Marc Darrow MD,JD

Throughout this website you read about our clinical observations surrounding the use of bone marrow derived stem cells in the treatment of degenerative joint, tendon, ligament, and spine disease. We are often asked to compare different types of tissues in treatments. In this article I will focus on umbilical cord derived tissue products.

A study published in October 2018 in the journal Regenerative Medicine (1) made this observation and suggestion: “Stem cell-based therapy for the treatment of orthopedic diseases is arguably one of the most remarkable developments in the field of regenerative medicine. A better understanding of Mesenchymal stem cell biology and identification of Mesenchymal stem cells in (umbilical) cord blood have added umbilical cord blood to the sources of stem cells used for treatment of nonhematopoietic diseases.”

In that same study, the researchers noted: “the data conclusively establish that (umbilical cord blood) is enriched in cytokines (proteins that communicate commands to cells) and growth factors that play an important role in bone regeneration and repair.” Much of the research surrounding umbilical cord derived tissue products use talks about cultured or expanding these umbilical cord products. Culturing or expanding umbilical cord stem cells is not permitted in the United States. In this study the authors noted: “The beginning stages of fracture healing are often associated with local inflammation, followed by Mesenchymal stem cells (MSCs) recruitment, differentiation and angiogenic activation (new blood vessel formation) phase.  Apart from mobilizing the patient’s own stem cells to the site of bone injury with pharmacologic interventions, clinicians often use ‘nonmanipulated’ cell preparations that are likely to contain a healthy pool of Mesenchymal stem cells (MSCs).” Again, laboratory-expanded mesenchymal stem cells  are subject to several restrictions. To be clear. This study also cited research where conditioned medium was used to expand the stem cell to support its findings. This is not allowable in patient treatments in the United States. Also, let’s point out that human umbilical cord derived products should not be described as stem cell therapy.

“A painless collection procedure”

For doctors and health care providers promoting the use of human umbilical cord derived products, one aspect is routinely featured. The painless collection process. There are many ways to obtain stem cells for use in orthopedic medicine. One way is to drill into the iliac crest of the pelvic bone. Another method utilizing adipose or fat tissue is to perform a liposuction procedure. Both of these methods are invasive. If you are using donated extracts, there is no need to harvest stem cells directly from the patient.

That’s what researchers wrote as the introduction to their paper, “Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy.” The paper appeared in the medical journal Cell Transplantation. While bone marrow stem cell therapy and adipose stem cells have shown themselves to be an effective and reliable treatment for musculoskeletal injury, a concern patients have with these treatments surround the discomfort of the stem cell harvest.(2)

Are umbilical cord derived tissue products safe?

Laboratories that process umbilical cord derived tissue products screen and test the donor mother with infectious disease panels. The screening process should be in accordance with and determined by the Food and Drug Administration (FDA) and American Association of Tissue Banks (AATB).

Is there a risk of rejection? Is there a risk of cell mutation? Rejection and risk of the cell’s mutation into cancer cells is a frequent question doctors get about these products. Here is selected research that should be considered non-definitive as more research continues.

Donated umbilical cord blood can pass as being “native” to the new host

In the journal, Stem cell reviews and reports, (3) researchers noted that in looking for bone marrow donors for cancer patients and those with other immunodeficient disease, umbilical cord blood may offer a better answer for those waiting donation. Why?

  • “Umbilical cord blood offers advantages over bone marrow because cord blood does not require perfect human leukocyte antigen (HLA) tissue matching, (simply donated umbilical cord blood cells easily passes for being “native” to the new host) has less incidence of graft vs host disease (rejection), and may be used allogenically.”

Used allogenically implies that the stem cells from the umbilical cord blood can mix and intermingle with the bone marrow stem cells of a cancer or immune deficient patient whose own bone marrow had been damaged or destroyed by disease, infection, or chemotherapy. This intermingling comes with little risk of gene mutation or rejection.

The authors of this study concluded: “While Mesenchymal stem cells (MSCs) can be isolated from adults via peripheral blood, adipose tissue, or bone marrow apiration, Mesenchymal stem cells (MSCs) derived from the discarded umbilical cord offer a low-cost, pain-free collection method of Mesenchymal stem cells (MSCs) that may be cryogenically stored (banked) along with the umbilical cord blood sample. From the umbilical cord, isolation of cells from the Wharton’s jelly has the greatest potential for banking, presently, because the most cells can be isolated consistently.”

This study tested the positive effects of umbilical cord derived tissue products in developing new cartilage. Researchers wrote in the journal BioMed research international (4) that umbilical cord derived tissue products have numerous advantages over bone marrow donor derived stem cells, including convenient collection, reduced immunogenicity (immune stimulating response), absence of tumor cell contamination, and lower risk of latent virus and pathogenic microorganism transmission.

