When I was a child I remembered about reading how cows were considered sacred and they would roam the streets. Well I can now attest that this is indeed true. I just returned from a trip to India. I had the good fortune to be invited to lecture in Chennai India. The meeting topic was an exciting one. This was the first annual ArthroPreserve Meeting. The concepts were quite fascinating. The meeting was about how we can preserve the joint rather than replace it. The meeting concerned methods that included surgery many of which I have done and some that were new to me. Unlike, some of the meetings that I have lectured at this meeting was essentially attended by orthopedic surgeons. I certain felt at home since I have practiced Orthopedic Surgery for the last 34 years.
Many people need to realize that Orthopedic Surgery unlike other surgical specialties involves treating patients outside the operating room. A good portion of an orthopedic surgeon's practice involves non-operative orthopedics. This is inherent in our training. I chuckle when I read an idea espoused by some that there is a new field called "interventional orthopedics". Hello, the last I checked the field of orthopedics surgery was built on intervention. Giving an injection into a joint or tendon could be considered "intervention" but I think calling it interventional orthopedics is misleading to patients. It gives the patients perhaps a false sense of expertise concerning the doctor. There is only one recognized board of medical specialties that has the word orthopedics and that is the American Board of Orthopedic Surgery (or equivalent in other countries).
Does this mean that non orthopedic physicians who are performing regenerative medicine using PRP and Stem Cell injections are not competent. The answer is absolutely not! Some of the best minds I have met in the PRP and Stem cell field are not orthopedic surgeons yet I hold them in the upmost esteem. They are not calling themselves interventional orthopedists. They are calling themselves regenerative medicine physicians.
Taking this concept one step further, I was approached by a few individuals with the idea of forming a board called the American Academy and Board of Regenerative Medicine (AABRM). We have gone ahead and took this idea to fruition. The board is now up and running. It is a non profit organization and none of the board members receive any type of salary. It is also non political.
Unfortunately, the world of Regenerative Medicine has taken on some politics of its own. Unlike many boards, the AABRM has moved into the 21th century. This organization recognizes the importance of PHDs in the field of Regenerative Medicine as it pertains to stem cells etc. The PHDs give us the concepts to use in the real world. Without the PHDs our progress would be stymied. The Academy welcomes PHDs to be part of this growing field of medicine. Also, the current board members have written approximately a 120 question examination. In order to become a member a candidate would have to pass the examination. The questions were designed to stimulate thought and at least show some acquisition of a fund of knowledge. Also one needs to show some experience in this field. We have designed a syllabus. The other interesting aspect of the organization is its willingness to help the industry. We would offer training programs to sales people of all companies selling items to the regenerative physician. Unfortunately, a poorly trained sales person is sometimes the first contact a new regenerative medicine physician has. The last thing we want is to have bad science perpetuated. If the sales person has a good fund of knowledge that will do nothing but help the field. The other concept that the Academy wrestled with was should only physicians in the United States be members. We feel that there should be chapters outside the United States but they must maintain our rigorous standards. We have been contacting various physicians and PHDs to become founding members and the actual Academy launch should come shortly.
I realized that I may have strayed from my original topic a bit namely my India trip. Perhaps it is because I am at the end of an 18 hour plane ride. My lecture was well received and then I did a few cases in India. I did a demonstration of the new Marrow Cellution needle from Ranfac. This needle is a quantum leap in bone marrow aspiration in that it takes samples from a new geographic area as the aspiration is being performed. This will dramatically increase stem cell yields and in the end better outcomes. I had the honor of doing one case with Dr. E. Kon of the Rizzoli Institute of Italy. It is a world famous facility known for its strides in orthopedics and regenerative medicine. The needle was well received. This was my second lecturing trip to India and I must say I have cultured many more friendships there. In India they are no different than the United States. They are seeking what works and what doesn't while staying within the guidelines of what is allowed.
