I continue to see advertisements concerning various cord blood and placenta products. Typically, the line of reasoning for using these products is that the patient’s own cells are “too old” to be effective. This is a very temping treatment method for the uninitiated physician. He can just take a vial of these products from a freezer and inject it into a joint and the magic will begin. Or so he thinks! For those of us who have been involved in regenerative medicine for a number of years, we know that this is simply not the case. We have been saying that typically these products do not have live cells with metabolic activity. Granted, they have growth factors, which will have some beneficial effects. But to say that these products are better than the patient’s stem cells, is not based on any science and is essentially untrue.These companies are quick to tell unassuming physicians that there are many live viable cells in their products. This is where things get murky. If there are live cells in their products that will actually have some type of biologic effect, than this appears to be a violation of FDA guidelines.FDA guidelines state that if a product has live cells with metabolic activity, than this product requires significant testing before it can be released to the public. So, there are two avenues that these companies can pursue. They either have to say that there are no live cells and register the product as a tissue product. This is a relatively easy process. If they claim live cells, than they have to apply for a biologics license. This is a process which requires a few years of testing and a biologics license which is a very arduous process.In order to make sure that my thinking was correct, I sent an inquiry to the FDA on Aug 23,2018 and here is my answer from them. I took the liberty of highlighting certain portions in yellow highlight:Dear Dr. Purita:Thank you for your email to the Center for Biologics Evaluation and Research (CBER). CBER, one of seven centers within the Food and Drug Administration (FDA), is responsible for the regulation of many biologically derived products, including blood intended for transfusion, blood components and derivatives, vaccines, allergenic extracts, and cell, tissue and gene therapy products.Cellular therapies are regulated by CBER as human cells, tissues and cellular and tissue-based products (HCT/Ps). FDA has a risk-based approach to the regulation of HCTP/s. Under the authority of Section 361 of the Public Health Service (PHS) Act, FDA established regulations for all HCT/Ps to prevent the transmission of communicable disease.The regulations in 21 CFR Part 1271 identify the criteria for regulation solely under Section 361. HCT/Ps that meet all of the criteria in 21 CFR Section 1271.10(a) are regulated solely under Section 361 of the PHS Act. If all of the criteria in 21 CFR Section 1271.10 are met then no pre- market review (application to FDA) is required.To satisfy these criteria, an HCT/P must be: No more than minimally manipulated (relates to the nature and degree of processing); intended for homologous use only (the product performs the same basic function in the donor as in the recipient); not combined with another article (with some limited exceptions); and the HCT/P does not have a systemic effect and is not dependent on the metabolic activity of living cells for its primary function, or if it does, the HCT/P is intended for autologous use or use by a first-or second-degree blood relative.HCT/Ps that do not meet all of the criteria of 21 CFR Section 1271.10 are also regulated under Section 351 of the PHS Act and/or the Federal Food, Drug and Cosmetic Act as drugs, devices and/or biological products and would require pre-market approval.Stem cell products have many different sources and potential biological activities and therefore need to be evaluated individually with respect to the 21 CFR Section 1271.10(a) criteria. Many experimental stem cell therapies do not meet at least one of these criteria.For a stem cell product that does not meet the criteria for regulation solely under Section 361, a Biologics License Application (BLA) would need to be approved before commercial marketing.The recently issued guidance documents titled “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use” and “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception” were provided to assist sponsors of HCT/P products in determining whether their products meet the first two criteria listed above. Even if a product meets both of those criteria, it must still meet the last two in order to be regulated solely under Section 361, and not require pre-market approval. Please know that guidance documents represent FDA’s current thinking on how sponsors of FDA regulated products can comply with current FDA requirements. Sponsors may adopt an alternative approach; however, that approach must still comply with FDA’s regulations, and in the case of cellular therapies, the regulations outlined in 21 CFR 1271.With the issuance of the guidance documents mentioned above, FDA is adopting a risk-based and science-based approach that builds upon existing regulations to support innovative product development while clarifying the FDA’s authorities and enforcement priorities. This risk-based