Table of contents

• – Introduction to stem cell therapy
  • –MSC – what is it?
  • -History
  • –Why there is no immune rejection?
  • -What types of stem cells are there?
  • -What are exosomes?
  • PRP and other Prolotherapies
• – Traditional Joint Replacement
• – Cortisone Steroid injections
• – Stemcell Science
  • – Introduction to umbilical chord technlology
  • – Arthritis
  • – ACL and Meniscus repair
  • – Disc repair and paralyses
  • – Heart disease
  • – Internal Medicine
    • ALS
    • Brain cancer and intra-nasal delivery
    • COPD
    • MS and other Autoimmune Disease

 

INTRODUCTION TO STEM CELLS and other injection therapies

 

What is evidence-based medicine?

Evidence-based medicine is an intelligent and personal approach to medical practice intended to optimize decision-making by emphasizing the use of the newest technologies and scientific research. This approach includes the use of personalized diagnostics that ensures the best strategy for your condition.  Your stem cell treatment will be analyzed and designed around the latest stem cell clinical research studies where both safety and efficacy have been shown. This includes the safe harvesting of tissue, the processing of cells and the administration of stem cells into your body. In short our approach  to medicine is based on evidence on what works best for you!

What are the different sources for Stem Cell Therapy?

Human tissue allogenic products derived from umbilical cord (UC-MSC) deliver industry-leading quality in a variety of form factors. There are several proprietary stem cell manufactures available. The extraction process is highly delicate, preserving natural elements and maximizing the density of viable cellular materials. In addition, the proprietary cryopreservation process maximizes the viability of live cells and the concentration of these products.  Autologous sources such as bone marrow and adipose are also discussed below.  All tissues are tested for disease and the manufacturing process is observed by FDA regulations.

 

What is a stem cell?

The definition of a stem cell is that it can replicate itself and differentiate into new specialized tissue such as cartilage, a heart muscle cell or a neuron. There are many different types of stem cells or progenitor cells.

MSCs (Mesenchymal) are so-called ‘multi-potent’ stem cells at a much later stage in development compared to a ‘toti-potent’ embryonic stem cell. Embryonic stem cells (ES) are only used for research purposes and cannot currently be used for therapy.

MSCs are safe but yet powerful. In addition there are HSCs (Hematopoietic) which are precursors of white blood cells. These stem cells have an immune modulator purpose. MSCs and HSCs are inter-convertible. MSCs do not necessarily ‘implant’ into the body but rather give the body a regenerative message. They are are highly anti-inflammatory, reduce scar tissue and mobilize the bodies own stem cells.

 

Terminology, what are the different available cellular biologics?

These are the currently available sources of cellular biologics – these are not embryonic and have nothing in common with fetal tissue research.

MSC = mesenchymal stem cell or stromal cell

Amniotic or placenta = these tissues contain very low numbers of MSCs

Umbilical chord cells= MSCs that are derived from Wharton’s jelly (a compartment of the umbilical chord)

Bone Marrow BMMSC = autologous derived from bone marrow aspirations (typically more rich in HSC – Hematopoietic stem cells)

Adipose = autologous or allogeneic also called SVF (Stromal Vascular Fraction)

iPS = induced pluripotent stem cells, genetically engineered 

CAR-T = a form of immunotherapy that uses genetically altered T cells – not stem cells

CAR-NK = a novel immunotherapy strategy by utilizing genetically-engineered NK cells to target specific cancer – not stem cells

HSC = Hematopoietic immature cell that can develop into all types of blood cells, including white blood cells, red blood cells, and platelets

Exosomes = extracellular vesicles generated by tissue cultured MSC cells 

 

What is an MSC?

MSC stands for mesenchymal stem cell, which is a type of adult stem cell that can differentiate into a variety of cell types, including bone, cartilage, muscle, and fat cells. Mesenchymal stem cells are found in various tissues throughout the body, including bone marrow, adipose tissue, and umbilical cord tissue.

MSCs have a unique ability to regenerate damaged tissues, modulate immune responses, and secrete growth factors that promote tissue repair and regeneration. This makes them an attractive candidate for use in cell-based therapies and regenerative medicine.

However, there is some debate if these cells truly meet the definition of a stem cell. MSCs have a finite life time of about 80 division cycles to ensure there is no risk for cancer. Some researchers prefer to use the term “mesenchymal stromal cell” instead, to reflect the fact that these cells may not have the full self-renewal and differentiation capabilities of toti-potent stem cells. For therapeutic reasons an MSC is preferable over a stem cell.

Mesenchymal stem cells (MSCs) are generally considered to be multipotent rather than pluripotent. This means that they can differentiate into a limited number of cell types related to their tissue of origin (such as bone, cartilage, and fat cells), as opposed to pluripotent stem cells, which can give rise to any cell type in the body. However, research in this area is continually evolving.

Here are some references you may find helpful for exploring the potential of MSCs, though it is important to consult the most recent literature for the latest findings:

1. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., … & Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315-317.
[PubMed](https://pubmed.ncbi.nlm.nih.gov/16923606/)

2. Phinney, D. G., & Prockop, D. J. (2007). Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells, 25(11), 2896-2902.
[PubMed](https://pubmed.ncbi.nlm.nih.gov/17656645/)

3. Caplan, A. I. (2007). Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. Journal of cellular physiology, 213(2), 341-347.
[PubMed](https://pubmed.ncbi.nlm.nih.gov/17620285/)

4. Chamberlain, G., Fox, J., Ashton, B., & Middleton, J. (2007). Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells, 25(11), 2739-2749.
[PubMed](https://pubmed.ncbi.nlm.nih.gov/17656641/)

5. Ullah, I., Subbarao, R. B., & Rho, G. J. (2015). Human mesenchymal stem cells—current trends and future prospective. Bioscience Reports, 35(2). https://pubmed.ncbi.nlm.nih.gov/25797907/

Remember that the terminology and understanding of MSCs and their abilities are evolving, so it’s crucial to continually update your knowledge from reputable sources.

Are Stem Cells safe and FDA approved?

Stem cell products go through comprehensive clinical and laboratory testing to ensure they are safe and effective for patient use. They comply with US FDA regulations for Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) identified in 21 CFR Part 1271 and Section 361 of the Public Health Service Act. Compliance with these regulations ensures the delivery of quality allograft products to healthcare providers with confidence. All manufactures undergo a rigorous yearly inspection to ensure a clean and safe record.

Why Umbilical MSCs?

The main difference of UC derived stem cells (UC-MSC) to autologous MSCs is probably the age of the cells and the regenerative message they provide. Nature has provided a rich stem cell tissue within the umbilical cord to regenerate the mothers tissue after birth and help grow the fetus. Wharton’s jelly is a gelatinous substance that is found in the umbilical cord. It is a type of connective tissue that surrounds the blood vessels in the cord, providing support and protection. Wharton’s jelly also prevents compression of the blood vessels in the umbilical cord, which can impede the flow of oxygen and nutrients to the developing fetus and is an ideal tissue for MSC cells.  UC-MSC come with an array of regenerative growth factors and anti-inflammatory cytokines. UC-MSC come with an array of regenerative growth factors and anti-inflammatory cytokines. These go to work right away:

• 1) Studies show that inflammatory markers such as TNFalpha and IL-6 are reduced by 80% in the first few days.
• 2) Then fresh exosomes produced or included by tissue culture production deliver a message to reduce old scar tissue.
• 3) Implanted MSCs stay in your body for month to stimulate your own body cells to regenerate proper tissue such as cartilage or tendons

In Summary:

Wharton’s jelly is an excellent source for mesenchymal stem cells (MSCs) because it contains a high concentration of these cells, which have the ability to differentiate into various cell types, such as bone, cartilage, and fat cells.

One of the advantages of using MSCs derived from Wharton’s jelly is that they are relatively easy to isolate and expand in the laboratory. Unlike other sources of MSCs, such as bone marrow or adipose tissue, which require invasive procedures to obtain, Wharton’s jelly can be obtained non-invasively from the umbilical cord after childbirth.

Additionally, MSCs derived from Wharton’s jelly have been shown to have unique properties compared to MSCs from other sources. For example, they have a higher proliferation rate and a greater potential for differentiation, which makes them an attractive option for use in regenerative medicine applications.

What are ‘autologous’ derived Stem Cells and what are the side effects?

