I can’t keep up with all of the new umbilical cord products entering the market. Because these are all only registered without any FDA approval, the ability to get a product to market is almost instantaneous. Today I’ll review the new product produced by Signature Biologics called “Signature Cord”.
Who is Signature Biologics?
Signature biologics appears to be a company owned all or in part by Neil Riordan. Neil has a Ph.D. in Health Sciences at the Medical University of the Americas, a small for-profit Caribbean medical school in Saint Kitts. He is not a physician but has a Physician Assistant degree (mid-level provider). Neil also owns a site in Panama where mostly birth tissue cells are cultured, but Signature is under the US FDA, so the company is limited to 361 registered and minimally manipulated tissues (i.e. culture is not permitted).
What is Signature Cord?
Signature cord is a Wharton’s Jelly tissue product. The Wharton’s Jelly is the part of the umbilical cord that provides its stiffness. It does have mesenchymal stem cells when fresh, but multiple authors have tested frozen products made from birth tissues including Wharton’s Jelly that claimed to have live and functional stem cells, but to date, none have shown any live stem cells (1-3).
A Clean Website?
The first bit of good news that I saw was that Signature had a clean website. Meaning nowhere on the site was there a mention that I could find of this being a stem cell product. Given that most competitors are making those claims, this was refreshing.
I have to say that I was intrigued and reached out to one of their sales reps to try to get a sample of the product to test. Our company is looking for a new birth tissue vendor as we’ll sometimes use non-viable amniotic tissue for its high b-FGF content. The rep (Dan Wagner) was nice enough and agreed that they could send us a sample to test in our lab. However, then an e-mail arrived from a physician giving seminars on his use of umbilical cord “stem cells” and I had to back off. Let me explain.
A Not So Clean White Paper
I got the Signature Cord white paper from Dr. Yankey, a family doctor in Iowa. A Linkedin contact had been to a presentation put on by his clinic and I reached out to Dr. Yankey to ask about some of the claims made in his ads, materials, and in the seminar. I was sent this white paper as “proof” that Dr. Yankey was indeed injecting his patients with stem cells. Hence before getting into Dr. Yankey’s claims in an upcoming blog, I thought it would be a good idea to dissect what he sent me.
The Digestion Deception
If you ask physicians what the term “digestion” means they’ll recant how acid and enzymes break down our food. In particular, in the context of cell biology and stem cells, most have no or little idea of what it means. Hence, this has long been a magic trick used by many labs trying to prove that stem cells are in their products. Let me explain.
Our fellows at Centeno-Schultz and Regenexx HQ are some of the smartest people on the planet when it comes to orthobiologics. Why? They’re provided intense education on these topics, we review these topics frequently, and they’re required to write countless research papers while they’re here. However, a few years back one sent me a paper that talked about the stem cell content of MFat (micro-fragmented fat). He thought that the paper showed many viable stem cells by using the kit featured (Lipogems). However, he missed one part of the magic trick-digestion.
In the world of stem cell biology, digestion usually means breaking down the collagen matrix that trap stem cells in tissue. So in the MFat paper, almost all of the stem cells were locked inside their collagen prisons, unable to do much. In fact, our later research proved as much with the Lipogems system. However, likely to make the results look better, the authors “digested” the collagen away with an enzyme. This gave a false and high stem cell count that otherwise would have never been there.
The Signature Biologics Digestion Trick
The doctor who sent me the Signature Biologics white paper on Signature Cord who thought that it showed loads of viable and available stem cells in the product likely never noticed the term “digestion” or knew what it was in this context. In fact, it appears only once, here: “Flow cytometry was used to measure total and viable cells recovered after digestion.”
Why was the Signature Cord product “digested”? Wharton’s Jelly stem cells also live in a collagen matrix, like adipose stem cells. While explant cultures can be used (where you just put the Jelly like substance on a culture plate and let some of the stem cells crawl out), you’ll see far fewer stem cells. Here, Signature digested away that collagen before testing the sample. Why is this important? They don’t sell a digested version of the product as that would violate FDA minimal manipulation rules. Hence, what was tested and what you can buy are apples and applesauce.
Lions and Tigers or Lions and Tigers and Bears?
The white paper also reports the viability results of Signature Cord. The live/dead staining that we see states that the viability was high, at 98%. This is great, but there’s a slew we don’t know. The biggest issue is that cell viability isn’t binary in the real world. Meaning, there are actually three categories: alive, dying, and dead. So instead of lions and tigers, it’s really lions, and tigers, and bears, oh my!