approach allows product developers time to engage with the FDA, to determine if they need to submit a marketing authorization application and, if so, submit their application to the FDA for approval. For the first 36 months following issuance of guidance documents above, the FDA intends to exercise enforcement discretion for certain products with respect to the FDA’s premarket review under the existing regulations. This policy will allow for a more orderly transition and limit the impact on available resources within the FDA. A recent article published in The New England Journal of Medicine by Peter Marks, M.D., Ph.D., CBER Center Director and Scott Gottlieb, M.D., FDA Commissioner, provide further insight into FDA’s regenerative medicine policies: http://www.nejm.org/doi/full/10.1056/ NEJMsr1715626We hope this information has been helpful. If you need further assistance, you may contact our office at [email protected] or 1-800-835-4709.Sincerely,Amy TempleConsumer Safety OfficerCenter for Biologics Evaluation and ResearchOffice of Communications, Outreach and Development U.S. Food and Drug AdministrationTel: [email protected] informal communication represents my best judgment at this time. It does not constitute an advisory opinion in accordance with 21 CFR 10.85, and does not necessarily represent the formal position of FDA or otherwise obligate the agency to the views expressed.—–Original Message—–
From: joseph purita]
Sent: Thursday, August 23, 2018 1:58 PM
To: CBER OCOD Consumer Account <[email protected]>
Subject: opinion from FDA concerning certain productsI am writing this email to obtain an opinion from the FDA concerning certain products that that are being marketed to various specialties. In particular, I am wondering about umbilical cord blood derived mesenchymal stem cell products. My understanding is that these products are registered as a 361 with the FDA. Yet, these products state in some of their advertising material that they contain live mesenchymal stem cells which have metabolic activity. My understanding is if a 361 registered product has live stem cells with metabolic activity than it becomes a 351 requiring an IND license. I would like some guidance from the FDA on these products. If indeed these products registered as a 361 contain live cells with metabolic activity is that a violation of FDA regulations if they are used to treat patients for a variety of conditions? Do they actually require a 351 classification and IND application?Thank you,Dr. Joseph PuritaIn the above letter, at the end, you can see my initial inquiry and subsequent answer from the FDA. On the surface this seems like a complicated letter. However, when you analyze it, it is fairly straight forward. As we can see the FDA is very specific that if a product has live cells with metabolic activity than this qualifies as a 351 product. A 351 product requires what is called an IND (Investigational New Drug application). This requires a few years of clinical testing and a few million dollars before the product is released for general use. It is fairly clear cut that these cord blood products fall into one of two categories. Either they do not have live cells with metabolic activity and thus they are essentially a growth factor tissue product or they have live cells with metabolic activity which is currently not allowed by the FDA regulations.I am sure the dance by these companies will continue for a while longer.The public needs to be aware that the chances are if a physician is utilizing these products you may not be getting what you were promised.Buyer beware! – Dr. P
I continue to see advertisements concerning various cord blood and placenta products. Typically, the line of reasoning for using these products is that the patient’s own cells are “too old” to be effective. This is a very temping treatment method for the uninitiated physician. He can just take a vial of these products from a freezer and inject it into a joint and the magic will begin. Or so he thinks! For those of us who have been involved in regenerative medicine for a number of years, we know that this is simply not the case. We have been saying that typically these products do not have live cells with metabolic activity. Granted, they have growth factors, which will have some beneficial effects. But to say that these products are better than the patient’s stem cells, is not based on any science and is essentially untrue.
These companies are quick to tell unassuming physicians that there are many live viable cells in their products. This is where things get murky. If there are live cells in their products that will actually have some type of biologic effect, than this appears to be a violation of FDA guidelines.
FDA guidelines state that if a product has live cells with metabolic activity, than this product requires significant testing before it can be released to the public. So, there are two avenues that these companies can pursue. They either have to say that there are no live cells and register the product as a tissue product. This is a relatively easy process. If they claim live cells, than they have to apply for a biologics license. This is a process which requires a few years of testing and a biologics license which is a very arduous process.
