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As you know, several times a year, I take select patients to our licensed Grand Cayman site to treat those patients with culture-expanded stem cells. However, this trip I’d like to not only once again tell you why, but also spend some time explaining why this Cayman site is unique in the world. Let me dive in.

Culture Expanded Stem Cells

What are culture expanded mesenchymal stem cells? These are the same cells we use in the United States that are derived from the patient’s bone marrow, but for culture expansion, we take that process further. First, we place those cells in culture to grow them to bigger numbers. Second, we freeze down any excess cells for future use.

These cultured cells come in handy in specific clinical situations or if you have a patient that needs or wants to get several areas treated with stem cells. Any physician on our Regenexx network can bring their patients down to Grand Cayman.

Two friends

This trip to Grand Cayman began differently, but that dilemma also gave rise to this blog. Let me explain.

I went in yesterday to see patients and I was told that the first bone marrow aspiration that I was performing for another physician on the Regenexx network had decided to cancel the procedure, despite being here in Cayman. I was also told that his friend was wondering if he should cancel his BMA as well, so as the founder of this company and concept, I offered up myself to speak to both of them.

The Developing World and Stem Cells

One of the things that I’ve noticed over the past few years and certainly coming out of the pandemic was that more sites offering culture expanded stem cells have opened up in the 3rd world, most of those being in what I call “Banana Republics”.

Almost all of these clinics have significant similarities and stark differences from the Regenexx Cayman site. So here’s what I explained to these two friends.

I broke this conversation into several parts:

• Cell Source
• Safety, Data Collection, and Experience
• Getting Cells Where They Need to Go

Cell Source

One of the more interesting issues here is that almost all Banana Republic clinics use umbilical cord stem cells from a donor. The sales pitch is clear. These young and plentiful cells are somehow better than your own old and tired cells. However, is this remotely true?

This past week I commented on a study out of Emory that clearly showed that culture expanded stem cells from an umbilical cord source were no better than bone marrow concentrate (not culture expanded) autologous cells in treating knee arthritis. I could have predicted this result before it happened and have done so many times on this blog. Why?

The sales pitch for using donor stem cells has always been that these cells are somehow invisible to the host’s immune system. This is in contrast to something like a kidney transplant from another person where the organ is promptly rejected, requiring close matching of the tissue to the host and a lifetime of immunosuppressive medication. However, is this true? Not exactly.

First, what most physicians and experts in this space never realize is that the animal research showing that you could use things like donor umbilical cord stem cells has a serious problem. These studies didn’t use a single donor animal, but instead cells that were pooled from multiple donor animals. Why? These specimens are too small to get many cells out of each, so its technically easier to pool the bone marrow or umbilical cords from many animals and then culture expand those cells. Why would this matter?

Ashlee Watts, PhD from Texas A&M has done this research and discovered why this is an issue (1,2). Others have published on it as well (3). In a horse model where you can use a single donor (because horses are big enough), she noted a much higher treatment failure rate in donor cells. In the end, it was figured out that the cells, like a kidney, were rejected by the host’s immune system and “taken out”. The rare home run cases of a great treatment result were happening because the cells happened to be a better match between the donor and host. In a pooled small animal model this is less of an issue because there is more likely to be a better matching cell line in the pooled material.

Hence, IMHO the umbilical cord cells in the Emory trial suffered the same fate. Most of the time they were attacked and deactivated by the host’s immune system. So while umbilical cord cells may look great in lab studies, in a human application, until this donor rejection issue is figured out, they are not yet ready for prime time.

What do we know about your own stem cells? They don’t get taken out by your body’s immune system and consequently, they can stay to not only mount a repair response, but also to differentiate into the needed tissue type (3). This is why Grand Cayman has never switched over to umbilical cord cells.

Safety, Data Collection, and Experience

I was the first human on earth to use autologous culture expanded bone marrow mesenchymal stem cells to treat an orthopedic problem. That was way back in 2005, long before any of these Banana Republic clinics were a gleam in their owner’s eyes (4,5). As a result, we have published the world’s largest safety study on the cultured bone marrow stem cells we use (6). Not a single worldwide clinic using umbilical cord stem cells has approached a study of this size or duration.

In addition, while placing cells in a knee and looking at what happens in that joint long-term is doable, once you begin injecting any cells IV, a large scale safety study becomes a nightmare to pull off. Why? Because those cells could end up anywhere. Hence, if you see three cases of Lymphoma in your safety study, you would need very sophisticated genetic phenotypic of your cells and the cancer cells to begin to prove that your cells didn’t cause these neoplasms. It will be many years before this type of data is available for IV stem cells.

So where are the large and sophisticated published safety studies that include thousands of patients followed for a decade for these Banana Republic clinics? If you find any, let me know, as I have yet to see a single one. That’s compared to our published safety study of that size and duration that continues to be referenced by many FDA trials in this space.

In addition, Regenexx Cayman has been collecting registry data on efficacy for more than a decade. Do these other clinics collect this data? Not that I have seen.

Getting Cells Where They Need to Go

Spine

One of the things that all Banana Republic stem cell clinics have in common is the story that by injecting cells IV they will somehow, magically, end up where they need to go [insert body part here]. While a great fairytale, we don’t have any evidence that this happens in the types of musculoskeletal issues that patients want to get treated. Why?

When you inject mesenchymal stem cells IV, there is a pulmonary first pass effect (7). That means that 97% will get stuck in the lungs (8). In addition, most of the places where people have chronic orthopedic issues are avascular or have a poor blood supply. Hence, cells given IV will never reach those areas.

