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Regenerative Medicine


Here is the Wikipedia definition of an urban legend:” An urban legend, urban myth, urban tale, or contemporary legend is a form of modern folklore. It usually consists of fictional stories, often presented as true, rooted in local popular culture. These legends can be used for entertainment purposes, as well as semi-serious explanations for random events such as disappearances and strange objects”. This seems to describe some of the thoughts that are found in the stem cell field. Things that I at one time assumed to be the gospel turned out to not be true or had no actual scientific studies to back up many of these concepts. I often wondered where these ideas came from. I would like to discuss a few of these “legends” to at least put a different spin on things. No one can say for sure where the truth lies but hopefully this will provoke some critical thinking!
One aspect in the stem cell field that is often overlooked but is of paramount importance is the individual cell and its environment and how they are related. We should all bear in mind what happens in vitro (the lab) does not always translate to what happens in the real world (in vivo). Any attempt to analyze a cell necessarily alters the nature of the cell at the time of isolation, thereby altering outcomes of subsequent differentiation events. The implications of this fact are enormous. I have read many studies that have shown that certain compounds are toxic to cells. Yet when used in clinical practice these compounds do not seem to make a difference. A good example of this is lidocaine, a common local anesthetic. In the lab, lidocaine seems to be toxic to cells yet we have used lidocaine on our patients for years with no deleterious effects. Realize of course that we still use lidocaine judiciously. What this all boils down to is the fact that when we study a cell we are taking it out of its native environment. Out of this environment it is missing its niche and the possible paracrine effect of neighboring cells. These aspects may dramatically affect the behavior of the cell.  Clinical will always trump the lab.  So, Urban Legend #1 is that in vitro is the same as vivo.

Another legend is the we are performing “stem cell therapy”. We should realize that we may be utilizing a small number of stem cells in our treatment but the majority of cells utilized are not stem cells.  When we are typically utilizing bone marrow aspirate we are using the “soup” of the bone marrow. To say that we are doing a stem cell transplant is not really accurate.  Granted there are stem cells in the aspirate but the majority of cells we are transplanting are not stem cells. These cells include a host of many different types of cells which work in concert to achieve regeneration. These cells would include macrophages and a whole array of other blood products including platelets. I, myself, am guilty of calling these procedures stem cell transplants but in reality, they are Regenerative Medicine procedures. Urban Legend #2 is that we are performing “stem cell” treatments.

Another Legend is the fact the one cannot take anti-inflammatories when utilizing Platelet Rich Plasma (PRP) injections. This idea came about from the premise that the anti-inflammatories (NSAIDs) will interfere with the platelet function and the inflammatory response. This is simply not the case. A number of years ago I spoke with Dr. Sherwin Kevy of Mass. General and Harvard. Dr. Kevy was one the early pioneers and giants in PRP therapy. I asked him his opinion on anti-inflammatories. He responded that they should not make any difference. When we are dealing with PRP injections and utilize NSAIDs this may affect the clotting of the platelets but not the release of growth factors which is what we desire. We must realize when we are doing a PRP injection we are not concerned with clotting, but the release of growth factors. The growth factors are released when the platelets come in contact with collagen which is found in most tissue. For several years now we have utilized anti-inflammatories around the time of the procedure and have seen no drop-off in results. So, at least in our hands anti-inflammatories will have no significant effect in the function of the platelet response in a PRP injection. So, Urban Legend #3 is the effect of NSAIDS on PRP function.