We now know supplements are extremely important in the field of Stem Cells, Platelet Rich Plasma Injections, and for that matter all of regenerative medicine. We take care of many professional athletes and it is not unusual for them to take fifty different supplements a day. These supplement regimens are designed by nutritional gurus. We have talked to these same gurus to design supplement programs for our patients. Before we talk about supplements we need to go back to the basics. None could better sum up our endeavors concerning supplements and what we are trying to achieve than the following taken from Popular Science Magazine from Aug of 2011. This is an article about my personal friend and colleague Dr. Williams Andrews. Dr. Andrews is the world’s foremost expert on Telomere science. Dr. Andrews and his company Sierra Science (www.sierrasci.com) are testing various compounds which may turn on Telomerase or the enzyme which restores the ends of the DNA strand. I have previously mentioned telomeres in another portion of the web site. The Telomere is the end of a DNA strand that is lost on cell division. As we age the DNA strand gets shorter and shorter until the cell is programed to die. The length of an individual's telomeres is closely associated with their biological age, and research suggests that control of telomere length has the potential to treat many diseases associated with aging, and possibly to allow humans to live at a physiologically "young" age beyond the current theoretical maximum human lifespan of 125 years. If someone states that Telomeres are an esoteric entity realize that the Noble prize in Medicine was awarded in 2009 for research on Telomeres. What does have to do with stem cells? The answer is plenty since in our procedures we are encouraging stems to replicate in the body. This replication will cause telomere damage and subsequent diminished stem cell effectiveness. This explains why many times younger people can recover from injuries much sooner than older individuals. The younger stem cells with longer telomeres can function significantly better than stem cells with shorter telomeres. Possibly one of the holy grails of stem cell science will involve the stimulation to turn back on the enzyme telomerase which helps to lengthen the telomeres. We only know of two cells which produce telomerase. One type of these cells is our reproductive cells. That is why our children are born young. The other types of cells are certain types of cancer cells. This is why some cancer cells are immortal. In our institute we are striving to at least slow down telomere degradation by the use of certain supplements.
The following diagram ties this all together. This diagram was taken from an article on Dr. Andrews in Popular Science. This slide represents the death spiral of a cell. This slide represents the multifaceted damage that occurs and accumulates. The telomeres shorten causing the activation of a certain gene which starts to repress mitochondrial function. The mitochondria are the powerhouses of the cells. When the mitochondria begin to fail the cell is doomed for failure. It is like a car running out of gas. When the mitochondria fail a host of other bad things happen. Stem cells are no different than any other cells.
The above diagram shows the fields we are attacking and trying to mitigate. We have discussed telomere shortening. Another important aspect in the supplement field of stem cell science concerns the mitochondria which is the powerhouse of the cell. We know that the mitochondria must be at their peak function in order for the stem cells to work properly. One such supplement which helps mitochondria achieve this goal is Melatonin. As we age our bodies become deficient in Melatonin. Cellular biologists have recently discovered that melatonin has an even more basic function, which is to protect oxygen-based life from the toxic effects of...., oxygen. Yes, oxygen. As we metabolize this life sustaining gas, we generate highly reactive molecules called free radicals, which can corrode our cellular membranes and damage our DNA. The process, known as oxidation, weakens our minds and muscles as we age, and contributes to at least 60 degenerative diseases, including cancer, heart disease and Alzheimer's. The body produces several enzymes to inhibit oxidation, and nutrients such as vitamin C, vitamin E and beta carotene can provide extra protection. But most of these so called antioxidants work only in certain parts of certain cells. Melatonin readily permeates any cell in any part of the body- including the brain. This research has been presented by Dr. Russell Reiter, a professor at the Univ. of Texas Health Science Center. I had the honor of lecturing at the same meeting as Dr. Reiter and spoke to him. Dr. Reiter’s research has recently shown in animal experiments that melatonin can protect tissues from an amazing array of assaults. As far as antioxidants claims go, melatonin has been acknowledged by many researchers as one of the elite antioxidants in the body. Directly and indirectly melatonin is said to exert a powerful antioxidant effect which is metabolized in all body tissue. Some reports say that melatonin is the most powerful anti-oxidant of all. One thing of supreme importance is the fact that melatonin effects all parts of the cell including the mitochondria. We can reverse free radical damage to the mitochondria with melatonin. If we can increase mitochondrial function we will have a very happy and effective stem cell. Perhaps a diagram of free radicals will help people understand better what we mean by free radicals. .