In order to make sure that my thinking was correct, I sent an inquiry to the FDA on Aug 23,2018 and here is my answer from them. I took the liberty of highlighting certain portions in yellow highlight:
Dear Dr. Purita:
Thank you for your email to the Center for Biologics Evaluation and Research (CBER). CBER, one of seven centers within the Food and Drug Administration (FDA), is responsible for the regulation of many biologically derived products, including blood intended for transfusion, blood components and derivatives, vaccines, allergenic extracts, and cell, tissue and gene therapy products.
Cellular therapies are regulated by CBER as human cells, tissues and cellular and tissue-based products (HCT/Ps). FDA has a risk-based approach to the regulation of HCTP/s. Under the authority of Section 361 of the Public Health Service (PHS) Act, FDA established regulations for all HCT/Ps to prevent the transmission of communicable disease.
The regulations in 21 CFR Part 1271 identify the criteria for regulation solely under Section 361. HCT/Ps that meet all of the criteria in 21 CFR Section 1271.10(a) are regulated solely under Section 361 of the PHS Act. If all of the criteria in 21 CFR Section 1271.10 are met then no pre- market review (application to FDA) is required.
To satisfy these criteria, an HCT/P must be: No more than minimally manipulated (relates to the nature and degree of processing); intended for homologous use only (the product performs the same basic function in the donor as in the recipient); not combined with another article (with some limited exceptions); and the HCT/P does not have a systemic effect and is not dependent on the metabolic activity of living cells for its primary function, or if it does, the HCT/P is intended for autologous use or use by a first-or second-degree blood relative.
HCT/Ps that do not meet all of the criteria of 21 CFR Section 1271.10 are also regulated under Section 351 of the PHS Act and/or the Federal Food, Drug and Cosmetic Act as drugs, devices and/or biological products and would require pre-market approval.
Stem cell products have many different sources and potential biological activities and therefore need to be evaluated individually with respect to the 21 CFR Section 1271.10(a) criteria. Many experimental stem cell therapies do not meet at least one of these criteria.
For a stem cell product that does not meet the criteria for regulation solely under Section 361, a Biologics License Application (BLA) would need to be approved before commercial marketing.
The recently issued guidance documents titled “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use” and “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception” were provided to assist sponsors of HCT/P products in determining whether their products meet the first two criteria listed above. Even if a product meets both of those criteria, it must still meet the last two in order to be regulated solely under Section 361, and not require pre-market approval. Please know that guidance documents represent FDA’s current thinking on how sponsors of FDA regulated products can comply with current FDA requirements. Sponsors may adopt an alternative approach; however, that approach must still comply with FDA’s regulations, and in the case of cellular therapies, the regulations outlined in 21 CFR 1271.
With the issuance of the guidance documents mentioned above, FDA is adopting a risk-based and science-based approach that builds upon existing regulations to support innovative product development while clarifying the FDA’s authorities and enforcement priorities. This risk-based approach allows product developers time to engage with the FDA, to determine if they need to submit a marketing authorization application and, if so, submit their application to the FDA for approval. For the first 36 months following issuance of guidance documents above, the FDA intends to exercise enforcement discretion for certain products with respect to the FDA’s premarket review under the existing regulations. This policy will allow for a more orderly transition and limit the impact on available resources within the FDA.
A recent article published in The New England Journal of Medicine by Peter Marks, M.D., Ph.D., CBER Center Director and Scott Gottlieb, M.D., FDA Commissioner, provide further insight into FDA’s regenerative medicine policies: http://www.nejm.org/doi/full/10.1056/ NEJMsr1715626
We hope this information has been helpful. If you need further assistance, you may contact our office at [email protected] or 1-800-835-4709.
Sincerely,
Amy Temple
Consumer Safety Officer
Center for Biologics Evaluation and Research
Office of Communications, Outreach and Development U.S. Food and Drug Administration
Tel: 800-835-4709
[email protected]
This informal communication represents my best judgment at this time. It does not constitute an advisory opinion in accordance with 21 CFR 10.85, and does not necessarily represent the formal position of FDA or otherwise obligate the agency to the views expressed.
