A Fatty and Muscular Problem for Cartilage Repair

As you may know from prior posts, I've been concerned that products that claim to mobilize adult stem cells from bone marrow to blood may be barking up the wrong tree when it comes to musculoskeletal repair.  In particular, the cells being mobilized are not true MSC's, but cells which are good at muscle repair and not cartilage, bone, ligament, or tendon repair.  A recent study just confirmed this again, this time in-vivo (meaning placing muscle stem cells in a rat knee joint to see if they were capable of cartilage repair).  This study showed that in fact, muscle derived MSC's performed very poorly, as did cells derived from fat.  However, synovial derived cells and bone marrow cells (the kind currently used by RSI), performed very well at cartilage repair.  While entire industries are now springing up to save adipose derived MSC's from liposuction surgeries, the ability of these cells to produce cartilage remains in doubt.  For now, it looks the bone marrow derived and synovial tissue derived cells are the only game in town.

Adipose Nightmare?

A recent study published in the journal stem cells raises a few questions on the appropriateness of using fat derived stem cells in clinical patients at this time.  While the study injected fat derived mesenchymal stem cells with tumor cells (nothing any clinician would ever consider doing) and found that they created bigger tumors, it does raise a point that long-term MRI follow-up for tumor creation is needed.  RSI has obtained that data over the past two years on the Regenexx procedure and is readying that for publication.  What it shows is that MSC's grown with our proprietary technique do not promote tumor formation as measured by state of the art 3.0 T MRI imaging (images before and after the procedure).  This is very important, as what we don't know is if cells grown with other procedures (for example one that requires exogenous growth hormones or other cells sources-fat instead of the Regenexx source of bone marrow) might promote tumor growth.  We will be readying this data for publication over the next few weeks and hope to have this in the research lexicon by fall of this year.  

Snake Oil?

In the last post, I discussed the sizable buzz out there about the phrase "stem cells" and how multiple groups were cashing in on that buzz with claims that don't make allot of scientific sense.  As an update, I had an exchange this past week with one of the companies using various chemicals to mobilize adult stem cells from the bone marrow to the circulation.  After a bit of scientific back and forth, it became clear that their web site was a bit misleading.  It makes it seem like they are mobilizing adult mesenchymal stem cells into the circulation, when in fact they admit that they are mobilizing a hybrid blood/muscle stem cell progenitor.  While this cell could be helpful from a theoretical standpoint in body building applications (to build muscle), of the 5,000 or so studies currently in the national library of medicine, only a handful reference this cell.  We don't know much about it at this point in time.

Perhaps Brian Alexander of MSNBC put it best:

“ADULT STEM CELLS are the BEST-KEPT SECRET in today’s wellness…” boasted a flyer for a dietary supplement called VitalStem. Take it and increase “the number of circulating stem cells in your body.” Not only can it “replace diseased cells with healthy cells” and provide “anti-inflammatory and immune system support” but also give users “mental clarity and mood elevation.”

But the products are really just a repackaging of a supplement that has been marketed aggressively since the 1980s, a form of blue-green algae called aphanizomenon flos-aquae. The science behind the claimed benefits for aphanizomenon is slight — whether the claim is for immune boosting as it was 20 years ago, or stem-cell enhancement as it is today. In fact, there has long been concern about the presence of toxins in blue-green algae products, though you wouldn’t know it from the marketers at the trade show. 

Brian is describing some of the claims being made at the A4M conference in Las Vegas this week.  Click here for full story.  

As I have blogged before, stem cells and other autologous biologics are no different than Penicillin.  First, a procedure must be put in place to ensure that the autologous biologic is in fact what it claims to be.  This procedure would at least need to involve isolation of that cell and culture expansion to a much higher number.  Then, dosing needs to be figured out. Finally, how the cell is applied to the area becomes a whole area of study in itself.  For example, applying the cell to fix bones is likely different than trying to fix cartilage or tendons.  

So again, there is no easy lunch here.  These cells have great promise, but simply slapping the phrase "stem cells" on a bottle of ancient supplements from the 1960's or a process using otherwise dangerous chemicals to bump up circulating blood cells isn't enough...

Stem Cell Hype vs. Medicine

As the medical director of a stem cell company building procedures that are less invasive and target specific tissues for regeneration, I see allot of hype out there. Here are some examples of stuff that sounds good to the lay reader, but when one looks at the basic science, don't add up:

1. Pills or drugs to mobilize stem cells: There are new supplements claiming to regenerate every tissue in the body from muscle to brain to liver to kidney. The best of these have actually had blood samples tested using Fluoresence Activated Cell Sorting to show some increase in circulating blood stem cells. The problem? The types of stem cells mobilized into the blood stream are cells destined to produce more blood, not repair tissues. In particular, one of the MVP's of the adult stem cell world (MSC's) don't circulate in the blood, so they stay put where they're located. These supplements might help if you had anemia, but not much else.

2. Embryonic stem cell injections or cord blood injections: These are stem cells from someone else injected IV. Most of this is happening in third world countries. A few issues. One question is how these stem cells were isolated, as there has been at least one significant allergic reaction (which should never happen with a true stem cell) reported on a California company offering embryonic stem cells in Mexico. Assuming they are stem cells, the second issue is disease transmission. First, there are the common diseases such as HIV, Hepatitis, and other viral infections we can detect. Second, there is the issue of stem cells being able to transmit genetic disease such as an increased risk for osteoporosis (see earlier post). Finally, there isn't much data that shows that if you have a bum knee, a bad kidney, and liver spots on your skin, that these cells will be able to home to one of these areas to allow repair. In fact, most studies show that even in severe injury models (where a severe life threatening injury is created like a heart attack or a lung injury) direct infusion of cells to the damaged area results in more repair than placing the cells in the blood stream.

