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Extracellular vesicles (EVs)
CYTOKINE THERAPY
OUR NEXT QUANTUM LEAP IN REGENERATIVE MEDICINE: CYTOKINE THERAPY
We believe the use of growth factors has taken our practice to the next quantum leap. We have been using growth factors to enhance our results with our stem cell and PRP treatments for some time now. Growth factors are signaling molecules that are typically secreted at the site of repair by many different cell types including platelets, stem cells and fibroblasts. These growth factors bind to the cell membrane and start the cascade of DNA synthesis, mitosis and cell repair. Some of these growth factors effect the stem cell environment or as it is sometimes called the “stem cell niche”. It will make the environment much more favorable to the various stem cells.

The technical term for the various growth factors is cytokines. Cytokines—from the Greek cyto- (“cell”) and kinos (“movement”)—are tiny cell-signaling protein molecules secreted by various cells. Constituting a category of signaling molecules utilised widely in intercellular communication, cytokines may be classified as peptides, proteins, or glycoproteins. You might think of the cytokines as the bodies mobile phone system. They can be the difference between success and failure. Cytokine imbalance is responsible for most disease processes.

Cytokines activity is mostly local, but in some cases they impact the entire body. There are several groups of Cytokines or growth factors. These growth factors can act in three main ways. The first is that it can act in an endocrine fashion. This means that the growth factors may affect cells in a distant area. This is similar to our bodies own endocrine system. For instance, our pituitary gland located in our head affects cells in many different parts of the body. The next aspect concerns Paracrine signaling action which means that the factors may affect neighboring cells. The last aspect is an autocrine action meaning that the factors affect the surrounding cells. Interestingly enough stem cells work in a very similar fashion. One should think of the cytokines as architects of cell repair. The repair occurs mainly at the cellular level. The area surrounding the cells is called the extracellular matrix.

We must realise that there are both good and bad cytokines. If you have a symptomatic osteoarthritis the chances are that your symptoms are caused by bad cytokines. Two bad cytokines that comes to mind are Interleukin 1 (IL-1) and Interleukin 6 (IL-6). These bad cytokines cause pain, swelling, and typically cell death. When you are causing cell death you are in what we call a catabolic state. This means you are breaking down tissue causing destruction of the cells and eventually failure of the system. Another important bad cytokine is called Tissue Necrosis Factor or TNF. TNF will cause cell death and block repair. In Regenerative Stem Cell Therapy we are trying to counteract these bad cytokines by manipulating good cytokines that come from both stem cell and PRP injections. We are to turn the tide and get the joint or tendon into an anabolic state. An anabolic state means we are now building up tissue.

Three very important good cytokines are Interleukin-1-Antagonist (AIL-1 also called IL-1A), Interleukin 10, and IGF-1. They can override catabolic action of the bad cytokines. What these growth factors actually do is try to modulate or diminish the inflammatory response. We now know this is one of the most important jobs of mesenchymal stem cells. If a significant inflammatory response is present than repair is jeopardised. Realise that the reduction of inflammation is more on a cellular level and thus non-steroidal anti-inflammatories will not achieve this goal.

In addition to modulating the inflammation, the good cytokines actually help repair the tissue. There are many good cytokines that can accomplish repair. I would have to write a book to discuss them all at length. What I would to do is give a brief synopsis of what is probably the more important ones but realise they are all important.

One of these factors is Transforming Growth Factor or TGF. TGF is important in collagen synthesis and tissue repair. This is a major repair growth factor. TGF appears to stimulate macrophages (a form of white blood cell) to secrete various growth factors. It also directs the macrophages and other cells to areas needing repair. Finally, it stimulates angiogenesis (which means that it forms blood vessels). Another important factor is Fibroblast Growth Factor or FGF. FGF helps organise connective tissue. FGF’s functions are similar to TGF but it seems more involved with stimulation of new growth of blood vessels.

Insulin Growth Factor or IGF-1 is the active form of Human Growth Hormone. This is a multi-talented growth factor. It is very important in cell division etc. It is so important that we are giving it as an intra-articular (joint) injection or an injection into a tendon. IGF-1 found in PRP and stem cells. It is secreted by the liver thru stimulation of Growth Hormone. Studies show that IGF-1 stimulates the glucose uptake by cells thus supplying them with more energy. It also inhibits protein catabolism (destruction). It is also believed that it affects cell receptors which drive a stem cell toward the formation of cartilage tissue. It seems to block many of the interleukin inflammatory pathways.