As a result, if you want cells to get into the injured shoulder rotator cuff, ligament, tendon, disc, or joint, you need to place them there via imaging guidance. This is where we separate the boys/girls from the men/women when it comes to Banana Republic clinics. To give you a taste of just how difficult this precise placement can be, let me take you through a thought experiment I used yesterday.

As I was seeing patients at the Cayman site, I treated several spine cases. The goal in those cases was to get stem cells:

• Epidural in the Foramen
• Into the cervical and lumbar facet joints
• Distributed into specific ligaments
• Placed inside the Sacroiliac joints

To do this, the doctor first needs the specific training to accomplish these procedures safely. Since Cayman allows US physicians to be licensed here, getting a US trained Interventional Spine doctor to this site is easier. That can’t happen in Banana Republics as they don’t allow US trained and qualified physicians to get licensed. In addition, finding a local Banana Republic doctor trained in Interventional Spine is almost impossible.

However, there’s another big problem in doing Interventional Spine in the developing world and that’s the lack of qualified Rad techs. These are professionals who know how to run the C-arm fluoroscope while assisting the doctor to get the exact right view so that all of the angles to the injection target line up safely.

How hard is this task? To give you a sense of it, the Rad tech we use in Cayman has been trained by us for the past half decade. He’s the only Interventional Spine trained Rad tech in all of the Caribbean. You can probably add all of Central and South America to that list.

Peripheral Joints and Nerves

There’s yet another big problem for Banana Republic clinics. To understand that issue, let’s review some of the areas I’ll be injecting this week in Cayman:

• Knee ACL
• Knee MCL
• Knee meniscus
• Shoulder superior labral anchor
• Carpal tunnel
• Talus bone
• Lateral ankle ligaments
• Hip labrum
• Shoulder Infraspinatus tendon
• Inferior glenohumeral ligament (IGHL)

Some of these injections are performed using ultrasound guidance and some using C-arm fluoroscopy. How many physicians in the US, where we developed most of these procedures, could competently hit all of these spots? Maybe a few hundred with many of those doctors being on the Regenexx network. Now move that clinic to a Banana Republic and you have a severe problem that’s almost unsolvable. Remember, you can’t get a US doctor licensed in these countries. Hence, while the professional salespeople from all of these clinics will claim to inject whatever the patient wants, this expertise exists at none of them.

In addition, none of these patients knew they needed these areas injected, which is the other part of this exacting calculus. The doctor needs to be trained to understand when each of these is needed and why. That training isn’t present in orthopedic surgery, neurosurgery, or family practice sports residencies in the US or elsewhere. That training can only be had through organizations like IOF, the Regenexx network, or in the US or fellowship programs like the one we run in Colorado. Hence, simply learning these procedures at a US course won’t work. You need to learn a completely different way of conceptualizing the body and understanding what needs to be treated and when.

Only Regenexx Network Doctors

We only permit trained and active Regenexx network physicians to practice at the advanced Cayman site. Why? because I can guarantee that these physicians have the training needed to exceed the above hurdles. I can also ensure that these physicians are up to date with the latest protocols which we distribute throughout our physician network.

Wouldn’t it be much more profitable to allow any old physician to practice at the Cayman site? Yep, but a high standard of care would be lost.

The upshot? So why does the Grand Cayman site exist? I’ve reviewed and visited clinics claiming to do stem cell work from China to Europe and throughout Latin America. If you want culture expanded stem cells and have orthopedic issues, there is no other site worldwide that meets the above specifications. It just doesn’t exist outside of the Regenexx Cayman site.

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(1) Joswig AJ, Mitchell A, Cummings KJ, Levine GJ, Gregory CA, Smith R 3rd, Watts AE. Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model. Stem Cell Res Ther. 2017 Feb 28;8(1):42. doi: 10.1186/s13287-017-0503-8. PMID: 28241885; PMCID: PMC5329965.

(2) Rowland AL, Miller D, Berglund A, Schnabel LV, Levine GJ, Antczak DF, Watts AE. Cross-matching of allogeneic mesenchymal stromal cells eliminates recipient immune targeting. Stem Cells Transl Med. 2021 May;10(5):694-710. doi: 10.1002/sctm.20-0435. Epub 2020 Dec 25. PMID: 33369287; PMCID: PMC8046071.

(3) Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014 Mar;32(3):252-60. doi: 10.1038/nbt.2816. Epub 2014 Feb 23. PMID: 24561556; PMCID: PMC4320647.

(4) Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, Hanson R. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011 Dec;6(4):368-78. doi: 10.2174/157488811797904371. PMID: 22023622.

(5) Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W. Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2010 Mar;5(1):81-93. doi: 10.2174/157488810790442796. PMID: 19951252.

(6) Centeno CJ, Al-Sayegh H, Freeman MD, Smith J, Murrell WD, Bubnov R. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016 Aug;40(8):1755-1765. doi: 10.1007/s00264-016-3162-y. Epub 2016 Mar 30. Erratum in: Int Orthop. 2018 Jan;42(1):223. PMID: 27026621.

(7) Ferrini E, Stellari FF, Franceschi V, Macchi F, Russo L, Murgia A, Grisendi G, Villetti G, Dominici M, Donofrio G. Persistency of Mesenchymal Stromal/Stem Cells in Lungs. Front Cell Dev Biol. 2021 Jul 16;9:709225. doi: 10.3389/fcell.2021.709225. PMID: 34336863; PMCID: PMC8322774.

(8) Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009 Jun;18(5):683-92. doi: 10.1089/scd.2008.0253. PMID: 19099374; PMCID: PMC3190292.

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. View Profile