3. Adult stem cell injections IV: I have seen clinics beginning to use various marrow concentrate systems to inject marrow nucleated cells into the veins (IV). Again, the issues with IV infusion as discussed above apply here as well. The other big issue that that MSC's make up about 1 in 50,000 to 1 in 500,000 of these marrow nucleated cells. This means a very very dilute stem cell population is actucally being injected. As an example, 50 cc of bone marrow might contain trillions of cells, but only less than 0.0002% (in some older patients) are actually stem cells capable of tissue repair.

4. Bone Marrow concentration via bedside centrifuge: There are companies advertising systems (as above) that take whole bone marrow and magically produce millions upon millions of stem cells. Actually, the stem cells they refer to are CD34+ heme progenitors (stem cells that make more blood products) and not MSC's which can repair tissue. So the same issues as above apply.

So as you can see, there's allot of hype. We at RSI continue to work hard to do the following:

1. Isolate and culture expand true mesenchymal stem cells (MSC's) from the same patient where they are harvested (meaning we can harvest a few hundred thousand stem cells and culture expand them to between 5-200 million in just a few weeks). This is done without exposing the cells to potentially harmful drugs or recombinant growth factors.
2. Test various procedures to place MSC's into the area being regenerated. As an example, the procedure for regenerating disc tissue is wholly different than the procedure that targets cartilage in the knee. As more examples, regenerating a partially torn rotator cuff is different than regenerating bone. We then use patient reported outcomes ("I feel great!") as well as before and after 3.o T MRI (the best quality MRI technology currently available) to convince ourselves that we have repaired the target tissue. We are also constantly pioneering new techniques to get the cells to the target area via injection (such as MRI planned fluoroscopy-this is where we use the MRI image to guide the placement of cells).

Stem cells have great potential, but with that opportunity comes the hype...

Cutting Out Tissue to Cure?

Much of modern surgery on joints involves the idea that cutting out torn or macerated tissue is a good idea. Take for example that a meniscus repair is actually removing the torn part or parts of that tissue that won't heal. While this can provide short-term relief, the research has shown that over the long run, it leads to more arthritis in the joint. This happens because the remaining tissue gets over-loaded and less meniscus tissue means less lubrication for the joint. The advent of regenerative medicine where we can now heal tissue means that we shouldn't be removing torn pieces. This also means that surgical debridement of a degenerative area will likely be replaced by more pro-active care.

Let me use myself as an example of this new paradigm. I injured the cartilage under my knee cap while jumping on a trampoline with the kids. Rather than improving over time, the area worsened over the next year until I had difficulty climbing stairs. Since I had failed conservative care, the next step in the traditional surgical paradigm would be to "debride" the area. This means that a surgeon would go in and cut out some of the cartilage around the area already missing some cartilage. Removing those pieces may have felt better for awhile, but ultimately would have lead to more arthritis in the area. Another option would be micro fracture, but that would mean 12 weeks on crutches, which for me, given the amount of disability wouldn't have been worth it. Since this was a small lesion, I had my one of my partners inject a patent pending Regenexx mixture which consisted of the growth factors isolated from my blood platelets and a component to cause a small micro-injury to kick off a healing cycle. Several days after this injection I was able to climb stairs without pain and to go back to trail running. What happened? A small micro injury was created by the injection at the specific site of the cartilage lesion. The growth factors then went to work to help increase my natural cartilage repair capabilities and lubrication.

As you can see, these new technologies now allow us to get ahead of the problem through promotion of repair rather than cutting out the broken parts. The new paradigm, heal before you consider cutting!

No Easy Stem Cell Lunch

Amgen today announced that Epogen, a blockbuster drug that is often used to produce new blood cells in anemic cancer patients undergoing chemotherapy, has significant risks. The problem is that the drug increases the risk of accelerated tumor growth and death. What does this have to do with stem cells? At least one US company has used this drug to mobilize adult stem cells from the bone marrow into the blood circulation so they could collect them for storage and future use. Several foreign companies are also using similar methods. This approach has been a bit of a scientific mystery, as the stem cells being mobilized were actually what's called CD34+ stem cells and not mesenchymal stem cells. Why is this a problem? CD34+ cells make new blood cells and blood components, but in primates like humans, it's doubtful they can turn into mesenchymal stem cells capable of repairing bone, muscle, cartilage, tendons, organs, or nerve tissue. So why collect them in the first place? Good question.

This problem with Epogen again brings up a big problem with our big pharma approach. Any drug designed to systemically ramp up one system is likely to have unintended side effects. In the end, the only way to treat many problem is a local approach, such as placing stem cells in an area in need of repair via needle guidance.

So in the end, there is no free stem cell lunch...

How Long are Your Telomeres?

In a recent study, 3 hours and 20 minutes of moderate exercise a week increases telomere length by about 200 base pairs. What does that mean? People that exercise like this were about 10 years genetically younger than couch potatoes.

Telomeres are the ends of your DNA that shorten as you age. This is the reason a dog lives 10-15 years while a person lives 70-100 years. The dog's telomeres shorten quicker, so they age faster. In effect, by not getting this amount of exercise, your telomeres are about 10 years shorter than the guy down the street who does.

I see middle aged and elderly patients all the time who are in too much pain to exercise. They have chronic knee, hip, shoulder, problems that prevent them from being active. The problem is that this impacts not just their overall health, but likely how many years they have left. These patients need to find non-invasive ways to get out of pain. The Regenexx procedure in one way to fix that joint pain without being out of commission for 3 months. Whatever you decide to do to help your injured or arthritic joints, one thing is clear, getting active will help more than just your heart, it will also extend your warranty!