One more important growth factor is called Vascular Endothelial Growth Factor or VEGF. VEGF is important in that it helps to establish a blood supply where typically there is no blood supply. This is a very important concept in stem cell science.

Up until now these specific factors were extremely expensive and sometimes had significant side effects. Previously, it was almost impossible to obtain these growth factors. They are now available and are extremely safe if used properly. The trick is to learn to use them in the proper dosage regimen and combination. Luckily the company we are dealing with is a company that has staff who are the expert’s expert in the field of cytokine medicine. In simplistic terms what we have now achieved is the ability to significantly affect the joints or tendons we are working upon in a very positive way. These factors dramatically increase the efficacy of the stem cells to accomplish repair.

Up until this time we had to depend solely on the body’s own production of growth factors such as those found in a PRP. The problem with the PRP is that the growth factors seem to run out after about one week. Now we are supplementing the cytokine production by giving these factors on an oral basis. We take this two steps further by using cytokines in the form of injectables and transdermal creams. With these different forms of cytokines a more sustained release of growth factors will occur enhancing the repair. We are now utilising these growth factors on patients on a daily basis. We will prescribe a regimen of multiple growth factors to be taken on a daily basis. These cytokines are what we call recombinant which means they are produced in a lab in culture medium.

Cytokine therapy is one the new exciting fields in medicine which like stem cells has the ability to dramatically change the face of medicine and treatment protocols designed to conquer a variety of conditions. We may come to the conclusion someday that just using these cytokines may eliminate the need for harvesting stem cells. Will these cytokines make stem cells obsolete? I doubt it but only time will tell if this comes to fruition. Cytokine Medicine truly represents a Quantum Leap in Medicine. It certainly represents a Quantum leap in our practice. Cytokines are the building blocks of life. When we master cytokine therapy we will significantly reduce the debilitating effects of most diseases.

To be on the cutting edge of the cutting edge we utilise exosomes with our PRP, Cell-Based and Cytokine treatments. We have a propriety method of obtaining exosomes from the plasma. Exosomes are important in that they help transport growth factors to various areas of the body.


EXOSOMES THERAPY

Exosomes are so-called Extracellular vesicles (EVs), or small bubbles (about 30 to 150 nanometres (nm is 1x10-9 m, or one billionth of a metre) in diameter: around the same size as many lipoproteins but much smaller than cells) , released from cells, especially from stem cells. They act as shuttles for certain genetic information and proteins and messenger RNA to other cells. They allow for cell-to-cell communication, transporting molecules that are important regulators of intracellular information between close and distant cells. They carry information from place to place with different functions and purposes telling cells how and when to react. Exosomes carry healthy and lost information and insert this to target cells. Exosomes released by young stem cells have shown to be very powerful in regulating regenerative processes in the body and assisting in rejuvenation. Exosomes are being heralded as the next frontier of cell therapy. While not being cells at all, they play a vital role in the communication and rejuvenation of all the cells in our body. Science has shown that the cell-to cell communication is important in maintaining a healthy cellular terrain. Age, chronic disease, environmental factors and genetic disorders can interfere with how our stem cells communicate with other cells, thus disrupting the healing process. Exosomes play a key role in the regulation of these communication processes.


Dr. Aubrey de Grey "Exosomes circulate and penetrate into tissue"
What Is Exosome Therapy?

Research has given us a valuable insight into the practical functionality of exosomes. By exposing the cells of an older organism to those of a younger organism we can see that exosomes from the young stem cells are responsible for rejuvenating the older cells. This healing mechanism can now be used in regenerative medicine.

A degenerative disease comes from a continuous deterioration of cells, affecting tissues or organs. While stem cells are usually responsible for the rejuvenation of the cells, external factors may hinder the stem cells in this function. They may not be able to supply all the information needed.

Supporting their function with external exosomes could have a greater positive effect, by providing new pieces of information to support the healing process.

Exosomes help regulate processes within the body. Patients with Lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases may benefit from including exosomes in their treatment regimen. Exosomes may also be beneficial as part of an anti-aging therapy. Patient with degenerative joint disease have also benefitted from the use of exosomes.