-----Original Message-----
From: joseph purita]
Sent: Thursday, August 23, 2018 1:58 PM
To: CBER OCOD Consumer Account <[email protected]>
Subject: opinion from FDA concerning certain products
I am writing this email to obtain an opinion from the FDA concerning certain products that that are being marketed to various specialties. In particular, I am wondering about umbilical cord blood derived mesenchymal stem cell products. My understanding is that these products are registered as a 361 with the FDA. Yet, these products state in some of their advertising material that they contain live mesenchymal stem cells which have metabolic activity. My understanding is if a 361 registered product has live stem cells with metabolic activity than it becomes a 351 requiring an IND license. I would like some guidance from the FDA on these products. If indeed these products registered as a 361 contain live cells with metabolic activity is that a violation of FDA regulations if they are used to treat patients for a variety of conditions? Do they actually require a 351 classification and IND application?
Thank you,
Dr. Joseph Purita
In the above letter, at the end, you can see my initial inquiry and subsequent answer from the FDA. On the surface this seems like a complicated letter. However, when you analyze it, it is fairly straight forward. As we can see the FDA is very specific that if a product has live cells with metabolic activity than this qualifies as a 351 product. A 351 product requires what is called an IND (Investigational New Drug application). This requires a few years of clinical testing and a few million dollars before the product is released for general use. It is fairly clear cut that these cord blood products fall into one of two categories. Either they do not have live cells with metabolic activity and thus they are essentially a growth factor tissue product or they have live cells with metabolic activity which is currently not allowed by the FDA regulations.
I am sure the dance by these companies will continue for a while longer.
The public needs to be aware that the chances are if a physician is utilizing these products you may not be getting what you were promised.
Buyer beware!
- Dr. P
P-53 PROTEIN: A NATURAL SENTRY, STEM CELL PROTECTOR, TUMOR SUPRESSOR, and ANTI-AGING CHAMPION
Could an elephant hold some of the secrets of longevity? The elephant is an animal which has great longevity. Scientifically speaking, this bucks the trends of nature. Typically, the more cells an animal has the more likely that a cancer or some other serious medical problem will arise and thus shorten life span. Yet the opposite is true for elephants, certain species of whales, and a host of other animals that have extreme longevity. The common thread for these animals is improved DNA repair and cell cycle regulation mechanisms to prevent DNA damage. This damage accumulates during the life course of the animal. The secret may be that these animals have extra amounts of the P-53 protein. This protein controls repair which in turn promotes longevity and resistance to age-related diseases.
Certainly, there is not just one factor which will increase longevity in large animals but there are some common threads. However, one very important thread concerns Telomeres which are the ends of the DNA in all cells. Every time our cells reproduce the telomere gets shorter until a certain critical length is achieved. This certain critical length sets a number of reactions into place. This is very evident in the following diagram. This diagram speaks of the work of Dr. Ron DePinho. It is called the unified theory of aging. This diagram comes from an article about a good friend, Dr. William Andrews. Dr. Andrews has a quest to search for substances which seem to stimulate telomerase. If we can stimulate telomerase we might prevent short telomeres. Remember that telomeres are the ends of the DNA which shorten every time our cells undergo division. Short Telomeres will cause the cell to becomes a wayward cell involved in all types of mischief. These cells are called senescent cells.
There is protein called P-53 which is activated by cells with short telomeres. The short Telomeres cause the cells to enter a phase called cell senescence. The diagram below explains better what causes senescent cells to arise and subsequently what problems senescent cell cause in the body.
What few people understand is that as cells age, some of them degenerate into a population of poorly functioning senescent cells that accumulate throughout our body. There is no value to retaining these lingering senile cells. Their continued presence underlies a myriad of degenerative disorders. Senescent cells should be purged from the body. The buildup of these dysfunctional senile cells contributes to decay of individual organs and greater susceptibility to disorders related to chronic inflammation and thus disease of aging. I have written a blog already on senescent cells. In that blog I spoke about some supplements which seem to attack senescent cells. The body has a much better way of attacking these cells. This method is called the P-53 protein. This is one of the foundations of giving elephants and other large animals their advantage in anti-aging.
This blog will target a very intriguing aspect of senescent cells called the P-53 protein. In the first diagram above we see that the P-53 activation is awoken by critically short telomeres. When the p-53 is activated it is a very good guardian. We can see the P-53 helps in cellular repair.