There is another concept out there that red and white blood cells cause significant inflammation in the joint, tendon, or soft tissue. There really are not many good clinical (in vivo) studies that back up this misconception. There is a perception that a “pure PRP” may be best in certain clinical situations. A pure PRP is one which has been centrifuged and has a significantly decreased numbers of red and white cells. The idea is that these cells lead to inflammation and possible damage. But then again, these studies were in vitro. I guess someone forget to tell the body about this. When I last checked most bodies don’t have their own centrifuge built in. The idea is that a pure PRP causes less of an inflammatory response thus the patient has less pain. I suspect the reason for less pain is that the PRP is probably less effective. If we look at the literature we realize it is probably best to take full advantage of the complete array of the components in the blood. Given the right environment most components of the blood can actually produce anti-inflammatory cytokines. Some excellent papers on using all components of the blood come from Dr. William Parrish. I strongly advise everyone to read his papers.
I am not a proponent of just using whole blood. I feel it is essential to concentrate platelets in higher numbers by centrifugation but it is not necessary to remove all red cells. There are several good clinical examples on how red cells do not seem to make a difference. One striking example on how this is not that significant comes from an orthopedic procedure called a micro-fracture technique. This is an arthroscopic technique used in the treatment of osteoarthritis. In this technique holes are made in the joint surface when there is no longer any cartilage (bare bone). The idea is that some stem cells will “leak out” from the bone marrow and help to grow new cartilage. This is the precursor to many modern day “stem cell” procedures that are performed for musculoskeletal joint conditions. The significance of the micro-fracture is that the bleeding from the holes will fill up the joint with whole blood which has a large number of red blood cells. The blood in the joint does not typically cause an inflammation. Another example of red blood cells not causing inflammation is when a patient suffers an injury such as a torn anterior cruciate in the knee. This will produce a good bit of bleeding in the knee resulting in what is called a hemarthrosis. This blood in the knee does not cause an inflammation. Furthermore, when the blood is removed the pain (caused by pressure) goes away. The last example is when someone has a spinal tap and they continue to have a headache from a spinal leak. The method to eliminate this problem is to take blood from a vein and inject it into the spinal canal so that it is in direct contact with the spinal cord. It plugs the hole but it does not cause an inflammation to the spinal cord (dura)skin. Would it make sense to put something that causes inflammation next to something as delicate as the spinal cord? As can be seen there is some good clinical evidence that red blood cells cause no inflammation yet little if any studies that show otherwise. Thus Urban Legend #4 concerns the benefits of a pure PRP.

Another myth concerns supplements.  When I first become involved in performing PRP and “Stem Cell” injections I had enough ridicule from the fact that I was involved in this science. Even more ridicule was laid upon me from the fact that I was advising the use of supplements. Like usual, I took a look toward the world of science to see the true value of supplements. One need to look no further than certain supplements that we advise to our patients. There is solid science behind these supplements. One supplement which we use is StemXcell. This is a supplement that was born out of the laboratories of the Univ. of South Florida. It was devised by Drs. Bickford and Sandberg, two prominent researchers. This supplement was shown to significantly increase the number of stem cells released from bone marrow. Actually, in the lab it seemed to perform better than Granulocyte Colony Stimulating Factor (GCSF). GCSF is expensive and not without potentially serious side effects. StemXcell is the exact opposite.
Another supplement is Neo-40 which hails from the labs of the Univ. of Texas. Neo-40 has been shown to dramatically increase nitric oxide levels in the body. Taking this one step further we know that increased levels of nitric oxide (NO) have many different effects including the release of stem cells. We must realize that there are a few different forms of NO. But this product is all good since it releases the form of NO which helps reduce inflammation and stimulates stem cells. As time goes on we will see more and more information concerning the use of NO as an adjunct in Regenerative therapies. The use of NO is one of the basics of hyperbaric oxygen therapy. There is still a misconception that hyperbaric oxygen works mainly by donating extra amounts of oxygen to the cells. This is not really the case. The true mechanism of hyperbaric oxygen is that it will dramatically increase nitric oxide release which in turn significantly increases stem cell release from the bone marrow. The stem cell release is what heals the diabetic foot ulcer or other problem that is being treated. The list of supplements and their effects goes on and on. The fact that supplements are not needed represents Urban Legend #5.

I have saved perhaps the most important Urban Legend for last. In the field of Regenerative Medicine there is a perception that “doctors heal the patients”. Actually, this perception seems to permeate all of medicine. As much as I hate to admit it, this perception is dead wrong. When I first heard this, I was disturbed and angry. After spending years studying the “healing arts” in medical school and post graduate training in orthopedics how could I not heal patients? The real answer is very simple: “CELLS NOT DOCTORS HEAL PATIENTS”. As a physician, I can help direct the cells and give them some guidance and aid but ultimately, they will repair and heal the problem not me.  The concept that “physicians heal patients” is Urban Legend #6.

I am sure there will be some disagreement with some of these premises but it should provoke some thought. One thing I can safely say, Regenerative Medicine is not an Urban Legend!  It is here to stay and will eventually permeate most medical specialties.


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