Exosomes and Lyme Disease

Lyme Disease is a very complex disease, caused by the Borrelia burgdorferi bacteria, which compromises the immune system. Tick-borne disease can also come with multiple co-infections. A combination of factors causes the onset of illness as immune system functions become disrupted leading to diminishing cellular health, immune function, metabolic function and dramatically increasing inflammation. Many Lyme patients often have dysfunction of the mast cells, increasing their inflammatory response. Inflammation is a central player in most neurodegenerative diseases as well. Incorporating exosomes into a multi modality treatment regimen may help break the inflammatory cycle and provide the body with necessary cellular information to facilitate healing. Exosomes from stem cells contain valuable cell information consisting of proteins and genetic information the cell needs to function correctly. These stem cell derived Exosomes have also shown to assist in transferring NK cells (Killer cells) into T-Regulator cells (Helper cells) By that they assist in calming an overreactive immune system and modulating it to respond in a coordinated fashion. They can also be used as a delivery system for medication.

How Is the Therapy Performed?

Exosomes can be administered as an IV treatment, IV push, transdermal cream, oral drink, nose drops, eye baths and any kind of topical medication. As a part of joint rejuvenation therapy, exosomes are administered directly into the affected joint area. The normal concentration is 1 billion exosomes per 1ml. One treatment may consist of up to 15 billion exosomes. The dosing is individual to every patient and there is no set or established protocol.

What Can I Expect After the Procedure? Are There Any Side Effects?

Exosome therapy is usually performed on an outpatient basis. Most patients should expect to leave the clinic without any down time. The patient will not experience any discomfort. Less than 10% of patients have reported developing a mild fever, headache, nausea or vomiting. However, these side effects have never lasted more than three days and usually resolve within 24 hours. No long-term negative side effects have been reported.

When Can I Resume Physical Activity?

In order to gain an optimal response from exosome therapy, we recommend the following:

  • Refraining from anti-inflammatory medication
  • No over strenuous activity for the first 24–48 hours
  • Resume cardio workouts after 3–4 weeks
  • After four weeks resume any weight lifting and running activity if part of your prior routine



  • Rapidly opsonized

    Prof. Dr. Raymond M. Schiffelers "Microvesicles communicate, and can be trasfered
    from one cell type to another as a clinical nanomedicine
    "
    Are Exosomes Safer Than Stem Cells?

    Both stem cells and exosomes have their place in a treatment protocol. This much depend on what the treating physician is trying to accomplish. When performed correctly, treatment with exosomes and/or stem cell therapy is safe. Stem cell derived exosomes can be safely harvested and do not proliferate but rather transfer valuable biological signals to the recipient’s tissues and facilitate the normalisation of various pathological processes.

    Is There Any Theoretical Risk of Viral Reactivation with Exosomes?

    This would be extremely unlikely. It is possible though to have an immune response to viruses due to the immune modulation. This is not viral reactivation.

    Is There Any Theoretical Risk of the Body Rejecting Exosomes with Them Being a Foreign Substance?

    This is extremely unlikely as there are no immune markers on the surface of the exosomes. They are not cells or tissue. It may be possible to experience die-off reaction after receiving exosomes as these activate the natural killer cells to become T-Regulator cells.

    Are All Exosomes the Same for Every Patient or Can They Be Individualised? And How Would They Be Individualised?

    There are different types of exosomes. The end product contains many anti-inflammatory cytokines and immune modulatory proteins. It is also possible to produce different kinds of exosomes. Some involve the use of a patient’s own tissue to provide specific markers in combination with laboratory produced exosomes. The legalities in each country also play a role in what is possible. The treating doctor can decide if individualisation is necessary and what that best type of individualisation may be.

    Is There Any Risk of Them Forming Teratomas?

    No, as they are NOT embryonic stem cells. Exosomes do not multiply. Exosomes transfer valuable biological signals to the recipient’s tissues and facilitate the normalisation of various pathological processes.

    Will People Need Multiple Rounds of Exosomes, and If So, How Should They Be Spaced Apart?

    In some case a follow-up treatment may be advised. There is no sustainable data about standard dosing and the treatment is as individual as the response. Some patients may need a single application, while others need multiple doses or a small booster therapy. In some cases, therapy may start with a small initial dose which is increased over time.