Research: Vulnerable patients were not rejecting the umbilical cord stem cells from unrelated and unmatched donors.

The research that umbilical cord stem cells produced growth factors needed to rebuild bone marrow stem cells and that the umbilical cord blood donors could be unrelated or “unmatched,” to the recipient goes back to the early 1990s. Here researchers were looking for answers in helping children with various cancers who needed bone marrow transplants and who were not getting these transplants in time.

After 12 years of using unmatched donor stem cells in pediatric cancer patients, researchers recorded in 2005 in the Journal of Clinical Investigations (5) that “over the 12 years since the first unrelated-donor cord blood transplant was performed at Duke University Medical Center, there have been more than 6,000 unrelated-donor transplants performed in more than 150 locations around the world. In the vast majority of these transplants, HLA mismatching between donor and recipient was present at 1 or 2 HLA antigens.”

In 2009, Joanne Kurtzberg, MD, the lead researcher in this 2005 study, published an update in the journal Current opinion in pediatrics. (6)

Umbilical cord blood from related and unrelated donors, matched or mismatched at one or two antigens, is now widely regarded as an alternate donor source to matched marrow or peripheral blood for allogeneic transplantation in children as well as adults for a variety of malignant and non-malignant disorders.

This use of cord blood dramatically increases access to transplantation therapy for patients lacking matched related or unrelated adult donors.

In one of her concluding statements, Dr. Kurtzberg wrote: “In the future, (umbilical cord blood) may emerge as a source of cells for cellular therapies focused on tissue repair and regeneration.”

Fluids and cells from the umbilical cord blood, placenta, and amniotic fluid are immunologically privileged

Learning points from researchers at Clemson University published in the Journal of Cell Science & Therapy (7) reinforces the observations of these earlier studies.

“Next to hematopoeitic stem cells (those found in blood), the most widely studied stem cells in bone marrow are marrow-derived mesenchymal stem cells, also known as marrow stromal cells. In the adult, mesenchymal stem cells are found in highest concentration in the marrow cavity. Mesenchymal stem cell-like cells can be isolated from umbilical cord blood, placenta, perivascular (surrounding blood vessel) areas, amniotic fluid, and from the tissue surrounding the umbilical cord vessels, i.e., Wharton’s jelly. The collection of Mesenchymal stem cell-like cells from tissues that are discarded at birth is easier and less expensive than collecting Mesenchymal stem cells from a bone marrow aspirate. During the collection of these tissues, there is no health impact on either the mother or the newborn. At least in theory, these cells may be stored frozen and then thawed to provide (cells) for therapeutic use decades after cryogenic storage. . .”

More from this research indicates that:

  • The stem cell material is not considered dangerous to the patient receiving the injection, even if the patient is in no way related to the donor.
  • Fluids and cells from the umbilical cord blood, placenta, and amniotic fluid are immunologically privileged meaning they cause no reaction even between completely unrelated donors and recipients.

Research: “(Treatment) without a major risk of rejection.”

A 2016 study from Korean researchers also demonstrated that umbilical cord derived tissue products, as well as other tissues, could also suppress the allogeneic response of lymphocytes and serve as a useful source for cell therapies and allogeneic stem cell transplantation between HLA-incompatible recipients. They noted in their research that “…allogeneic MSCs derived from umbilical cord blood can be a useful candidate for allogeneic cell therapy and transplantation without a major risk of rejection.” (8)

Long-term observations on risk and the use of donated umbilical cord blood stem cells: The findings of a 7-year study.

In 2017, doctors reported their findings in the journal Stem cells translational medicine (9) of a seven-year observation of patients who had received a regenerative product called Cartistem (a composite of culture‐expanded allogeneic human umbilical cord blood‐derived mesenchymal stem cells and hyaluronic acid hydrogel), Cultured-expanded products are not available in the United States.

Here are the learning points of this research:

  • This study revealed that treatment with an allogeneic human umbilical cord blood products can be safe.
  • The results of the study show that the patients had no significant adverse effects or undesired effects over the seven years of follow‐up.
  • None of the study participants had substantial permanent degenerative disease.
  • The study found no evidence of abnormal findings suggesting rejection or infection.
  • The researchers suggest that the characteristics of the human umbilical cord blood and tissue such as hypoimmunogenicity (does not cause an immune system reaction) and immunomodulatory (the immune system does not consider these “foreign” cells to be invaders) activity contributed to the lack of the treatment rejection.
  • There were no cases of osteogenesis (bone mutation) or tumorigenesis over 7 years.