One of the main purposes of P-53 is to have some control over the cell division. If the cell has significant damage especially to its DNA than that cell is flagged and the cell is programed for death. This programed death of a cell is called Apoptosis. When the damage to the cell’s DNA is not that great than the P-53 protein will direct the DNA to repair itself. The following diagram is a bit more technical. It shows us what happens when P-53 is working properly and when it is damaged.
What we can see in the above diagram is that an abnormal P-53 may lead to cancer. For this reason, the P-53 protein is also called the tumor suppressor gene.
P53 is a tumor suppressor involved in a wide variety of tumor types. At least 50% of known tumors contain mutations of P-53 in humans and animals. These mutations are found in different cell and tissue types. This has made P-53 the one of the targets in cancer research and therapy worldwide.
Main stream medicine targets this tumor suppressor in gene therapy and uses the protein extensively in cancer therapy. Just like recombinant cytokines growth factors, there is a recombinant P-53 protein. Recombinant DNA technology is when we join together of DNA molecules from two different species that are inserted into a host organism to produce new genetic combinations that are of value to science, medicine, agriculture, and industry. Typically, bacteria can be programed by the recombinant DNA technique to produce medicines proteins etc. Nowadays Insulin is produced in this fashion.
The vision of using P-53 comes from the work of Dr. Biava who isolated the P-53 protein from the zebra fish, creating a recombinant protein. This P-53 protein carries the signaling and the function of the P-53 tumor suppressor factor allowing the practitioner to program the microenvironment of the cancer patient or anti-aging patient.
P-53 is a transcription factor. Transcription factors are proteins involved in the process of converting, or transcribing, DNA into RNA. Regulation of transcription is the most common form of gene control. The action of transcription factors allows for unique expression of each gene in different cell types and during development. P-53 modulates gene expression and induces Cell Cycle arrest, senescence or apoptosis (cell death), thereby preventing tumor formation. P-53 is killing those bad senescent cells. So, it seems that P-53 is a smart protein able to detect and regulate oncogene (cancer causing genes) activity. When there is no risk, P-53 is flagged for inactivity and degradation which suppresses its expression so that it does not interfere with normal healthy cell proliferation.
P-53 IS A BIG PLAYER IN THE CELL CYCLE
Abnormalities in the Cell Cycle lead to tumors. The normal Cell Cycle has four phases: Synthesis of DNA
Mitosis (cell division), 2 gap phases; one before each active phase; that is, before Synthesis and before Mitosis (cell division) respectively. But regulation of the cycle is also dependent on tumor suppressor genes such as P-53.
Getting back to the reason why elephants seem to have excellent longevity is due to the fact that elephants have evolved unusual P-53 genes. While we only have one copy of the gene, elephants have 20 copies. Research teams have observed that the elephant’s swarm of P-53 genes responds aggressively to DNA damage. Like many things in life it is a numbers game.
If we were to recap the many facets of P-53 we would find the following:
MAIN PROPERTIES OF p53
Tumor suppression which can dramatically reduce the incidence of cancer.
Maintains genomic stability in somatic cells. This means that the cells will not develop mutations that leads to all kinds of problems.
Regulates transcription, especially in stress responsiveness. Remember transcription involves the production of messenger RNA which turns on or off a variety of genes.
Regulates genes that control Cell Cycle arrest and cell death
Regulates homeostasis in cellular metabolism and Cell Cycle
Regulates autophagy. Autophagy is the process where sub-cellular organelles are destroyed and new ones are rebuilt to replace it. Think of it as similar to replacing parts on a car. Instead of replacing the entire car you just replace the defective parts. In autophagy old cell membranes, organelles and other cellular debris can be removed. This is done by sending it to the lysosome which is a specialized organelle containing enzymes to degrade proteins.
Involved in metabolic maintenance
Involved in fertility
Involved in cellular reprogramming
We can see the P-53 protein has far reaching tentacles. The P-53 protein responds to cellular stress in general. Oxidative stress in aging or degenerative pathophysiology can trigger the sentry to duty, so a recombinant P-53 protein can ostensibly be used in anti-aging therapies, degenerative conditions and prevention of tumorigenesis. This is the seminal point to this entire blog.
