?
The biggest test of Liveyon for our medical provider network was whether the product has MSCs. After all, many of the other cells we would be interested in for orthopedic therapies (like HSCs) can be found aplenty in the patient’s own bone marrow. From listening to sales reps talk about these umbilical cord products or how medical providers then sell them to patients, you would assume that they contain millions of live and functional mesenchymal stem cells. Or if the company or clinic doesn’t quote a number, they often use a statement like this one form the Liveyon PURE FAQ:
“Yes, age definitely matters. In Vitro research by the International Journal of Molecular Sciences has shown that while young, vibrant umbilical cord stem cells can duplicate themselves every 28 hours for up to 65 generations or more, 50+ year old bone marrow aspirate and adipose-derived stem cells duplicate at a much slower rate of 3 to 5 days for an average of only 11 to 13 generations. Also of note is that older cells undergo senescence (aging) at a much faster rate than young, vibrant umbilical cord cells…”
What’s being discussed here is the number of MSCs, which declines as we age. Liveyon has even taken that one step further. They claim that their cells are rapidly proliferating and grow for up to 65 doublings!
So does Liveyon’s second product have MSCs? We plated Liveyon PURE at 30,000 nucleated cells per cm2 in monolayer culture (FBS+AMEM+bFGF) and we also plated bone marrow concentrate from a middle-aged and unhealthy woman (poor activity levels for years due to injury). So this test compared, head to head, the number of MSCs in Liveyon to an aging woman. The result? You can see that below:
Note the microscope screen on the right. The spindle-shaped cells are the beginnings of MSC colonies after seven days in culture. Note that in the screen on the left, you see none of these spindle-shaped cells. While we won’t stain these samples until the end of this week, at seven days in culture, the differences were obvious. There are no cells that look anything like MSCs in the Liveyon sample. The bone marrow from the middle-aged woman in poor health has many areas where there are obvious MSCs. Meaning at seven days, it’s clear that Liveyon is an MSC-poor product compared to bone marrow from an unhealthy woman.
Why Didn’t We Find MSCs in Liveyon PURE?
While you can get MSCs from cord blood, it’s very hard to do and requires isolation and culture expansion of the MSCs. Because MSCs are so rare in cord blood (not found in 80–90% of donated cords), you have to input a bunch of blood from different donors (or reject the individuals’ cords without cells) and then use a special separation and isolation tool (which is not FDA approved for human use) just to get a few MSCs. Then you have to grow these in culture to get enough to be clinically useful. See my video below for more information:
If This Product Has Some Live Cells, Is It an Unapproved Drug?
The short answer is yes. Don’t take my word for it, take the FDA’s from their recent press release on the Liveyon Regen Series that was actually manufactured by Genetech and pulled from the market:
“These products were distributed by Liveyon in Yorba Linda, California as ReGen5, ReGen10 and ReGen30. The Genetech products are not intended for homologous use (products that are intended for the same function in the recipient as the donor), and while the products have a systemic effect, they are not intended for allogeneic (genetically similar) use in a first or second-degree blood relative. As such, the products are regulated as both drug and biological products.”
However, that hasn’t stopped the company from continuing to claim that its product is now somehow a 361-registered tissue rather than a drug. What’s the difference? If this is a drug, the product requires FDA approval for every medical indication, which requires tens of millions of dollars in clinical trials for every diagnosis. If it’s a tissue, it’s a free 45-minute registration that FDA neither approves nor clears. Liveyon has no clinical trials.
How is the company now able to rationalize that this is only a tissue that gets a pass on FDA clinical trials? Look no further than an e-mail recently sent my way by a physician who challenged one of their sales reps on this issue. To understand his response, you need to know that the actual regulation to determine if your product is a drug or a tissue says this:
“The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function…”
Meaning, your product can’t work through living cells that would have an impact on the whole body. Since Liveyon has living immune cells, it’s very clear that these would have an impact on the whole body. So what’s the take of Liveyon sales rep Greg Williams?
“The key word here is AND. Both systemic effect AND dependent upon the metabolic activity of living cells.
Yes, there are live cells, but we do not market, advertise, label or promote our product for systemic use. Legalese – but since the product meets only one of those two items, it still is compliant per Section 361.”
Here, Liveyon has turned the regulation on its head. Instead of the cells having a systemic effect, they claim that the word systemic apparently applies to the treatment route? Here, Mr. Williams seems to be referring to an intravenous injection which the company doesn’t recommend. I ran this interpretation of the FDA’s 1271 regulations by a regulatory attorney this morning. He laughed. Why? The statement from the 1271 regulations quoted above clearly relates the word “systemic” to a property of cell action (HCT/P). More importantly, the FDA has already weighed in on Liveyon’s claims of umbilical cord blood not being a drug (see above). The agency concluded that their first product was a drug because the cells had a systemic effect and were not from the patient and were not being used for the same purpose that the donor’s body used them (non-homologous).
Might Umbilical Cord Blood Be the Best Thing Since Sliced Bread?
I obviously can’t rule out that some future study shows that umbilical cord blood, when injected into joints, for some reason we don’t yet understand, can help arthritis. Or that it’s good for some other ailment. However, sitting here in early 2019, we don’t have that clinical data. In fact, the medical providers who are using this stuff are using the data on bone marrow or fat orthopedic treatments where living mesenchymal stem cells are used and claiming that those treatments are like theirs because both have MSCs. However, our new data here and that collected by others would suggest that there are no MSCs in umbilical cord blood products, like Liveyon, or at least that they are MSC poor compared to bone marrow.
The upshot? Round one of Liveyon PURE testing didn’t find what was advertised. In particular, the MSC content discussed in the company’s white paper and FAQ is not supported by this test. We will be testing more Liveyon samples as well as other umbilical cord products next week, and then we’ll be sending more samples to CSU for testing this month.