In the Chinese journal of reparative and reconstructive surgery, (10) doctors reported on the effects of umbilical cord blood stem cell therapy on their patients. Here are the learning points of their study:

  • Between January 2015 and January 2016, 36 patients with moderate or severe degenerative knee osteoarthritis were randomly divided into 2 groups of 18 patients each.
  • Intra-articular injection of human umbilical cord stem cell suspension (expanded cells which cannot be used in the United States) was performed once a month for 2 times as a course of treatment in the cell treatment group; sodium hyaluronate by intra-articular injection was used once a week for 5 times as a course of treatment in the control group.
  • All patients of 2 groups received a course of treatment.
  • The patients were followed up for 6 months.
  • In the expanded c ells group, standardized pain and function scores at 2-6 months after treatment were significantly better when compared with scores before treatment, and no recurrence of knee pain was observed during follow-up.
  • The standardized pain and function scores at 1 and 2 months after treatment between 2 groups were similar but the scores of the cell treatment group were significantly better than those of the control group at 3 and 6 months.

A December 2018 study in the medical journal Stem cells translational medicine (11) examined single versus multiple umbilical cord blood stem cell treatments in patients suffering from knee osteoarthritis. This study was on cultured stem cells that are not the treatments used in the United States.

The patients in this study either:

  • Received hyaluronic acid injections at the baseline of the study and at 6 months.
  • Received a single-dose cultured stem cells treatment at baseline.
  • Received two cultured stem cells treatments at baseline and 6 months.
  • Clinical scores and magnetic resonance images (MRIs) were assessed throughout the 12 months follow-up.
  • No severe adverse events were reported.
  • Only umbilical cord cultured stem cells treatment patients experienced significant pain and function improvements from baseline.
  • Patients reached significantly lower levels of pain in the two umbilical cord blood stem cell treatment group as compared with the hyaluronic acid injection group.

Doctors speculate on how the treatment may work: Growth factors.

In the research cited above, investigators suggest that human umbilical cord tissue are considered safe and effective in treating musculoskeletal disorders. But how do they work?  Umbilical cord blood contains a great amount of mesenchymal stem cells. Mesenchymal stem cells are part of the tissue building mechanism that makes connective tissue such as cartilage, muscles, bones, and fat pads. As a baby develops in the womb, these mesenchymal stem cells proliferate (grow) and differentiate (change) into creating the musculoskeletal system of the baby.

However, the baby needs more than stem cells. The baby needs growth factors and “cell signalers” that help the stem cells understand what they need to do.

In a study I referenced earlier in the journal BioMed research international, (4) researchers examined the pathway to cartilage repair with umbilical cord blood products. This was not a clinical study, but rather a study to test whether umbilical cord blood stem cells could repair cartilage in a laboratory setting.

What the researchers found was that human umbilical cord blood mesenchymal stem cells could be induced to differentiate into mature bone and cartilage cells by stimulation with growth factors.

This was supported by research in the journal Molecular medicine reports,(12) which explored the effect of human umbilical cord mesenchymal stem cells on chondrocytes (cartilage building block cells) from patients with osteoarthritis in a laboratory setting. The researchers found human umbilical cord mesenchymal stem cells and chondrocytes have mutual effect on each other that causes the creation and proliferation of new cartilage cells. Therefore, human umbilical cord stem cells could significantly reduce the effects of osteoarthritis. However more research is need before such a blanket statement can be verified.

How the umbilical cord blood growth factors work in degenerative joint and spine disease

In research published in the International wound journal (13) doctors at Stanford University School of Medicine and the Georgia Institute of Technology along with author colleagues at collaborating medical universities, focused on growth factors presented in afterbirth material.

The researchers found these growth factors facilitated normal wound healing functions, including cell proliferation and chemotaxis (cell migration and movement to the site of injury), as well as promoting angiogenesis (blood vessel formation), deposition of Extracellular Matrix (the scaffold where stem cells grow) and regulating inflammation. I am going to explain these processes in greater detail below.

In simple terms, the growth factors found in the placenta/umbilical material:

  • Helped guide stem cells and support cells already in a damaged joint to the sites of degenerative damage.
  • Supported these cells by helping create new blood flow to the damaged areas so healing elements could get there and damaged tissue could be whisked away.
  • Then, the growth factors helped build the scaffolds that spanned the damage that stem cells could adhere to and differentiate into what they needed to become, cartilage, synovial tissue, collagen for ligaments and tendons, etc.