So called “autologous” Bone Marrow and Adipose tissue derived Stem Cells (and from other tissues if possible) means that you harvest cells from your own body. However in reality this means a “reuse” of your own body ‘aged’ stem cells. Although these procedures can have benefits in certain cases they generally do not produce the same outcome as UC derived stem cells. In addition, these procedures have a high occurrence of side effects. According to this large study provided by one of the biggest stem cell therapy companies about 14% of the patients treated from their own bone marrow had serious side effects. In contrast UC-MSC stem cells provide a rejuvenating therapy and have no serious side effects. However both procedures to harvest bone marrow and adipose stem cells have advanced in recent years and are certainly viable sources for stem cell therapy. Bone marrow stem cell contain more hemopoietic stem cells that work on the blood level and are less useful for joint repair. Adipose tissues need to undergo a substantial manipulation with mechanical or enzymatical procedures to harvest the pluripotent MSCs.

Adipose derived procedures are relatively safe however there is a small risk of embolism during liposuction; but it is relatively rare, but it is a serious complication that can be life-threatening. Pulmonary embolism, specifically fat embolism, is the most concerning type of embolism associated with liposuction. Fat embolism occurs when fat tissue enters the bloodstream and travels to the lungs, causing respiratory distress and potential circulatory collapse.

The exact incidence of embolism during liposuction is difficult to determine, as many cases may go unreported or undiagnosed. A study published in the journal Aesthetic Surgery Journal in 2008 reported an incidence rate of 0.002% for fat embolism during liposuction. Another study in the Journal of Plastic, Reconstructive & Aesthetic Surgery from 2006 reported an overall incidence of pulmonary embolism in liposuction patients as 0.0001%. These numbers suggest that while the risk is low, it is still present and should be taken seriously.

To minimize the risk of embolism during liposuction, surgeons follow strict safety guidelines and use appropriate surgical techniques. Patients should choose a board-certified plastic surgeon experienced in liposuction and discuss any personal risk factors and concerns during the consultation process.

Sources:

1. Grazer, F. M., & de Jong, R. H. (2000). Fatal outcomes from liposuction: Census survey of cosmetic surgeons. Plastic and reconstructive surgery, 105(1), 436-446.
2. Dillerud, E. (1990). Suction lipoplasty: a report on complications, undesired results, and patient satisfaction based on 3511 procedures. Plastic and reconstructive surgery, 86(5), 891-897.

 

Are there any side effects or rejections?

To our knowledge, in clinical practice, there are no side effects other than some mild pain and bruising from the injection needle itself. The stem cells are isolated from Umbilical cord C-sections. All donors are screened to ensure they meet the eligibility criteria established by the FDA. To avoid any possible contamination blood testing is performed by an independent lab to ensure donor screening is complete for communicable diseases including, HIV I/II, HBV, HCV, Treponema pallidum, HTLV I/II, WNV/NAT, and Cytomegalovirus (CMV). Additional donor screening includes a medical history interview, physical examination, behavioral risk assessment, and information from other sources or records which may pertain to donor suitability.

The placenta does not mix with the blood of the mother and there is no issue with compatibility with amniotic tissue. These UC stem cells have been tested and there are no markers on the cell surface that would cause an immune response. There has never been a reported case of an adverse reaction from this source of MSC stem cells in the US. However, like in any medical procedure more serious side effects can not be excluded from the procedure.

 

Why is there no immune-rejection?

On the contrary MSCs have been show to positively regulate your immune system and down regulate inflammation. Several studies have shown that these cells exert an immunosuppressive effect on cells from both innate and acquired immunity systems. Mesenchymal stem cells can regulate the immune response by inhibiting the maturation of dendritic cells, as well as by suppressing the proliferation and function of T and B lymphocytes and natural killer cells.  Graft vs host disease was actually shown to be lower after UCB transplantation compared to that of BM HSCT.  

How long will the treatment last?

The stem cells are injected into your joint and attach to your target tissue; The Cells and the included growth factors then recruit and stimulate your bodies’ own stem cells, so in essence this process will last 6 month or more. Most people only need one injection however in more serious cases or if internal medical problems are treated a repeat treatment may be necessary. 

 

What is PRP?

Platelet-Rich Plasma (PRP) therapy is ‘considered’ a regenerative medicine technique wherein a concentration of platelets from a patient’s own blood is injected into damaged tissues to promote healing. However, it is NOT a ‘stem cell therapy’ and PRP often has massive side effects and should not be confused with MSCs. The understanding of PRP’s inflammatory and anti-inflammatory properties can be complex, so let’s break it down:

1. Platelets and Inflammation: Platelets, by nature, play a role in both coagulation (blood clotting) and the body’s inflammatory response. When tissues are injured, platelets release a variety of growth factors and cytokines. Some of these molecules can induce inflammation, which is a part of the body’s natural healing process. Inflammation can help remove damaged cells and pathogens and prepare the tissue for repair.
2. Anti-Inflammatory Effects?: While platelets certainly initiate inflammation and many inflammatory markers such as IL-6 are present with this fraction of blood preparation, PRP also contains  molecules that can reduce inflammation and pain. For instance, PRP has been shown to release anti-inflammatory cytokines and decrease the production of pro-inflammatory cytokines in certain settings. However the question remains if an individual (usually untested) blood sample has any such message.
3. Variability in PRP Preparations: Not all PRP is the same. Depending on how PRP is prepared, it can have different concentrations of platelets, white blood cells, and other components. For example, leukocyte-rich PRP (L-PRP) contains more white blood cells and might produce a stronger inflammatory response compared to leukocyte-poor PRP (P-PRP). The specific preparation and application can influence whether the PRP acts in a more inflammatory or anti-inflammatory manner.
4. Clinical Uses: PRP is used in various clinical settings, from orthopedic injuries to aesthetic medicine. The goal isn’t necessarily to induce inflammation but to stimulate healing. In some cases, a short-term inflammatory response might be beneficial for healing, while in others, the anti-inflammatory and regenerative properties of PRP are more desired.
5. Research and Outcomes: The effectiveness of PRP is still a topic of research, and results can vary based on the condition being treated, the PRP preparation method, and individual patient factors. While there’s evidence supporting the use of PRP for certain conditions, it’s not universally accepted as effective for all proposed applications.
6. Adverse Reactions: PRP injections of any kind and especially inter-osseous can have significant side effects of long term pain and trauma.

So PRP (platelet rich plasma) injections are prepared from the patient’s OWN blood with a strict sterilized technique. After being centrifuged, the activated platelets are injected into the target area, releasing growth factors that recruit and increase the bodies’ own healing capacity.

Understanding PRP and Inflammation:

1. Role of Platelets in Healing: Platelets release growth factors and cytokines that are essential for initiating the healing process, which starts with inflammation. This inflammation is a natural and necessary phase of tissue repair.
2. Inflammatory vs. Anti-Inflammatory Effects: PRP can have both pro-inflammatory and anti-inflammatory effects, depending on various factors like the concentration of platelets, the method of preparation, and the presence of white blood cells (leukocytes) in the PRP. Leukocyte-rich PRP tends to be more pro-inflammatory, while leukocyte-poor PRP may have less of an inflammatory effect.
3. Context-Dependent Effects: The impact of PRP on inflammation may vary depending on the tissue type and the specific injury or condition being treated. For example, in certain orthopedic conditions, the initiation of an inflammatory response promoted by PRP can be beneficial for healing.

 

Isolating Platelets from the Buffy Coat:

1. PRP Preparation Process: PRP is typically prepared by centrifuging a sample of the patient’s blood. This process separates the blood into different layers, with the “buffy coat” layer containing a concentration of platelets and white blood cells.
2. Removing Platelets: It is possible to isolate and concentrate platelets from the buffy coat. The precise method of doing this can vary. Some protocols involve a two-step centrifugation process: the first spin separates red blood cells from plasma and the buffy coat, and the second spin concentrates the platelets within the plasma.
3. Customization: The PRP preparation can be customized to some extent. For instance, adjusting the centrifugation parameters can alter the concentration of platelets and the presence of other cells like leukocytes. This customization allows for the creation of PRP formulations that are more or less inflammatory, depending on the intended use.
4. Technique Variability: There is considerable variability in PRP preparation techniques, which can affect the final composition of the PRP and, consequently, its effects. Standardization in PRP preparation is a topic of ongoing discussion in the medical community.

In summary, PRP is generally pro-inflammatory, but this can be part of its mechanism in promoting healing. The degree of inflammatory response depends on various factors, including the specific preparation of the PRP. It is possible to isolate platelets from the buffy coat, and the method of doing so can be adjusted to suit different therapeutic needs.