Take a patient example. We all know that a patient who is healthy and being seen in the ER for a minor laceration is not the same as a patient dying in the ICU or one dead in the morgue. One is highly likely to be alive next month, one is highly likely to soon be dead, and one is already clearly dead. The same holds true for cells after being frozen. Some are healthy, some are dying, and some are dead.
The problem with live/dead stains is that they generally count the dying cells that will soon be dead the same as the healthy ones. Hence, that’s why high-level viability tests look at alive, apoptotic (dying), and dead. That wasn’t done here, so we have no idea how many of those cells will soon be dead.
On page four of the white paper we see the image I have placed on the left above. It’s a microscopy image of what the digested cells looked like after 72 hours in culture. These look like mesenchymal stem cells that aren’t all that healthy (bloated appearance), but they are supposedly still around after 72 hours. The lack of a tight spindle morphology could be due to the digestion itself.
While this is intriguing, what we don’t know is whether these cells continued to grow in that the average colony-forming test would last for about 10 days and the image above on the left is what’s seen after 3 days. On the right above is what bone marrow mesenchymal stem cells from a middle-aged donor look like at about 7-10 days out (these were grown in our research lab). You see far more cells growing in a dense group of cells (a colony). Hence, this image raises more questions than it answers:
- How many MSCs survived in this Signature Cord sample?
- Did these cells die or thrive after 72 hours?
- Was a bone marrow or fresh Wharton’s Jelly control also grown? How did the Signature Cors sample compare?
- How many lots out of 10 or more grew cells? Meaning are we seeing the rare lot that grows a few cells or are we seeing what every lot looks like?
- Do these cells meet the other criteria for MSCs like the ISCT flow cytometry markers and trilineage differentiation? Meaning, they could also easily be fibroblasts and not stem cells at all.
I spoke to Dan Wagner from Signature Biologics who didn’t believe that a white paper claiming that the product had stem cells was an issue. This is what he sent me:
“Signature Biologics designed our products to be in compliance with CFR 1271 Section 361 as outlined in the Guidance issued by FDA in Nov/Dec 2017. The product you have referenced, Signature Cord, is prepared with minimal manipulation, is intended for homologous use only as a supplemental cushioning agent by a licensed health care provider, does not involve combination of cells or tissues with any other article (except for crystalloids and preserving/storage agents which do not raise new clinical safety concerns) and our products do not have a systemic effect and are not dependent upon the metabolic activity of living cells for its primary purpose.”
The Regulatory Problems with Signature Cord
Every company in the birth tissues space seems to have the same song and dance and you can choose from one of these:
- Our product is intended for homologous use (but we know it’s not being used that way)
- Our products don’t have a systemic effect, hence there is no issue with our claims of live cells (ignore the fact that many FDA warning letters to date has declared that any claims of live cells make the product an unapproved drug)
- Other companies are claiming the same thing, so this must be fine (but again ignore all of those warning letters)
Here, in my opinion, Signature is using the homologous use and systemic effect dodges. To view some of the FDA Warning Letters sent to other umbilical cord product manufacturers claiming live cells, see FDA 1, FDA 2, FDA 3. To make sure I wasn’t alone in this opinion, I consulted a regulatory expert on the phone about these claims and he agreed that they were not FDA compliant.
The upshot? So does the Signature Cord product have loads of live and functional stem cells? None of the data reviewed above proves that and as the British would say, the data is “a few sandwiches short of a picnic”. Meaning there would need to be much more reported to get there. I reached out to Signature to get more of that information but was told it’s not available. Is this an FDA compliant product? Not as far as I can tell and my regulatory consultant agrees. So will we use it? No, the claims of live stem cells are just too much for me. We’ll stick with companies that make no such claims.
(1) Berger D, Lyons N, Steinmetz, N. In Vitro Evaluation of Injectable, Placental Tissue-Derived Products for Interventional Orthopedics. Interventional Orthopedics Foundation Annual Meeting. Denver, 2015. https://interventionalorthopedics.org/wp-content/uploads/2017/08/AmnioProducts-Poster.pdf
(2) Becktell L, Matuska A, Hon S, Delco M, Cole B, Fortier L. Proteomic analysis and cell viability of nine amnion-derived biologics. Orthopedic Research Society Annual Meeting, New Orleans, 2018. https://app.box.com/s/vcx7uw17gupg9ki06i57lno1tbjmzwaf
(3) Panero, A, Hirahara, A., Andersen, W, Rothenberg J, Fierro, F. Are Amniotic Fluid Products Stem Cell Therapies? A Study of Amniotic Fluid Preparations for Mesenchymal Stem Cells With Bone Marrow Comparison. The American Journal of Sports Medicine, 2019 47(5), 1230–1235. https://doi.org/10.1177/0363546519829034