Rather than depend entirely upon our own P-53 protein, which potentially may have some mutations and loss of effectiveness, we are able to supplement it with a recombinant form of the P-53 protein. Remember, just like the elephant, it is a numbers game with P-53. We will have available a recombinant form of P-53. This will be supplied in the form of a patch which contains the P-53 with penetrating molecules. The patch is kept on overnight and then discarded. We feel this will be another nail in the coffin of aging. We still have a way to go but it is certainly a step in the right direction.
Thanks,
- Dr. P
In the diagram, we see one aspect on how we can increase stem cell numbers in some of our procedures in a safe and efficient way. We are constantly looking for ways to increase the stem cell output from the bone marrow. We know all too well that most of the regenerative cells that we inject into the joint typically survive for only a short period of time. Their release of growth factors is what gives the various signals for more cells to visit the area or, just as importantly, for some of the neighboring cells to help accomplish repair. It becomes a numbers game. The more cells we have in circulation the better chance we have to achieve success. Now, if we are able to find a medication that can increase stem cell numbers and at the same time have an effect on the health of the cartilage than we have something special. Parathyroid hormone (PTH) may be just the ticket.
For a number of years now we have been using a clone of Parathyroid hormone (PTH). Another PTH clone is known as Forteo. Forteo is used in the treatment of Osteoporosis. We are actually using another analog clone of PTH which has given us considerable cost savings and at the same time may work better. We first started using PTH as a stimulator of Very Small Embryonic Like Stem Cells (you can read about these cells on a previous blog). There is still some controversy to these cells but that controversy is on the wane. There is a receptor on the V cell surface that seems to stimulate these cells when the PTH binds to the cell membrane. It appeared to activate these V cells.
When we investigated PTH we were very intrigued by a number of scientific articles that show PTH can have some interesting effects on articular cartilage. The Univ. of Rochester is studying PTH for its ability to inhibit chondrocyte hypertrophy and induce cartilage matrix production. Chondrocyte hypertrophy is the beginning of the death spiral for chondrocytes which produce and maintain cartilage. Chondrocyte hypertrophy-like changes play a role in early and late stage Osteoarthritis (OA). Since not all cells in an OA joint are synchronized in their stage of the cell cycle, inhibition of hypertrophy-like changes might be a therapeutic target to slow down further OA progression. There are a number of studies that show that PTH is chondro-regenerative. There were many preclinical findings providing proof-of-concept that (PTH) may be useful for decelerating cartilage degeneration and inducing matrix regeneration in osteoarthritis patients. In addition to bone as a target, signaling downstream of the type I parathyroid hormone receptor (PTHR1) regulates chondrocyte differentiation. Parathyroid hormone-related peptide (PTHrP) a clone, is a potent stimulator of proliferation and collagen synthesis and suppressor of maturation. One classic article on this effect of PTH comes from the work of Dr. Eric Sampson and his group from Univ. of Rochester. They were able to show the chondro-regenerative properties of PTH. So, we can see that PTH may have some powerful effects on improving the status of articular cartilage and its underlying bone.
Another aspect of Parathyroid hormone is that it increases Prg4 expression which has been reported to inhibit articular cartilage degeneration in arthropathic joints. Lubricin is present in synovial fluid and on the surface (superficial layer) of articular cartilage and therefore plays an important role in joint lubrication and synovial homeostasis. Lubricin is the most lubricating and anti-adhesive molecule in the human body. Lubricin biosynthesis and bio distribution are mostly regulated by cytokines and growth factors. When first isolated, cartilage lubricin was called "superficial zone protein" (SZP) Lubricin, MSF, and SZP are now collectively known as Proteoglycan 4. Lubricin was originally identified as a lubricating glycoprotein present in the synovial fluid, specifically synthesized and expressed by articular chondrocytes (cells that makes cartilage) of the superficial zone. It is recognized to have a major protective role in preventing cartilage wear, synovial cell adhesion and proliferation and reducing the coefficient of friction of the articular cartilage surface. The best way to think of lubricin is that it is a very high-powered hyaluronic acid. Hyaluronic acid has been used for years as a treatment for symptomatic osteoarthritis of the knees. We are looking into getting a bioengineered form of Lubricin and Hyaluronic acid. Both Lubricin and Hyaluronic acid are more than lubricating agents. Lubricin and Hyaluronic acid as a biologically active molecules that regulates tissue repair process on multiple levels. They are signaling agents affecting many different cell processes. Hyaluronic acid (HA), one of the main components of the extracellular matrix, is considered a key player in the tissue regeneration process. It has been proven to modulate, via specific HA receptors that are located on cell membranes, inflammation, stem cell migration, and angiogenesis (formation of blood vessels). These are the main phases of healing. We typically use Hyaluronic acid in our treatment protocols. It is a very specialized form we are using. Unfortunately, many offices performing stem cell treatments do not go to this length and utilize Hyaluronic acid.