The challenge in isolating platelets without also collecting some leukocytes (white blood cells) and potentially a small number of red blood cells (RBCs) during the preparation of Platelet-Rich Plasma (PRP). The “buffy coat,” which is targeted in PRP preparation, indeed contains a mixture of these cells. Let’s clarify this process and the inherent difficulties:

1. Buffy Coat Composition: The buffy coat layer formed during centrifugation of blood contains not only platelets but also leukocytes. This layer is typically situated between the plasma and the red blood cell layers.
2. Challenge in Isolation: Completely isolating platelets from leukocytes using standard centrifugation techniques is challenging because both cell types are present in the buffy coat. The goal of PRP preparation is to concentrate platelets, but this often involves some degree of leukocyte inclusion.
3. Leukocyte-Rich vs. Leukocyte-Poor PRP: Depending on the centrifugation technique and protocol used, the resulting PRP can be either leukocyte-rich (L-PRP) or leukocyte-poor (P-PRP). L-PRP contains more white blood cells and is more pro-inflammatory, whereas P-PRP has fewer leukocytes.
4. Customization of PRP: By adjusting centrifugation speed and duration, it’s possible to influence the composition of the PRP. Higher centrifugal forces may pack more RBCs and leukocytes at the bottom of the tube, allowing for a clearer separation from the platelet-rich layer. However, this also means that the resultant PRP might have fewer platelets.
5. Clinical Implications: The presence of leukocytes in PRP can be both beneficial and detrimental, depending on the clinical situation. For example, in certain orthopedic applications, the pro-inflammatory response driven by leukocytes may aid in healing. In other cases, such as in aesthetic medicine, a more purified form of PRP (with fewer leukocytes) might be preferred to minimize inflammation.
6. Advanced Techniques: Some newer methods and technologies are being developed to improve the purity of PRP. These can include more sophisticated centrifugation techniques or filtration systems designed to increase the concentration of platelets while reducing leukocytes and RBCs.
7. Standardization Issues: There is currently no universally accepted standard for PRP preparation, leading to variability in PRP compositions used in different clinics and research studies.

In summary, while it is possible to concentrate platelets from the buffy coat, the process typically also includes some leukocytes and potentially a small number of RBCs. The exact composition of the PRP can be influenced by the specific preparation technique used, and the choice of technique may depend on the intended clinical application of the PRP.

But what do the studies show?

Essentially, the effects of PRP are comparable to prolotherapy and are usually minimal, short lasting, highly inflammatory and can counteract stem cell therapy. Some clinical studies show that PRP can have an effect compared to placebo.

Even the most recent meta-analyses agrees that studies are of low quality to this point. As the effects do show some improvement of the outcome scores the question remains if there is any advantage to the general idea of prolotherapy. Here are the problems with the studies.

1. No proper “saline” – placebo is used (eg, HA is not a proper control)
2. Evaluation of the outcome is based on many subjective scores, however WOMAC and KOOS are valuable when done properly.
3. No “sham” injection is used to compare a mere prolotherapy injection to “no injection”; these are difficult to do that is why they are rarely done. Therefor a simple saline injection can show a significant “placebo” effect or in other words the injection itself is a treatment.
4. MRI quantification of cartilage regrowth or other tissue as available from stem cell therapy is absent in PRP studies

Conclusion: Intra-articular PRP injection appeared to be more efficacious than HA injection for the treatment of KOA in terms of short-term functional recovery. Moreover, PRP injection was superior to HA injection in terms of long-term pain relief and function improvement. In addition, PRP injection did not increase the risk of adverse events compared to HA injection.

To be clear HA (hyaluronic acid) is not exactly a placebo (saline) control, it can be considered a drug treatment. “However, the Lequesne Index scores, KOOS scores, and adverse events did not show any significant difference between groups.”

Conclusion: Although the studies were of mostly of low quality, isolated arthroscopic meniscal repairs augmented with PRP led to significantly lower failure rates (10.8% vs 27.0%; odds ratio, 0.32; P = .03) as compared with repairs without PRP. However, most studies reported no significant differences in patient-reported outcomes.

 

So what about Prolotherapy?

What is Prolotherapy?

Prolotherapy also called proliferation therapy is an injection-based treatment used in chronic musculoskeletal or joint conditions. Injections can consist of “non-drug” solutions such as saline, glycerol, hyperosmolar dextrose, (sometimes lidocaine or other drugs) or homeopathic compounds.  Prolotherapy is generally viewed as an investigational or experimental therapy with an inconclusive evidence base and generally not covered by insurance. However some studies provide limited support for the hypothesis that prolotherapy is effective in both reducing pain and improving function for lower limb tendinopathy and fasciopathy.

Studies show that PRP is slightly more effective than prolotherapy (PRL) but both outcomes are only slightly above the placebo effect.

Wang 2022: “Meta-analysis of clinical trials focusing on hypertonic dextrose prolotherapy (HDP) for knee osteoarthritis” – At a mean of 22.8 weeks follow-up, HDP treatment significantly improved total WOMAC score (WMD = 13.77, 95% CI: 6.75-20.78; p < 0.001; I² = 90%), pain (SMD = 1.33, 95% CI: 0.49-2.17; p < 0.001; I² = 91%) and knee function (SMD = 1.30, 95% CI: 0.45-2.14; p < 0.001; I² = 91%) compared with control group. 

This analyses clearly shows that a mere “placebo-like” prolotherapy shows a significant improvement of the WOMAC scores! Therefor the discussion above renders the use of PRP questionable. The improved WOMAC score reported for dextrose injections was 13.7; where as the average improvement for PRP was only less than 2 (compared to HA)! This in effect actually shows a nocebo effect!

 

Is it necessary to add PRP to Stem cell therapy?

Some Stem cell manufacturers include parts of “PRP” growth factors from Umbilical birth tissue. It is not recommended to include a separate autologous PRP with stem cell therapy for the simple reason that it is inflammatory! Adding PRP to the MSCs injections did not provide additional benefit in this study. 

Bastos 2020

Barman 2022

There is definitely more proper research needed to decide this issue on adding inflammatory platelets to stem cell therapy. 

In summary, PRP (platelet rich plasma) can be considered “inflammation therapy”, that is because of the inflammatory purpose of ‘platelets’ within the bodies function. However there are differences in preparations that can have various effects in different patients and applications. PRP was show to be effective over some placebos but not without often strong side effects and even though long term effects have been show, they are questionable and comparable to general prolotherapy.

Does platelet-rich plasma accelerate recovery after rotator cuff repair? A prospective cohort study? – NO EFFECT

A total of 60 patients underwent arthroscopic double-row supraspinatus tendon repair. After randomization, half the patients received 2 ultrasound-guided injections of PRP to the repair site at postoperative days 7 and 14. ->  image-guided PRP treatment on 2 occasions does not improve early tendon-bone healing or functional recovery.

 

PRP vs PRF

Platelet-Rich Fibrin (PRF) and Platelet-Rich Plasma (PRP) are both platelet concentrates used in various medical and dental procedures to enhance healing and tissue regeneration.

• Fibrin is involved in wound healing, where it serves as a temporary matrix for cellular invasion and tissue growth.
• Fibrin is formed from its precursor protein, fibrinogen, a soluble plasma glycoprotein produced by the liver.
• The conversion of fibrinogen to fibrin is catalyzed by thrombin in the final steps of the coagulation cascade.
• D-dimer is a degradation product of fibrin and is often measured in the blood to diagnose conditions that involve thrombosis, such as deep vein thrombosis (DVT), pulmonary embolism (PE), or disseminated intravascular coagulation (DIC).