From the preceding diagram we see what a free radical actually is. It is an unpaired electron in the outer shell of an Oxygen molecule. Antioxidants will neutralize this. The free radicals are cell killers. They damage DNA. They alter biochemical compounds and reactions. They destroy cell membranes. The cells that are damaged by free radicals will go on and cause disease. We must remember free radicals come from 1. The Environment (air pollution, drugs, certain foods) 2. Internal Production from the body 3. Stress Factors (aging, trauma, disease, and infection) 4. Chain Reactions resulting DNA damage. Free radicals can be attacked on many different fronts including a diet, exercise, and other common sense things. Many people always the question what is the best anti-oxidant? There is probably no one correct answer. If I was pushed on the question I would probably say that that glutathione (GSH) is the body's master antioxidant. It functions both as an antioxidant and an antitoxin and is a major defense system against illness and aging. Our glutathione level actually indicates our state of health and can predict longevity. Glutathione is intimately related to the regulation of the nitric oxide cycle, which is critical for life. Remember the Nitric Oxide is very important in increasing stem cell output from the bone marrow. It is used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system and the lungs. Raising GSH levels through direct supplementation of glutathione is difficult. Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract. It is known that Vitamin D will act as catalyst for glutathione production
Another important factor in our quest to achieve repair of joints and tendons is to use a product which will restore the collagen to these areas. Collagen is a vital component of structural matrix throughout almost all tissues and organs of the body. It is particularly concentrated in skin, bone, tendons and cartilage where it plays a major role in the integrity of joint-related connective tissues. Studies reflect a relationship with collagen not only to normal healthy joint metabolism, but also to collagen-related alterations related to the aging process. Collagen alterations also play a role in osteoarthritis wherein alterations in collagen structure result from an imbalance in synthesis versus catabolism with resultant articular hyaline cartilage breakdown. A special form of collagen (known as Type II collagen) is a crucial component of cartilage, and to the structural integrity of your joints. So boosting collagen is a critical part of rebuilding cartilage, reinstalling those joint shock absorbers, and erasing arthritis pain for good. We are now using a collagen product from Germany which seems to fit all the needs we are looking for. Collagen hydrolysate passes across the mucosal barrier in the small bowel as a complete peptide that is no longer subject to enzymatic cleavage, accumulates in cartilage tissue, and stimulates production of type II collagen (the major protein in articular cartilage) and proteoglycans in the extracellular matrix of cartilage. What this means in common terms is that this is one of the few products that can be taken orally and be absorbed into the blood system and subsequently be delivered to the joint and be effective. In another words it is not broken down by the intestine.
The other quest that we have in our procedures is to stimulate the release of stem cells from the bone marrow. Remember that the cells which we inject into a joint or tendon are much like a Navy Seal strike team. They will secure the area but will depend on other forces eventually getting the job done. In order to accomplish repair the body will have to send large numbers of stem cells (mainly hematopoietic) to the area. One substance which does this is GCSF called granulocyte colony stimulating factor. The problem with GCSF is that it is very expensive and has some inherent risks. We feel that we have found a combination of supplements which can achieve similar results as GCSF without the risks or costs. We have come across a supplement devised at the Univ. of South Florida by Drs. Bickford and Sandberg. These two doctors are two very prominent stem cell scientists who have come up with a formula that dramatically increases stem cell output from the bone marrow. This product is called StemXcell. This product has been shown in the lab to have a similar effect as GCSF only it has built in safety.
Many of the supplements we will use help boost Nitric Oxide (NO) production which is a potent stimulator of stem cell output. Nitric oxide is a powerful neurotransmitter that helps blood vessels relax and also improves circulation. One example of a supplement we use is arginine. In the body, the amino acid arginine changes into nitric oxide (NO). Nitric oxide is a powerful neurotransmitter that helps blood vessels relax and also improves circulation. Nitric oxide (NO) plays a key role in triggering stem cell mobilization from the bone marrow via release of the stem cell active cytokine (growth factor). The suspicion is that arginine can mimic hyperbaric oxygen and by producing NO formation enhance stem cell production. It is also felt that arginine has a direct effect on the pituitary gland and stimulates HGH production. Interestingly enough, there is a good chance the Viagra and Cialis may also release nitric oxide and cause increase in CD 34 stem cells. Presently, the World Anti- Doping Agency (WADA) is looking into this fact especially for the exercising and sports performance. We are also looking into using these compounds to increase stem cell output.