In 2011, doctors at the University of Aberdeen published research in the journal Arthritis and rheumatism that provided the first evidence that resident stem cells in the knee joint synovium underwent proliferation (multiplied) and chondrogenic differentiation (made themselves into cartilage cells) following injury.(14)

This paper, presenting the idea that stem cells in an injured knee increased in numbers in preparation of healing, has been cited by more than 52 medical studies. If the stem cells in your knee synovial lining are abundant and could rebuild cartilage after injury, why isn’t your knee fixing itself? This is where umbilical cord materials could help.

One of those 52 medical studies I just mentioned, was performed by researchers at the University of Calgary in 2012. Among their questions, was the same question we just speculated on: “If the stem cells in the knee synovial lining are abundant and have the ability to rebuild cartilage after injury, why isn’t the knee fixing itself?” Here is what they published in the medical journal PLOS ONE.(15)

“Since osteoarthritis leads to a progressive loss of cartilage and synovial progenitors (rebuilding) cells have the potential to contribute to articular cartilage repair, the inability of osteoarthritis synovial fluid Mesenchymal progenitor cells (growth factors) to spontaneously differentiate into chondrocytes suggests that cell-to-cell aggregation and/or communication may be impaired in osteoarthritis and somehow dampen the normal mechanism of chondrocyte replenishment from the synovium or synovial fluid. Should the cells of the synovium or synovial fluid be a reservoir of stem cells for normal articular cartilage maintenance and repair, these endogenous sources of chondro-biased cells would be a fundamental and new strategy for treating osteoarthritis and cartilage injury if this loss of aggregation and differentiation phenotype can be overcome.”

In common terms, the “reservoir of stem cells for normal articular cartilage maintenance and repair,” already in the knee, are not fixing the knee because of a confused communication. The joint environment has changed from healing to degenerative and made clear communications “murky.” This is attested to in the research by this concluding statement:

“These results reveal a fundamental shift in the chondrogenic ability of cells isolated from arthritic joint fluids, and we speculate that the mechanism behind this change of cell behavior is exposure to the altered milieu of the osteoarthritis joint fluid.”

The paper suggests that getting these stem cells communicating and healing would create a fundamental new strategy in healing. Umbilical cord blood stem cell therapy helps with this problem of communication as demonstrated in the above studies.

This research was supported in a study from December 2017 published in the journal Nature reviews. (16) The paper suggested that recognizing that joint-resident stem cells are comparatively abundant in the joint and occupy multiple niches (from the center of the joint to the outer edges) will enable the optimization of single-stage therapeutic interventions for osteoarthritis.

Growth factors bring blood and healing factors to the degenerative damage

You need blood circulation for healing – growth factors make new blood highways

From my early start in regenerative medicine until now, the role of inflammation in healing and the need to bring circulation to a degenerated joint has not changed. To heal a bad knee, a bad hip, a bad shoulder, to heal anything, you need blood circulation and the healing and growth factors blood brings to the site of injury and degeneration. These are the amazing things blood does:

  • Blood brings healing elements to the site of joint damage
  • Blood takes away diseased tissue from that site.
  • Blood also brings oxygen that helps create an “anti-oxidant” healthy joint environment and takes away the “oxidant” toxic sludge that develops as a byproduct of chronic inflammation in the joint’s synovial tissue.

Above we discussed the role of umbilical cord blood products in changing a diseased joint environment into a healing joint environment.

To get blood to an injury you need new blood vessels

Angiogenesis is the scientific term to describe the process of creating new blood vessels, “Angio” meaning related to blood vessels, “Genesis,” the creation of new blood vessels are formed as new branches of existing blood vessels. One of the growth factors found in human umbilical cord blood is called ANG-1.

ANG-1

ANG-1 is an Angiopoietin. Angiopoietins are protein growth factors in a developing baby that helps with vascular development and the formation of the blood circulatory network. When this growth factor is introduced into a degenerative joint it starts talking to the endothelium tissue cells that line the patient’s blood vessels.

What do they talk about?

It works together with the surrounding cellular matrix (the growth factors already in your body that surround your stem cells) and mesenchyme, the cells of the connective tissue, and your mesenchymal stem cells. ANG-1 also talks to your lymphatic vessels to prepare them for an increased flow of toxins and damaged tissue, that will be coming out of your joint.

Basic Fibroblast Growth Factor (bFGF)

Another important growth factor found in human umbilical cord blood is called basic fibroblast growth factor (bFGF). bFGF does many things, but in the context of this chapter, I want to focus on bFGF’s activity during injury repair.