PRP and PRF are prepared differently and have distinct properties:

1. Preparation Method:
   • PRP: To prepare PRP, blood is collected and then centrifuged to separate the plasma phase and platelet concentrate from the red and white blood cells. Anticoagulants are used during centrifugation to prevent clotting. The resulting platelet-rich plasma can then be collected and used therapeutically.
   • PRF: PRF is obtained by centrifuging blood without anticoagulants, allowing the blood to clot naturally. This process concentrates platelets and white blood cells into a fibrin mesh. The resultant product includes not only a higher concentration of platelets but also leukocytes and circulating stem cells within a fibrin matrix.
2. Fibrin Content:
   • PRP: Does not typically contain fibrin because of the anticoagulants used in its preparation.
   • PRF: Has a rich fibrin network because it is prepared without anticoagulants, which allows for natural clotting.
3. Growth Factor Release:
   • PRP: The release of growth factors from platelets in PRP is rapid and short-lived as it lacks a scaffold to control the release.
   • PRF: The fibrin matrix in PRF acts as a scaffold that helps to sustain the release of growth factors over a longer period.
4. Cellular Content:
   • PRP: Primarily contains platelets with variable numbers of white blood cells (leukocytes) based on the preparation protocol.
   • PRF: Contains a higher concentration of leukocytes and also includes progenitor cells, which may contribute to the healing process.
5. Use in Procedures:
   • PRP: Often used in a liquid form that can be combined with other substances or used as an injectable.
   • PRF: Because of its semi-solid nature (due to the fibrin matrix), PRF can be used as a membrane or plug to fill or cover surgical sites.
6. Clinical Applications:
   • PRP: Commonly used in orthopedic surgery, sports medicine, and cosmetic procedures.
   • PRF: Often used in dental and oral surgery

In summary, fibrin does not really contribute to regenerative medicine but it can be helpful for acute wound healing. However, in the broader scope of regenerative medicine, fibrin’s role is expanding due to its natural presence in the body, its capacity to integrate with host tissue, and its ability to support the complex processes of tissue regeneration. Its biological properties can be harnessed to create environments conducive to the regeneration of skin, bone, vascular, and other tissues, making it a valuable component in advanced therapeutic strategies.

 

How are Exosomes made from MSCs?

Exosome therapy is a form of regenerative medicine. After getting exosome therapy, your exosomes will communicate new, healing messages to your cells. This leads to your cells telling your body to heal itself through its own regenerative process.

Exosomes are small extracellular vesicles that are released by many types of cells, including mesenchymal stem cells (MSCs). Exosomes contain various types of biomolecules, including proteins, lipids, and nucleic acids (such as RNA and DNA).

The specific message contained within exosomes can vary depending on the cell type and the conditions under which the exosomes were produced. However, in general, exosomes are thought to play a role in cell-to-cell communication and can transfer bioactive molecules between cells.

For example, exosomes released by MSCs have been shown to contain a variety of growth factors and cytokines that can modulate immune responses, promote tissue repair and regeneration, and protect against cellular damage. Additionally, exosomes can contain miRNAs (microRNAs) which can regulate gene expression in target cells, potentially altering cellular processes and signaling pathways.

Overall, exosomes are thought to be important mediators of intercellular communication, and their precise content and functions are an active area of research in the fields of regenerative medicine and drug delivery.

Mesenchymal stem cell (MSC) exosomes are typically isolated from culture supernatants of MSCs that have been grown in vitro (in a lab). Here is a general overview of the steps involved in producing MSC exosomes:

1. Isolate MSCs: First, MSCs are isolated from a donor source, such as bone marrow, adipose tissue, or umbilical cord tissue. The cells are then expanded in culture to generate a sufficient number of cells for exosome production.
2. Condition media collection: Once the MSCs have reached a certain density, the culture media is replaced with fresh media and the cells are allowed to incubate for a period of time. During this time, the MSCs release exosomes into the culture media. After a specified time period, the media is collected.
3. Centrifugation: The collected media is then centrifuged at low speeds to remove any remaining cells or debris. This step is important to obtain a clean sample of exosomes.
4. Ultracentrifugation: The cleared media is then subjected to ultracentrifugation to pellet the exosomes. This step involves multiple rounds of centrifugation at high speeds to separate the exosomes from other small particles in the media.
5. Characterization: The isolated exosomes are then characterized to confirm their identity and purity. This step may include examining the size and morphology of the exosomes using electron microscopy, and analyzing the protein and RNA content of the exosomes using various biochemical assays.

It’s worth noting that there are alternative methods for isolating exosomes from MSCs, including precipitation-based methods and size-exclusion chromatography, which may be preferred in some cases depending on the specific application. Every manufacturer has their own proprietary procedure which is monitored by the FDA for safety and GMP standards. 

What is a microRNA?

Several different species of RNA (ribonucleic acid) are found in the body, each with its own unique functions not to be confused with microRNA. While most RNA species are degraded rapidly, microRNAs are very small and stable within the body. Here are some of the main types of RNA:

1. Messenger RNA (mRNA): mRNA is synthesized in the nucleus of cells and carries genetic information from DNA to ribosomes in the cytoplasm, where it is used as a template to synthesize proteins.
2. Transfer RNA (tRNA): tRNA is a small RNA molecule that binds to a specific amino acid and carries it to the ribosome, where it is added to a growing protein chain.
3. Ribosomal RNA (rRNA): rRNA is a major component of ribosomes, the cellular machinery responsible for protein synthesis. Ribosomes are composed of both rRNA and proteins.
4. Small nuclear RNA (snRNA): snRNA is involved in the processing of pre-mRNA (the precursor to mRNA) in the nucleus of cells.
5. Long non-coding RNA (lncRNA): lncRNA is a class of RNA molecules that are longer than 200 nucleotides and do not code for proteins. LncRNAs are involved in a variety of cellular processes, including gene expression regulation and epigenetic modifications.
6. Small interfering RNA (siRNA): siRNA is a small RNA molecule that is involved in the process of RNA interference, a mechanism by which gene expression can be selectively silenced.
7. MicroRNA (miRNA): miRNA is a small RNA molecule that regulates gene expression by binding to mRNA and either inhibiting translation or regulating the degradation of mRNA molecules.

These are just a few examples of the different species of RNA in the body. Each type of RNA plays a unique role in the regulation and expression of genes, and understanding their functions is an active area of research in molecular biology and genetics.

MicroRNAs (miRNAs) are small RNA molecules that play a crucial role in post-transcriptional regulation of gene expression. Here are some of the main functions of miRNAs:

1. Gene regulation: miRNAs regulate gene expression by binding to messenger RNA (mRNA) molecules and inhibiting their translation into proteins. By targeting specific mRNAs, miRNAs can control the expression of entire networks of genes, regulating a variety of cellular processes.
2. Development: miRNAs are involved in the regulation of embryonic development and differentiation of cells into different tissue types. For example, miR-430 is required for the development of the zebrafish embryo.
3. Immune response: miRNAs are involved in the regulation of immune responses, including the differentiation and function of immune cells such as T cells, B cells, and dendritic cells. For example, miR-155 is important for the development and function of immune cells and is dysregulated in various autoimmune and inflammatory diseases.
4. Cancer: Dysregulation of miRNA expression is a hallmark of many types of cancer. Some miRNAs act as tumor suppressors, inhibiting the expression of oncogenes, while others promote tumor growth and metastasis by inhibiting tumor suppressor genes.
5. Neurological function: miRNAs are involved in the regulation of synaptic plasticity, memory formation, and neural development. For example, miR-124 is highly expressed in neurons and is involved in the differentiation of neural stem cells into neurons.

Overall, miRNAs play a crucial role in the regulation of gene expression and the maintenance of cellular homeostasis. Dysregulation of miRNA expression can lead to a variety of diseases, including cancer, neurodegenerative disorders, and cardiovascular disease. As a result, miRNAs are an active area of research in the development of new therapeutic approaches for these and other diseases.

Mesenchymal stem cell (MSC) exosomes contain a variety of microRNAs (miRNAs) that can be transferred to recipient cells, potentially affecting gene expression and cellular processes. Here are a few examples of miRNAs that have been identified in MSC exosomes:

• miR-21: This miRNA is known to be involved in cell proliferation, apoptosis, and differentiation. MSC-derived exosomes containing miR-21 have been shown to promote angiogenesis and reduce fibrosis in a mouse model of myocardial infarction. (Source: Zhang et al., 2015)
• miR-146a: This miRNA is known to be involved in the regulation of immune responses and inflammation. MSC-derived exosomes containing miR-146a have been shown to attenuate inflammation and promote tissue regeneration in models of acute lung injury and liver fibrosis. (Source: Lou et al., 2020)
• miR-133a: This miRNA is known to be involved in muscle differentiation and regeneration. MSC-derived exosomes containing miR-133a have been shown to promote myogenesis and improve muscle function in a mouse model of muscular dystrophy. (Source: Yin et al., 2019)
• miR-122: This miRNA is highly expressed in liver tissue and is involved in the regulation of lipid metabolism. MSC-derived exosomes containing miR-122 have been shown to reduce hepatic steatosis and improve insulin sensitivity in a mouse model of nonalcoholic fatty liver disease. (Source: Liang et al., 2020)

It’s worth noting that the specific miRNAs present in MSC exosomes can vary depending on a variety of factors, including the culture conditions used to produce the exosomes and the source of the MSCs. However, the potential therapeutic applications of MSC exosomes containing specific miRNAs are an active area of research in the fields of regenerative medicine and drug delivery.