Some of the supplements which we are currently using can be found on the following diagram.
The supplements we are using are our own propriety combinations and dosages which we prefer not to divulge here. Each of these supplements has a specific purpose in our treatment protocols.
As I read more and more about supplements I am convinced about the wondrous properties of Curcumin or as it is sometimes called Turmeric. There is quite a bit of interest in using Curcumin in the treatment of cancer therapy. This is typically a field that I stay clear of since it is out of my area of expertise. However, if we borrow some of this research we can see how Curcumin can be useful in the treatment of various orthopedic conditions.
Curcumin is a polyphenol extracted from turmeric, which has been safely used in foods such as curries for a long time. Curcumin is a promising therapeutic food material because of its anti-inflammatory and antioxidative functions. It has long been used as an anti-inflammatory treatment in traditional Chinese and Ayurvedic medicine.
Curcumin is perhaps an ideal supplement in that it has profound effects on various cytokine pathways. Remember that cytokine pathways involve the various growth factors that are found in the body. Many of these pathways are very beneficial while others are detrimental to the health of the joint. In addition to thee cytokine pathways, curcumin also targets a number of other processes that involve among other things genes that regulate cell proliferation or apoptosis (cell death). Interestingly enough the cell death usually involves cancer cells. The anti-inflammatory effect of curcumin seems to be comparable with those of steroidal drugs and NSAIDs. It has also been suggested that an important mechanism of curcumin is inhibition of NF-kB activation , which is a key event in the chronic inflammatory process. This is some of the same processes that stem cells are trying to accomplish with their secretory patterns. This is typically what the mesenchymal stem cell (MSCs) tries to accomplish. MSCs is an immune modulator. Another interesting fact about curcumin is the fact that is a potent inhibitor of the production of inflammatory products that are produced by cartilage cells. The fact curcumin can have such an effect on the joint makes it an ideal therapeutic agent to help in joint repair. In stem cell and PRP therapy we are always striving to improve the extracellular matrix. The extracellular matrix is the surrounding environment of the cells. The matrix is what the cells interact with. The less hostile the matrix the better the stem cell /PRP mixture will work. Again this is what we call immune modulation which is typically the job of the mesenchymal stem cells. There have been double blind studies (typically a double blind study is used wherever items are to be compared without influences from testers' preferences or expectations to eliminate the placebo effect) showing that curcumin is very effective in dealing with osteoarthritis. The randomized, double-blind, placebo-controlled study showed curcumin was significantly effective in deceasing pain and NSAID necessity with no major adverse events.
The one problem that we have with curcumin is the bioavailability. It typically is not very well absorbed. We have scoured the landscape and believe we have found two forms of curcumin which seem to have acceptable bioavailability. One of the forms is combined with liposomes. Liposomes help encapsulate the curcumin and deliver it to the areas that need it. We have found another form of cucurmin that dramatically increase the bioavailability of cucurmin by 1500%. We will start to offer this form of curcumin shortly. As I eluded to in the beginning of this blog, one interesting fact about Curcumin is that it has a profound effect on cancer stem cells. There is some very intriguing studies that show curcumin will dramatically increase the effectiveness of various cancer treatments. It has the ability to selectively kill cancer cells while leaving regular cells intact. It is many times combined with laser therapy with some intriguing results. I leave those comments to those who are more experienced than I am in those fields.
Lasers and light energy are taking on increased importance in the world of stem cell and PRP injections. There is now very good scientific evidence of the effect of light energy on various aspects of the stem cell field. I believe light energy will become a new paradigm in the use of stem cells for the regenerative medicine field. There are a number of physiological interactions that are contributed to low level laser therapy. It is important to remember that in the energy transfers that occur between LLLT (low level laser therapy) emitted photons and the receptive chromophores found in the various cells and sub cellular organelles, compromised cells and tissues respond more readily than healthy cells or tissues. Cells and tissues that are ischemic and poorly perfused as a result of inflammation, edema and injury have been shown to have a significantly higher response to LLLT irradiation than normal healthy structures.