  • bFGF helps with the formation of new blood vessels in conjunction with ANG-1.
  • bFGF lives in the subendothelial extracellular matrix of blood vessels, the growth factor pool of stem cells in the blood vessel lining. Here it helps move oxygen and nutrients to support the cells healing damaged tissue and it helps with the sprouting of new blood vessels during angiogenesis.

Vascular Endothelial Growth Factor (VEGF)

As its name implies, Vascular Endothelial Growth Factor (VEGF) is involved in vascular and blood vessel cell development. VEGF makes blood vessels that helps form new bone and cartilage.

  • Blood flow assists bone and cartilage

Now let’s watch the interplay between these growth factors in the development of new bone and cartilage.

  • Basic fibroblast growth factor (bFGF) is involved with the differentiating of mesenchymal stem cells into osteoblasts, bone cells.
  • Vascular Endothelial Growth Factor (VEGF) makes bone from cartilage cells.
  • In a developing baby, growth plates are soft areas at the end of long bones. The area remains soft through puberty or until the adolescent reaches a state of maturation and growing has stopped.
  • At this point, the soft, flexible cartilage-like growth plate turns into bone. A constant state of blood flow is needed for this new and developing bone. VEGF makes sure it is there.

So now you understand how this works in a baby and a developing adolescent, but, how does this work in the aging population and their challenges of degenerative disease? Researchers at Harvard give this recap in the medical journal Bone: (17)

  • “VEGF is one of the most important growth factors for regulation of vascular development and angiogenesis. Since bone is a highly vascularized organ (abundant blood circulation) and angiogenesis plays an important role in osteogenesis (formation of bone) VEGF also influences skeletal development and postnatal bone repair.
  • Compromised bone repair and regeneration in many patients can be attributed to impaired blood supply; thus, modulation of VEGF levels in bones represents a potential strategy for treating compromised bone repair and improving bone regeneration.
  • Local administration of VEGF may be useful in treatment of impaired bone healing/regeneration as a consequence of age or osteoporosis.” In other words, bring blood to the damaged bone.

You need cellular communication for healing – growth factors make new communication networks that send signals to grow bone

Above, I touched on cell signaling, and that  stem cells start conversations with the cells in an already damaged joint.

Basic fibroblast growth factor (bFGF) in addition to its role as a growth factor, is a signaling protein. Signaling proteins help cells communicate with each other and provide navigational signals. Navigation is obviously an important element in healing, in that healing cells need to know where they are going to in the damaged joint.

Transforming growth factor-beta (TGF-β)

Transforming growth factor-beta (TGF-β) found in umbilical cord blood is a growth factor of great interest in bone healing. What makes it so interesting is that it stimulates your own stem cells to reboot the healing process. How? By way of communicating with the other cells.

In January 2019 researchers examined the role of growth factors in helping stem cells in a damaged joint get to the point of injury. The study published in the journal Biochemical and biophysical research communications (18) found that “Endogenous (your own) bone marrow-derived mesenchymal stem cells are mobilized into peripheral blood and injured tissues by various growth factors and cytokines (messenger cells) that are expressed in the injured tissues, such as transforming growth factor-beta (TGF-β).”

Umbilical cord blood growth factors work with your stem cells

In the research above, we see that stem cell growth factors help the damaged healing communication system in degenerative joints reset and restart. In doing so, the healing communications network starts giving commands to the cells to start healing again.

Here is some interesting research from doctors in the United Kingdom published in the November 2017 issue of Future science OA (19). The study from the University of Leeds and Leeds Teaching Hospital discusses native stem cell activity in degenerative knee disease.

The researchers found signs of tissue adaptation and attempted repair responses in osteoarthritis-affected osteochondral (bone and cartilage) tissues. What this means is that even in advanced osteoarthritis, the knee (and the stem cells within it) is trying to heal itself. But it is an attempted repair that never completes. So now the focus shifts to what can doctors do to help the stem cells complete the repair. One answer is more communicating growth factors from native and injected stem cells

Do you have questions? Ask Dr. Darrow

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PHONE: (800) 300-9300 or 310-231-7000

Stem cell and PRP injections for musculoskeletal conditions are not FDA approved. We do not treat disease. We do not offer IV treatments. There are no guarantees that this treatment will help you. Prior to our treatment, seek advice from your medical physician. Neither Dr. Darrow, nor any associate, offer medical advice from this transmission. This information is offered for educational purposes only. The transmission of this information does not create a physician-patient relationship between you and Dr. Darrow or any associate. We do not guarantee the accuracy, completeness, usefulness or adequacy of any resource, information, product, or process available from this transmission. We cannot be responsible for the receipt of your email since spam filters and servers often block their receipt. If you have a medical issue, please call our office. If you have a medical emergency, please call 911.

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