MicroRNAs (miRNAs) primarily interact with messenger RNA (mRNA) molecules and regulate gene expression at the post-transcriptional level. However, there is some evidence to suggest that miRNAs can also interact with DNA at specific loci in the genome.

Another mechanism by which miRNAs can also interact with DNA and change gene expression is through the recruitment of epigenetic modifiers, such as histone-modifying enzymes or DNA methyltransferases, to specific gene promoters. For example, the miRNA miR-29 has been shown to bind to the promoter region of the DNA methyltransferase DNMT3A, leading to the downregulation of DNMT3A expression and changes in DNA methylation patterns.

In addition, some studies have suggested that miRNAs can directly bind to DNA sequences in the genome. For example, a study published in 2013 found that the miRNA let-7 binds to specific sites in the genome and regulates the expression of target genes in a manner that is independent of its effects on mRNA stability.

However, the extent to which miRNAs interact with DNA in the genome is still an active area of research, and the functional significance of these interactions is not yet fully understood. Most studies to date have focused on the role of miRNAs in post-transcriptional gene regulation, and it is generally thought that miRNAs primarily act through their interactions with mRNA molecules.

What is FDA Certification?

“FDA Certification” does NOT mean the product has been evaluated or approved by the FDA for any condition. All it means is that the product is included in the agency’s National Drug Code (NDC) Directory as an OTC product. Giving the impression that inclusion in the NDC Directory indicates any sort of FDA approval is “misleading and constitutes misbranding.” However the FDA approval process is changing rapidly and manufactures are undergoing IND (initial new drug) approval.

 

Does Knee Replacement surgery work?

Studies show that there is little to no benefit for long term joint replacement surgery:

• surgeries are at high risk for infections and even death due to blood clots and anesthesia
• long recovery times and painful rehab
• patients still have pain in the joints
• limited range of motion and strength
• limited lifetime of artificial joints and the need for repeated surgery
•  

In this controlled trial by Moseley 2002 involving patients with osteoarthritis of the knee, the outcomes after arthroscopic lavage or arthroscopic debridement were no better than those after a placebo procedure!

Human umbilical cord mesenchymal stem cells promoting knee joint chondrogenesis for the treatment of knee osteoarthritis: a systematic review!

Kirkley 2008: Arthroscopic surgery for osteoarthritis of the knee provides NO additional benefit to optimized physical and medical therapy.

Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis?

Does meniscus surgery work?

In this trial involving patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure. 

Does Hip Replacement work?

Hip arthroscopy and personalized hip therapy both improvements  are actually below placebo (nocebo effect). Hip arthroscopy led to only a 6.8% greater improvement than did personalized hip therapy. 72% reported adverse effects, 7 patients serious.

Details:

At 12 months after randomization, mean iHOT-33 scores had improved (27·2%) for participants in the hip arthroscopy group, and from 35·6 (18·2) to 49·7 (25·5%) in the personalized hip therapy group. In the primary analysis, the mean difference in iHOT-33 scores, adjusted for impingement type, sex, baseline iHOT-33 score, and center, was 6·8 (95% CI 1·7-12·0) in favor of hip arthroscopy (p=0·0093). 

 

Danger of Cortisone injections

Cortisone injections cause bone and cartilage loss! Major side effects are:

1. Skin discoloration or thinning: Injections near the surface of the skin can cause lightening of the skin color or thinning of the skin at the site of the injection.
2. Elevated blood sugar levels: For people with diabetes, a cortisone injection can cause a temporary increase in blood sugar levels.
3. Allergic reactions: Some people may experience an allergic reaction to the cortisone.
4. Osteoporosis: Repeated cortisone injections can weaken bones (osteoporosis), particularly if given in the same location repeatedly.
5. Tendon rupture: While rare, a cortisone injection near a tendon can lead to a rupture of the tendon.
6. Nerve damage: If the needle touches a nerve during the injection, it can cause damage and pain.
7. Steroid flare: This is a reaction to the injected cortisone that can result in increased pain and inflammation for up to 48 hours after the injection.
8. Cartilage damage: Long-term, repeated injections into a joint can degrade cartilage, potentially accelerating joint damage.

Steroid injection linked with significant bone loss in postmenopausal women treated for back pain

Multiple Epidural steroid injection can reduce BMD in postmenopausal women with low back pain.

 

Boutine 2021: Rapidly progressive idiopathic arthritis of the hip: incidence and risk factors in a controlled cohort study of 1471 patients after intra-articular corticosteroid injection. We found that approximately 7% of patients undergoing steroid hip injection developed RPIA. More advanced patient age, greater joint space narrowing, and more severe osteoarthritis are risk factors for the development of RPIA after intra-articular steroid injection.

 

 Daily doses of more than 2.5 mg prednisolone or equivalent are associated with a higher fracture risk. Randomised studies reveal adverse skeletal effects with daily doses as low as 5 mg. 

more articles:

 

 

Dr. Spencer on Regenerative Medicine

 

SCIENCE:

How do Stem Cells reduce inflammation?

This process is of course an ongoing research topic. The results of this study showed a significant increase of TGF-β and IL-10 levels which are major anti-inflammatory messengers. MSCs become activated and can adopt immune-suppressive phenotype (MSCs type-2). Vice versa, studies show that neutralization of TGF-β1 in vitro inhibits the differentiation of helper T cells into Th17 cells necessary for inflammation control. (The loss of Th17 cell populations at mucosal surfaces has been linked to chronic inflammation and microbial translocation.) In reality, it is important that a balance between inflammation and anti-inflammation has to be maintained at all times. MSCs can travel to the site of inflammation and there contribute to local healing. Then a balance of M1+2 Macrophages is necessary for tissue healing: M1- pro inflammatory = remove damaged debris tissue; M2- anti inflammatory = mediate tissue repair. This is just one example of the complexity of immunity. 

Scar tissue and functional tissue : In addition MSCs have shown to contain stable microRNAs that contribute to Scar tissue removal. EG. microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression. Again the picture is more complex. While the inflammatory response aids in clearing out dead cells and debris, the fibrotic cascade helps maintain tissue integrity through the deposition of matrix proteins such as collagen, fibronectin and tenascin C. In the case of a cardiac damage, heart regeneration depends on the Upregulation of miR-101a. Hi expression between 7 and 14 days is essential to stimulate removal of the scar tissue in this zebra fish model.

MSCs have the capability to remove scar tissue and restore hear functions. Many of the cells  expressed cardiac-specific proteins, including sarcomeric α-actinin, cardiotin, and atrial natriuretic peptide, as well as the cell cycle markers cyclin D1 and proliferating cell nuclear antigen. A calcium current similar in amplitude to that of ventricular myocytes was present in 16% of the cells.

 

 

SCIENCE

This website is continuously being updated. Please keep checking in frequently!

Researching Stem Cell Therapy on your own can be very frustrating and overwhelming. The world of stem cell research is exploding and the number of publications and clinical trials is more than 100,000. So we are trying to make this process easier for you.

Please use “ctrl F” to search for your condition of interest!

(Eg: “osteoarthritis” or “COPD”)

How is the growth of new healthy tissue possible?

Umbilical Cord and many other tissues related to the placenta contain massive amounts of pluripotent stem cells. This is a gift from nature to allow the mother to regenerate after birth! E.g. Wharton’s jelly cells (connective tissue within the umbilical cord) have mesenchymal features. These cells can be cultured for more than 80 population-doubling cycles with NO changes in morphology or indication of senescence!

These mesenchymal cells contain and secrete growth factors, cytokines, RNA and other molecules to initiate the healing process.

Please note that our stem cell therapy has nothing in common with embryonic or fetal stem cell research. No fetus or mother has ever been harmed!

What happens when the stem cells enter an injury or chronic inflammation site?

1. Immune-modulatory factors down-regulate inflammation. This reduces swelling, redness and pain within a few days.
2. Old scar tissue is being removed and no longer needed cells are undergoing cell death (apoptosis). This is similar to the healing process of a fracture where all bone splinters and dead blood vessels etc. have to be removed first before new bone tissue can be formed.
3. The body sends out chemokines at the injury site to attract stem cells which then in turn recruit your bodies own cells to become pluripotent stem cells
4. Stem cell then are differentiating into ‘progenitor’ cells which are the first step to becoming new tissue such as cartilage, ligaments, blood vessels, or even nerve cells and cardiac myocites.
5. New tissue ist being formed over the course of several month until the functionality of the joint or other tissue is restored.

Why are there no side effects or rejection?