What we are actually finding is that there is an energy transfer to those cells and structures that are the most metabolically challenged. The cells that are effected by the light energy have a lower threshold. We can say the healthier the cell the less effect light therapy has on the cell. The light will interact with a variety of enzymes. These enzymes are called cytochromes. The cytochromes act as energy producers for human biological functions at the cellular level. There are two main cytochrome enzymes, Cytochrome c Oxydase and Nitric Oxide Synthase (NOS). These enzymes have been found to be particularly reactive to laser photon stimulation. The particular affinity of these and other photo-reactive enzymes to accelerate their functions in the presence of LLLT provides critical increases in ATP and NO (Nitric Oxide) which enhances cellular metabolism,circulatory improvement and nerve function. The ATP is the energy that the cells utilize.
This energy comes when we utilize oxygen. When the laser is used intravenously the mitochondria increase in size. They also crank up the production of ATP. ATP will contributing to cellular repair, reproduction and functional ability. The increased ATP can make the difference between a stem cell surviving in a hostile environment or allow the cell to die which is what we call apoptosis. Remember under normal conditions we are lucky if 3% of the stem cells survive even for a short period of time. Thus if we can make an additional 3% of the cells survive this is a significant achievement. Nitric Oxide(NO) has a variety of functions including cell signaling, stem cell activation, increased stem cell survivability, and the list goes on and on. To read more about NO read some of my previous blogs. These two actions that I have spoken about are presented in a very basic manner. The process is much more complicated than I have mentioned. The laser will also help balance the free radicals that the body produces.
When laser therapy is being discussed we need to address what colors are utilized. Unfortunately, many of the lasers that are utilized are using only one color. This is laser therapy of yesterday. We now know that certain colors will accomplish certain tasks. Another important aspect of laser therapy is how it is utilized. One way that our clinic is utilizing lasers is by the use of lasers in an acupuncture setting.
We use this for various musculoskeletal conditions. We will also use lasers in an intra-articular fashion. We determine what laser colors to use depending upon the condition be treated. Typically with an acute inflammation we will use a blue laser while for a more chronic condition we will utilize a red or infra red laser. The red laser will help to achieve healing. The other method that you are starting to utilize is a laser setup that is used intravenously.
As you now understand, we will utilize a variety of colors in an intravenous fashion. There is no doubt in my mind that lasers will become increasingly important in the stem cell field. One concept that I wish to impress upon everyone is the fact that the lasers I am speaking of have little in common with those that we find in a physical therapy or chiropractic office. Those lasers have some benefit for local injuries but due to their lack of penetration their effectiveness in the stem cell arena is questionable at best. There will be more to come.
At one time medical professionals thought the only purpose of platelets was to form a clot in order to heal cuts and other injuries. This is only a small part of the whole picture. Another crucially important function of platelets is the release of various growth factors responsible for almost all repair processes that occur in the body. These growth factors, also called cytokines, are extremely important in cellular communication, having both direct and indirect effects on stem cells and other types of more mature cells. They work as a communication network between the cells.
Around 20 years ago the idea of concentrating platelets became widespread in cardio-thoracic surgery. Further research was carried out in the field of oral surgery in 1998 by Dr. Robert Marx at the University of Miami, who revealed what constituted a platelet-concentrated product. In the years since his research concentrated platelets have become known as Platelet Rich Plasma, or PRP, which stimulates healing.
Methods of Producing PRP
There are many different methods of preparing a PRP product, however all techniques use centrifugation. The type of centrifuge and the speed at which the centrifuge runs varies from one PRP producer to the next. The PRP product that various companies produce varies widely in the concentration and cell types that are found in a PRP product.
The problem PRP producers face is that current scientific literature has no good definition as to what constitutes a PRP. Thus, while one article may show significant positive effects from PRP the next may show that PRP is no better than a placebo. It is important to note that this problem stems largely from disparities in quality between the various companies that produce PRP products, not from lack of efficacy of PRP therapy. Later in this section we will explain the science behind what constitutes an effective PRP product.
The amount of blood needed to produce a PRP depends upon the joint or tendon requiring treatment and the type of system used. Some systems require up to 60 cc's (about 2 ounces) while others require about 10cc's. The amount of centrifugation time varies from one company to the next. Much variation exists in PRP products produced by various companies in terms of different concentration of platelets, red blood cells, white blood cells and other types of cells. These concentrations can make a difference between success and failure of a PRP injection.
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