This is not where the story about the benefits of PTH stops. One of the missions of the regenerative medicine doctor is to come up with ways in which we are able to increase stem cell output from the bone marrow. We are aware that certain supplements may help in this endeavor. On such supplement that comes to mind is StemXcell which is licensed by the Univ. of South Florida. In some lab studies StemXcell was found to have similar effects as granulocyte colony stimulating factor (GCSF). GCSF is sometimes called Neupogen. Neupogen is used in cancer treatment to increase the numbers of white blood cells after for instance chemotherapy. GCSF will increase the number of white blood cells released into the system. At the same time, it will increase the number of other blood components released from the bone marrow including stem cells into the circulation. The problem with these medications is that they are very expensive and at the same time do present some substantial risks. Another product which increases stem cell output is Procrit. Procrit increases the number of red blood cells released into the circulation. Procrit and GCSF are manufactured by recombinant DNA technology meaning it is produced by Escherichia coli (E coli) which are bioengineered. Many of our medicines are produced by bio-engineered E. coli. We have utilized some of these recombinant DNA products in our lab.
What initially got our attention with PTH was the effect it has upon bone marrow. PTH has been demonstrated to influence and expand the bone marrow stem cell niche where hematopoietic stem cells, capable of both self-renewal and differentiation, reside. Moreover, intermittent PTH treatment is capable to induce mobilization of progenitor cells from the bone marrow into the bloodstream. This is what has wet our appetite. We now have a safe method of increasing the number of circulating stem cells in the circulation. This is similar to the effect of hyperbaric oxygen. Thru the work of Dr. Thom of the University of Pennsylvania we have discovered that hyperbaric oxygen will increase the number of circulating stem cells in the circulation. Dr. Thom discovered that hyperbaric oxygen works on a nitric oxide (NO) mechanism. The enzyme responsible for the production of NO in this case is endothelial nitric oxide synthase. The NO will stimulate the marrow to release large numbers of stem cells. We will give a NO supplement to increase the effects on bone marrow. This supplement is called Neo-40. We have used it for years to help increase the marrow stem cell output. However, PTH seems to have a more profound effect on marrow stem cell release. The PTH is given in intermittent doses. Stimulation with PTH showed a significant increase of all characterized subpopulations of bone marrow-derived progenitor cells (BMCs) in peripheral blood (1.5- to 9.8-fold) similar to GCSF. Luckily, PTH has a much better safety profile than GCSF. Also, our source is much more reasonably priced. This is a piece of our Advanced Cellular Repair Division.
On doing research we find one more important aspect of PTH. PTH seems to increase the amount of a chemokine called SDF-1 also known to many PHDs as CXCL-12. The major role of chemokines is to act as a chemoattractant to guide the migration of cells. The receptor on the cells that attracts the SDF-1 is called CXCR-4. The CXCR-4 is expressed on many circulating progenitor cells. The CXCL-12 and the CXCR-4 axis is one of themain axis of stem cell migration and homing. SDF-1 acts as a “tractor beam” on stem cells much in the spirit of Star Wars.
We continue to expand our uses of PTH. Luckily, we have an excellent source of a clone of PTH which is both effective and cost efficient. We are using the PTH on an intermittent basis. As time goes on we will find other medications and supplements to complement our use of PTH. We are ever pushing the envelope. Thanks DR. P