No immune rejection of undifferentiated umbilical cord cells in vivo has been recorded and these cells were well tolerated in an allogenic transplantation.

The reason for this wonder lies in the nature of the perinatal tissue. During pregnancy the mother’s body has to temporarily recognize the baby as “self” which means:

1) these mesenchymal cells come with an immune-modulatory message to down-regulate inflammation

2) there are no immune-presenting markers (MHC) present on the surface of these stem cells to cause a response. Moreover these human cells can be transplanted into animals without rejection.

NIH is currently listing over 9500 clinical trials for stem cell therapies as of 2023

Why use umbilical chord stem cells – Introduction:

Regenerative medicine is a field of medical research developing treatments to repair or re-grow specific tissue in the body. There is a rising body of studies that reveals the power of mesenchymal stem cells (MSCs). Stem cells are multipotent stromal cells that can differentiate into a variety of cell types, including: osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), adipocytes (fat cells), neural cells. liver cells, heart muscle cells and many more. This phenomenon has been documented in many specific cells and tissues in living animals and their counterparts growing in laboratory tissue culture. Most Human Tissue has a rapid turnover rate. It is the availability of stem cells that assists in this process of regeneration. However with advanced age, your stem cells also age and proliferate much slower. In order to rejuvenate this process stem cell therapy becomes necessary.

 

Intra-nasal Brain treatment

Recent studies have shown promising results in the application of mesenchymal stem cells (MSCs) for the treatment of brain tumors and traumatic brain injury, with a particular focus on intranasal delivery methods. Here are the key findings from several studies:

1. Intranasal Delivery of MSCs for Brain Tumors: A study investigated the use of intranasal (IN) delivery of MSCs for treating glioblastoma multiforme, a type of brain tumor. This approach was tested due to the difficulty in delivering treatments across the blood-brain barrier (BBB). The study found that MSCs could penetrate the brain from the nasal cavity and infiltrate intracranial glioma xenografts in a mouse model. The MSCs were engineered to express TNF-related apoptosis-inducing ligand (TRAIL), and irradiation of tumor-bearing mice increased the penetration of these MSCs in the brain. This approach demonstrated an improvement in the median survival of irradiated mice bearing intracranial glioma xenografts compared to controls​​.
2. Intranasal Application of Stem Cells for CNS Diseases: The intranasal application of stem cells, including MSCs, has been explored for treating central nervous system (CNS) diseases. This method can bypass the BBB, allowing for non-invasive delivery of stem cells to the brain. The intranasally delivered stem cells show potential in treating diseases like Parkinson’s disease and Alzheimer’s disease, and they have been observed to migrate extensively to injured or damaged areas in models of brain injury or tumors. However, it is noted that the efficiency of stem cell migration via intranasal delivery is relatively low, as many cells remain in the upper nasal cavity shortly after administration​​​​.
3. Application of MSCs in Targeted Delivery to the Brain: Treating brain tumors remains challenging due to the BBB. MSCs have shown the ability to cross biological barriers and migrate to injury sites, making them ideal for transporting anti-tumor agents to the CNS. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) inherit valuable properties from the parent cells and are being explored as cell-free treatments for neurological diseases. Compared to using whole MSCs, MSC-EVs have a better pharmacokinetic profile and avoid many issues of cell-based systems. They are being studied for targeting brain tumors, showing promise in experimental models​​.
4. Intranasal Delivery of MSC-Derived Extracellular Vesicles in Traumatic Brain Injury: Another study focused on the intranasal delivery of human MSC-derived extracellular vesicles (hMSC-EVs) post-traumatic brain injury (TBI). This treatment was shown to prevent the evolution of acute neuroinflammation into chronic neuroinflammation and alleviate long-term cognitive and mood impairments associated with TBI. The study demonstrated that a single intranasal dose of hMSC-EVs could match neurogenesis levels to those of naive control levels and reduce the loss of pre-and post-synaptic marker proteins in the brain. This suggests that intranasal delivery of MSC-derived EVs can ease TBI-induced declines in neurogenesis and synaptic integrity​​.

These studies indicate that intranasal delivery of MSCs and their derived extracellular vesicles holds promise for treating brain tumors and CNS diseases. However, further research and clinical trials are necessary to fully understand the efficacy and safety of these approaches in humans.

Again, Here is Reitz 2012 showed how MSC cells enter the brain through intra-nasal delivery to the site of a human glioblastoma !

3 days after intra-nasal administration labeled stem cells (black and blue) migrate to a tumor site inside the brain.

 

Stem Cell Discovery History

Amniotic Membranes have been used in clinical practice for over a century. Mainly, it was used in surgery as a biological coating. Ingraldi 2023: “Fetal membranes were first used in the 1900s to successfully treat acute and chronic traumatic wounds, burns, ulcers, and as a novel skin substitute for grafting [7,8,9,10]. The amniotic membrane’s inherent elasticity allows it to conform to complex contoured surfaces, which led to its application in many reconstructive procedures, including the creation of artificial vaginas, and treating chronic complex wounds in diabetic patients [2,13,14]. “

Since at least 1974 we have know about the power of umbilical cord healing cells. The umbilical cord stem cell injections became more common since  2000 and we are now almost 20 years into the clinical application of these MSCs in humans. Umbilical cord stem cells were initially only used in treating patients with joint problems. It was soon discovered that they contain naturally developing anti-inflammatory agents that actually do much more than stimulation of tissue repair. There have been no reports of patient rejection recorded so far. It is estimated that more than 500,000 injections have been used on patients without any cases of rejection or serious adverse side effects.

Stem cells currently are derived from several sources: amniotic, umbilical cord stem cells and adult stem cells.  Adult stem cells are undifferentiated multipotent cells, found throughout the body, usually derived from bone marrow or adipose tissue. Stem cell therapies as we use them today uses only mesenchymal stem cells derived from umbilical cord tissue or autologous sources.  No stem cells  are ever obtained from embryonic or fetal sources!

Amniotic membrane., placenta and umbilical cord derived tissue matrix presents as an excellent collagen scaffold, presenting with active Collagen Types I, II, III, IV, V, and VII together with fibronectin and laminin, natural hyaluronic acid, fibroblasts, growth factors, cytokines, exosomes, alpha2macroglobulin, miRNA, and a wide spectrum of growth factors. Please keep in mind that there are many sources of stem cells such as autologous bone marrow and adipose tissue. As all of these represent the general strategy of “stem cell therapy” they may not represent the effectiveness of our stem cell sample.

Arthritis

Overview of Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease, one of the most common forms of arthritis, typically affecting the elderly but can also occur in younger individuals. It is characterized by the breakdown of cartilage—the cushioning material at the end of bones—as well as changes in the bone and deterioration of tendons and ligaments. The primary symptoms include joint pain, stiffness, swelling, and reduced mobility.

Pathophysiology:

• Cartilage Degradation: In OA, the cartilage in the joint breaks down, leading to pain and difficulty in movement.
• Bone Changes: Over time, there may be bone growths (osteophytes) and the underlying bone may also undergo remodeling.

Risk Factors:

• Age: Incidence increases with age.
• Genetics: A family history of OA can increase risk.
• Obesity: Extra weight puts more stress on joints, particularly weight-bearing joints like the hips and knees.
• Injury and Overuse: Repeated stress on a joint can lead to OA.

Measuring Outcomes in Osteoarthritis

Lequesne Index:

The Lequesne Index is a questionnaire designed to assess the severity of OA. It considers factors like pain or discomfort, maximum distance walked, and activities of daily living. The index is used to evaluate the effectiveness of treatments and the progression of the disease.

WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index):

• Purpose: WOMAC is widely used in the clinical evaluation of OA, particularly of the knee and hip.
• Components:
  • Pain: Assesses pain severity during various activities.
  • Stiffness: Measures the degree of joint stiffness.
  • Physical Function: Evaluates the difficulty experienced in daily activities.
• Scoring: Patients rate their experiences in these categories, which are then combined for an overall score.

Visual Analogue Scale (VAS):

• Usage: The VAS is a simple and commonly used method for assessing the intensity of pain.
• Format: It typically consists of a straight line, often 10 centimeters long, where one end signifies ‘no pain’ and the other ‘worst pain imaginable’.
• Scoring: Patients mark a point on the line that corresponds to their perceived pain level.

Traditional Treatment Approaches:

• Lifestyle Changes: Weight loss, physical therapy, and exercise can help reduce symptoms.
• Medications: Pain relievers and anti-inflammatory drugs are commonly used.
• Surgical Options: In most cases, joint replacement surgery is the final result of untreated joint degeneration.