    How Do They Work for MCAS? Is There Any Risk of MCAS Getting Worse If It Shifts Your Immune System Further the Wrong Way?

    Exosomes insert information in the cell. The information is basically ‘This is what a healthy cell is like and this is how to get there”. This process happens in 2 stages. In the initial phase the exosome inserts proteins into the cell. We know exosomes contain a whole array of inflammation regulating proteins. These basically quench the immediate inflammatory response. The exosomes also insert messenger RNA into the cell which is the recipe and instructions for the cell to make its own inflammation regulating substances. One has to keep in mind that MCAS is only possible with dysfunctional or damaged mast cells. Exosomes are thought to insert the missing information into the mast cells to help normalise or stabilise them and prevent them from being dysfunctional.

    How Long Do Exosomes Work in the Body? What Is the Timeline?

    Exosomes trigger a so-called bi-phasic response. First, an immediate reaction. This usually last about 24 hours until the initial proteins have been broken down. Then the messenger RNA, which has been inserted into the target cells becomes active and helps ‘reprogram’ the cell. This usually takes 6-8 weeks. So the timeline is about 8-10 weeks. The continued effects may continue for months afterwards.

    Are Exosomes the New Immune Modulator?

    Immune modulation using supportive therapies and healthy food to reestablish foundational body systems and functions is recommended. This includes establishing a healthy immune response by balancing the immune cells and sensitising the immune system to pathogens. An immune response may be enhanced or suppressed by exosomes depending on their cell of origin and its functional state. Stem cell derived exosomes have been reported to impair dendritic cell maturation and to regulate the activation, differentiation, and proliferation of B cells. They have been shown to control natural killer cell activity and to suppress the innate immune response (IIR).

    Do They Multiply in the First 100 Days like SVF or Only Work at Signaling Cells Without Multiplying?

    Exosomes do not multiply themselves but can assist other cells in their proliferation by inserting missing cell information in them. This before mentioned bi-phasic response will last approx. 3 months and can influence the stem cell activity in the body.

    What Are the Signs That Exosomes Are Working and When Can a Person Can Expect to See the Benefits?

    The bi-phasic response can be accompanied with a certain set of symptoms. These may indicate that the exosomes are assisting in the repair and regulation process. In the initial phase patients generally report a reduction of their inflammatory symptoms. After 6-8 weeks the second phase of the response takes place in which the information the exosomes transferred to the cells is used by the cells to regulate and reprogram the cell function and aid in repair processes. This process can result in episodes with low energy or light flew like symptoms and a flare up of individual symptoms. Typically, early benefits of therapy are observed in 3-4 months. However, it is not uncommon, to see the benefits after 9 to 12 months.

    Can Exosomes Cause Cancer?

    Cancer Exosomes can cause cancer to grow. These are not to be confused with exosomes derived from young day zero stem cells which are used for treatment. Stem cell derived exosomes can actually be indicated in the treatment of some cancers as they can insert the missing proteins into the cancer cells and stop their replication.

    Do Exosomes Help Chronic Inflammation?

    Research has shown that stem cell-derived exosomes have an anti-inflammatory potential and induce high levels of anti- inflammatory cytokines and can therefore assist to regulate the inflammatory response. In addition, they can also inhibit abnormal macrophage activation. The macrophage is a large white blood cell that is an integral part of our immune system. Its job is to locate microscopic foreign bodies and ‘eat’ them.

    Can Patients with Chronic Infections and Autoimmune Diseases Benefit From Exosomes?

    Chronic infections have a lot in common with autoimmune diseases, including dysregulated immune response incapable of protecting our body from intruding pathogens (bacteria, viruses, molds etc.) while attacking its own tissues and organs thus causing significant structural damage. One of the key mechanisms controlling the direction of immune responses is a balance between specific immune cells involved in protection vs autoimmune responses, the Th17/Treg ratio. Exosomes from mesenchymal stem cells have shown to normalise the Th17/Treg ratio and bring the deviant immune response back to normal.

    Can Exosomes Benefit Neurodegenerative Diseases?

    Research has shown that:

    Exosomes can penetrate the blood-brain barrier and stimulate neuronal differentiation, neuronal growth, and suppress inflammatory processes within the brain tissue.


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