The Regenerative Alternative

• Recent advancements include injections of peptides or hyaluronic acid and combination with surgical therapies.
• Emerging ‘stem cell’ alternatives as discussed here

Timmons 2022: Homologous Use of Allogeneic Umbilical Cord Tissue to Reduce Knee Pain and Improve Knee Function!

In summary, Osteoarthritis is a chronic condition that significantly impacts quality of life. Accurately measuring its severity and treatment outcomes is crucial for effective management. Tools like the Lequesne Index, WOMAC, and VAS provide standardized methods for assessing these factors, aiding in both clinical research and patient care.

Cartilage growth measured by MRI

Selected Articles:

1. 1. Cartilage Regrowth (the above image shows a study from Vega et al 2015. This study concludes: The MSC-treated patients displayed significant improvement in algofunctional indices versus the active controls treated with hyaluronic acid only. Quantification of cartilage quality by T2 relaxation measurements showed a significant decrease in poor cartilage areas, with cartilage quality improvements in MSC-treated patients. Allogeneic MSC therapy may be a valid alternative for the treatment of chronic knee osteoarthritis that is more logistically convenient than autologous MSC treatment. The intervention is simple, does not require surgery, provides pain relief, and significantly improves cartilage quality. Not only did this study show significant new cartilage growth but also the worse the initial injury or joint damage the better the outcome was! In other words stage 3 and 4 osteoarthritis has even better healing outcomes.
2. Kim 2023: Conclusions: Improved clinical and radiological outcomes and favorable cartilage regeneration were seen after surgery for varus Knee OA in both SVF and hUCB-MSC groups.
3. the cartilage lesions were covered up with new tissue after treatment:

4. MORE Applications for joints: 

•  

1. Rheumatoid Arthritis Cosensa-2018 demonstrated that both MSCs-derived microparticles and exosomes (secretions from stem cells) exerted an anti-inflammatory role on T and B lymphocytes independently of MSCs priming (predisposition). MSCs and their secretions were more efficient in suppressing inflammation in vivo. Our work is the first demonstration of the therapeutic potential of MSCs-derived secretions in inflammatory arthritis.  The clinical score for RA was decreased by 35% as compared to control group.
2. Degenerative disc disease: Twenty of the patients treated underwent post-treatment MRI and 85% had a reduction in disc bulge size, with an average reduction size of 23% post-treatment. In this study: VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low and high cell doses. In this study: Of 26 patients, 24 (92 %) avoided surgery through 12 months, while 21 (81 %) avoided surgery through two years.Clinical trial of stem cell therapy for traumatic spinal cord injuryVisual analogue scale (a) and Oswestry Disability Index (b). Six patients (cases 2, 4, 5, 7, 8, and 9) presented an effective reduction in pain and ODI (≥50% improvement of VAS and ODI compared with pretreatment) at 12 months
3. Surgery outcomes: As there is There is no clear method available to evaluate patients before surgery and there appears to be little agreement on the selection criteria for surgical treatment. Good to excellent surgical results in past studies range widely from 66 to 98% of patients [3, 5, 7, 12, 22, 23, 24, 29]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229822/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843080/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154366/
4. Sharan 2022, Conclusion: We have demonstrated for the first time that MSC injection into the lumbar facet joints and epidural space results in significant improvement of lower back pain and additionally has the capability to improve symptoms in other spinal regions without engendering the risks associated with intradiscal injections or epidural use of corticosteroids. https://pubmed.ncbi.nlm.nih.gov/35762554/
   
5. ACL knee repair: Seventy-seven percent of patients treated with BMC injections into the ACL showed significant improvement (p < 0.01) in objective measures of ACL integrity at an average of 8.8 months (median 4.7 months).
6. Meniscus knee repair:We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Another article showed MSCs and BMC preferentially migrate toward tissue areas showing OA features in the meniscus and cartilage and in detail near inflammatory zones in the synovial membrane.
7. Dr. Rhiordon treats T12 Fracture paralyses.
8. Dr. Rhiordon treats T8 Fracture paralyses.
9. Mayo clinic does studies on paralyses
10. Transplantation of HUMSCs is beneficial to wound healing after spinal cord injury in rats.
11. Regenerative Medicine Did This to A Spinal Cord Injury? (youtube.com)

Degenerative Disc repair

Nerve Inflammation

Morton’s neuroma: Stem cell injections may provide the additional benefit of structure restoration. Chronic foot pain is common in the general population and has significant associated morbidity and disability.

Internal Medicine

 

A recent review summarizes many ongoing clinical studies:

Chetty 2022: “Umbilical cord mesenchymal stromal cells—from bench to bedside”. Discussed are the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). 

 

 

1.  

•  

1. Heart Disease Prevention 1 million Americans suffer a heart attack each year, resulting in about a 38% mortality rate. In this prospective heart study, the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF (heart failure). Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment. It was shown that stem cell therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF. Furthermore cell-treated patients had significantly improved maximal myocardial oxygen consumption indicating a rejuvenation of the heart.
2. Heart Attack  Patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. This study concluded that Intramyocardial injection of autologous MSCs into akinetic yet non-revascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV (left ventricle) function. Subjects receiving MSCs exhibited increased LV ejection fraction and decreased scar mass  MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement whereas surgically revascularized and nontreated segments demonstrated no changes.
3. Theory of Heart Repair: The regenerative potential of bone-marrow-derived stern cells may be explained by four mechanisms: 1) direct cell differentiation from monoclear cells to cardiac myocytes, 2) cytokine-induced growing and increase of residual viable myocytes, especially within the border zone of the infracted area, 3) stimulation of resident cardiac stern cells (endogenous stern cells), and 4) induction of cell fusion between transplanted stem cells and resident myocytes.
4. MRI can accurately track the location of ferumoxytol-labeled hESC-CPCs transplanted into a pig’s heart for up to 40 days after delivery;
5. Diabetes Reversal Mesenchymal stem cells (MSCs) harbor differentiation potential, immunosuppressive properties, and anti-inflammatory effects, and they are considered an ideal candidate cell type for treatment of DM. MSC-related research has demonstrated exciting therapeutic effects in glycemic
   control both in vivo and in vitro, and these results now have been translated into clinical practice. In animal models, MSC treatment demonstrated exciting therapeutic effects on glycemic control byrestoring islet function and ameliorating insulin resistance. These results have now been translated into
   clinical practice. A total of 96 registered phase I/II clinical studies among T2DM patients can be found with the clinical trials registry (http://www.clinicaltrials.gov). Results showed that insulin requirements decreased by 50% and GIR significantly improved by 6 months after multiple intravenous injections of UC-MSCs in T2DM patients with poor glycemic control. This result confirmed that UC-MSCs reduce hyperglycemia in T2DM patients in part by ameliorating insulin resistance of peripheral tissue. In contrast, Bonemarrow-MSC transplantation did not improve insulin. resistance results however they were shown to be effective in T1DM. In this study: The clinical target HbA1c <7% (53 mmol/mol) was achieved by 33% (5 of 15) of the subjects who received the 2.0 × 10(6)/kg dose vs. 0% of those who received placebo (P < 0.05).
6. Type1 and 2 Diabetes was studied here in 2020 :In T1DM, BM-HSCs are a good source for stem cell transplantation. In T2DM, HbA1c and daily insulin requirements were significantly improved after MSC therapy. c level, and daily
   exogenous insulin requirement after stem cell treatment.
7. According to the pooled estimates, compared with the control group, after 12-month follow-up the ABM-MNC therapy group had a lower level of HbA1c and lower required insulin dose for diabetes improved. Studies conclude Stem cell therapy is safe and effective .
8. Stroke MSC therapy is safe and effective in treating IS by improving the neurological deficits, motor function and daily life quality of patients. At the stroke post-acute phase, hMSC intracerebral injection rapidly and transiently modifies the cerebral microvasculature. This microvascular effect can be monitored in vivo by MRI. The administration of stem cells for stroke is done by  intra nasal delivery. The particular anatomy of the olfactory and trigeminal neural pathways connects the nasal mucosa directly with the brain and the perivascular pathway by circumventing the blood brain barrier.
9. Macular Degeneration and other Retinal Disease. Stem cells provide a variety of potential treatments for many eye diseases and are considered to be the future of currently untreatable problems. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses. Delivery of MSCs was found to improve retinal morphology and function and delay retinal degeneration.
10. Autism is now fully curable with stem cells therapy in record time. Essentially all inflammatory markers like TNFalpha and IL-6 are reduced by 75% and more. This resets the autoimmune chronic inflammatory response, regulates digestion and behavior…
11. Breast Cancer:  Results demonstrate that MSC-CM suppresses breast cancer cells growth and sensitizes cancer cells to radiotherapy through inhibition of the Stat3 signaling pathway, thus, providing a novel strategy for breast cancer therapy by overcoming radioresistance.
12. ACL knee repair: Seventy-seven percent of patients treated with BMC injections into the ACL showed significant improvement (p < 0.01) in objective measures of ACL integrity at an average of 8.8 months (median 4.7 months).
13. Meniscus knee repair:We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Another article showed MSCs and BMC preferentially migrate toward tissue areas showing OA features in the meniscus and cartilage and in detail near inflammatory zones in the synovial membrane.
14. Multiple Sclerosis: patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. In another study MCSs were cultured and co-injected with the secretome (MSC-CM).   The study finds both BM-MSC and MSC-CM are safe with relative
    efficacy in stabilizing the disease and reversing symptoms.
15. Celiac Disease Modulation of immune system response through intraction of MSCs with all of the immune cells involved in celiac pathogenesis, consisting of B-cells, regulatory T-cells, T lymphocytes and endothelium. Inhibitory effects of MSCs depend on cell to cell intraction and via different factor and chemokines like: NO, CCL2 and CCL7, FoxP3, HLA G, IFN Y, IL16 and IL6, IDO, CSF and PEG2. Also via claudin for reassembling tight junctions. MSCs induce its beneficial effect through immunomodulation of T cell response by shifting the Th1/Th2 ratio toward Th2 profile. HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials and has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases.
16. COPD Multipotent mesenchymal stem/stromal cells (MSCs) possess robust self-renewal characteristics and the ability to differentiate into tissue-specific cells. Their therapeutic potential appears promising as evident from their efficacy in several animal models of pulmonary disorders as well as early-phase clinical trials of acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD).
17. Reversal of bronchopulmonary dysplasia and pulmonary hypertension Reversal of key features of hyperoxia-induced BPD and its long-term adverse effects on lung function can be achieved by a single intravenous dose of MSC-CM, thereby pointing toward a new therapeutic intervention for chronic lung diseases.
    (PDF) Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. The potential of mesenchymal stem cell therapy for chronic lung disease.
18. Emphysema and Pulmonary Fibrosis: two doses of MSCs enhanced lung repair and improvement in cardiac function, while inducing T cell immunosuppression, mainly of CD8+ cells, in elastase-induced emphysema.
19. In this Pulmonary Fibrosis was shown to MSCs are capable of of healing fibrotic process. Below is a CT scan before and after of a 56 year old patient that was treated with stem cells.
20.  Lung tissue before stem cell treatment and after 12 month.
21. Cornea disease. It maybe possible to avoid unnecessary surgery for eye problems
22. Retina repair. Cellular therapies are reaching clinical applications in the retina. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. 
23. Lens regeneration using endogenous stem cells with gain of visual function in congenital cataract!
24. This study in Nature shows lense regeneration: Our Method preserves endogenous lens epithelial stem/progenitor cell (LECs) and their natural environment maximally, and regenerates lenses with visual function
25. Sickle cell anemia The team found that the stem cell transplant reversed the disease in 26 of 30 patients (87%). The patients had normal hemoglobin, fewer hospitalizations, and lower use of narcotics to treat pain from the disease. The patients didn’t experience graft-versus-host disease—in which donor cells attack the recipient—after a median follow up of 3.4 years. Fifteen patients successfully stopped immunosuppression medications a year after the transplant.
26. Cerebal Palsy 2013 study  MSCs may be a safe and effective therapy to improve symptoms in children with cerebral palsy. _________2018 Improvements were observed especially in functional sc
27. COVID mesenchymal stem cells (MSCs)-based immunomodulation treatment has been proposed as a suitable therapeutic approach and several clinical trials have begun.
28. Israeli COVID-19 treatment with 100% survival rate tested on US patient
    1.  

ALS and MS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disorder that affects the motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy, and eventual paralysis. Mesenchymal stem cells (MSCs) are a type of stem cell that can be found in many tissues, including bone marrow and adipose tissue, and have shown promise in treating ALS.

Here are some studies on ALS and stem cell therapy with MSC:

1. “Mesenchymal stem cells transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial” (2014) by Karussis et al. This study was a Phase I clinical trial that evaluated the safety and feasibility of intrathecal (into the spinal cord) injection of MSCs in 14 patients with ALS. The results showed that the treatment was safe and well-tolerated, with some patients experiencing a slight improvement in muscle strength and function.
2. “Mesenchymal stem cells in amyotrophic lateral sclerosis: a systematic review and meta-analysis of clinical trials” (2018) by Bianco et al. This systematic review and meta-analysis analyzed the results of six clinical trials that evaluated the use of MSCs in ALS patients. The results showed that MSC therapy was safe and well-tolerated, and some studies reported improvements in muscle strength, respiratory function, and survival.
3. “Combination therapy of adipose-derived mesenchymal stem cells and their secreted factors attenuates ALS progression in an SOD1/G93A mouse model” (2020) by Zhang et al. This study investigated the effects of both MSCs and their secreted factors on ALS progression in a mouse model of the disease. The results showed that the combination therapy significantly improved muscle strength, motor function, and survival in the mice.

Overall, these studies suggest that MSC therapy is a promising approach for treating ALS.

MS therapy with hematopoietic stem cells (HSCs) inducted significant recalibration of pro-inflammatory and immunoregulatory components of the immune system. 

Alanzi 2022: The best source of MSCs seems to be the UC due to the easiness of extraction, the noninvasive method of collection, their higher expansion ability and more powerful immune-modulating properties compared to other locations in the body. Studies showed there was a significant decline of mRNA expression of several cytokines after the administration of MSCs derived from the UC (UCMSCs). Other researchers were able to repair the defects of Tregs in MS patients by co-culturing Tregs from these patients with UCMSCs, which decreased the production of the pro-inflammatory cytokine IFN $\text{γ}$γ , and also suggested a strong link between Tregs lack of functionality in MS patients with the pathogenesis of the disease.

Are there Famous Athletes that received Stem Cell Therapy treatment?

Unfortunately these statistics are not always available but here is an older list of 40 Athletes that received treatment all over the world. The list is growing daily. Athletes are choosing stem cell therapy procedures because they are less invasive than surgery and have the potential to speed and augment repair. While the effectiveness of surgeries is largely unknown and the recovery time is long, what is clear is that a growing number of athletes are turning to this approach.

5 Famous athletes who have used treatment with stem cells!

Celebs’ stem cell facial treatments include sheep placenta, others get human cells

 

More links:

Preview YouTube video Neil Riordan PhD – Stem Cell Therapy for Spinal Cord Injury (Part 4 of 5) || Stem Cell Treatments

Neil Riordan PhD – Stem Cell Therapy for Spinal Cord Injury (Part 4 of 5) || Stem Cell Treatments

Preview YouTube video Spinal Cord Injury patient demonstrates progress after treatment at Stem Cell Institute Panama

Spinal Cord Injury patient demonstrates progress after treatment at Stem Cell Institute Panama

What about stem cell therapy for leukemia:

Cancer is a complicated problem that is discussed multiple times here. Does bone marrow grafting work for leukemia in the long term? The question is complex and has more to do with the general allopathic approach to treating cancer:

“In this study, we reported that even after almost 40 years from diagnosis of HL, patients triple the risk of death from all causes, compared to the general population. When studying the different causes of death, only 22.76% of them were due to the lymphoma itself. Therefore, the excess death observed in these patients is mainly due to other causes, primely second tumors, fatal cardiac events or other causes not related to the primary tumor). It is postulated that the risk of developing second malignancies is mainly due to complications derived from radiotherapeutic treatment used in HL”

Other subjects of interest:

Are Insurances paying for stem cell therapy?

To our knowledge there is currently no insurance coverage for this procedure.  The reasons for the refusal on the part of insurances to cover this therapy despite of many studies and much clinical research are unclear. However insurances can typically only pay for “FDA approved drugs” or therapies and this process takes decades even for large biotech companies; Companies are undergoing IND but unfortunately we are not there yet. Here is what the lung institute has to say. In some cases your insurance can cover amniotic injections. This procedure has to be pre-approved. Please contact your insurance for further information.

 

Disclaimer: I hope this information is helpful to you. Please note that this content is not medical advice, and you should always consult with a healthcare provider before making decisions about your health. This content is for informational purpose only