Stem Cell Therapy V.S. Platelet Rich Plasma (PRP)

Now that we have the basic science under our belts, we can turn back to the concept of regenerative medicine…

Platelet-rich plasma (PRP)

Platelet-rich plasma (PRP) is the product of using specialized centrifuge techniques (putting the test tubes in a spinning machine) to separate platelets from whole blood (separate the blood into its different components). Platelet-rich plasma (PRP) is a suspension of concentrated platelets in a small volume of plasma (as discussed above; the liquid portion of blood). The whole process takes approximately 15 minutes and produces a platelet concentration of 3–5x that of regular blood.

Platelet-rich plasma (PRP) has been advocated as “regenerative” medical treatment. It is proposed PRP boosts are own body’s natural tissue healing and regeneration capabilities through the local introduction of increased levels (above baseline) of platelets and their associated bioactive molecules (specifically the growth factors mentioned in the inflammatory phase of wound healing, above). In theory, the increased levels of autologous (from your own body) growth factors (GFs) and other proteins provided by the concentrated platelets may enhance the wound healing process.

Researchers believe the primary benefit of PRP is platelets are a natural source of growth factors (GFs). Growth factors, stored within platelet α-granules, include platelet derived growth factor (PDGF), insulin like growth factor (IGF), vascular endothelial growth factor (VEGF), platelet derived angiogenic factor (PDAF), and transforming growth factor beta (TGF-β). We have learned, these growth factors help with the following components of healing:

  1. GFs help recruit reparative cells to the site of injury
  2. GFs help increase growth of little blood vessels involved in the early wound repair process (angiogenesis).
  3. GFs promote cell proliferation (replication and division of cells, or “growth),

What Conditions are Treated with PRP?

The concept of PRP is not new; autologous platelet-rich plasma has been used over the past 3 decades in dentistry, ophthalmology, maxillofacial surgery, and cosmetic surgery. Research into the efficacy of PRP for musculoskeletal disorders is ongoing. Treating tendons, ligaments and cartilage injuries with PRP is not without controversy. Even though the basic science data supporting the potential beneficial effects of growth factors (key component of PRP) in augmenting connective tissue healing is promising, the clinical benefits of using PRP to improve functional outcomes have been inconsistent.

Currently, common conditions treated with PRP injections (and, of course, supportive rehabilitation) include:

  1. Tendons:
    • Tennis elbow (lateral epicondylopathy)
    • Achilles tendinopathy
    • Patellar tendinopathy (between the kneecap and the top of the shin bone)
    • Gluteus medius tendinopathy (tendon from the outer glute muscle that attaches to the greater trochanteric and may or may not be associated with bursitis)
  2. Ligaments:
    • Medial collateral ligament (MCL) sprains of the knee
    • Acromioclavicular joint sprains (A-C joint) of the shoulder
  3. Joints/Cartilage:
    • Early knee osteoarthritis (OA),
    • Early hip osteoarthritis (OA).

One potential reason for the lack of translation from the lab (in vitro studies are very encouraging) to clinical results (clinical studies have had mixed results) is the wide variance in the final PRP product.

The large variance of the PRP preparations currently offered to patients (both for clinical studies and everyday use) is causing confusion to the medical community (interpretation of research results) and the patient population (does PRP work? Where should I go for my treatment?). Therefore, it is incumbent upon anyone using a specific PRP product to understand the product they are offering. In addition, it is the responsibility of the patient to pursue basic knowledge of the medical treatment they are pursuing, so they make informed decisions.

STEM CELL THERAPY

Stem cells are unspecialized cells (undifferentiated) of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. Stem cells provide new cells for the body as it grows and replace specialized cells that are damaged or lost.

Stem cells, therefore, act as the internal repair systems of the body. Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome to fully understand the safety and efficacy of stem cell therapy.

Types of stem cells: Understanding stem cell potency: It is common to divide stem cells into two categories:

  • Embryonic stem cells (ESC). These stem cells come from embryos (fertilized egg) that are less than five days old. These are pluripotent stem cells, meaning they can differentiate (specialize) into any type of cell in the body.
  • Adult stem cells. These stem cells are found in adult tissues, such as bone marrow or fat. Adult stem cells have a more limited ability to give rise to various cells of the body. The disadvantage of adult stem cells is the difficulty in harvesting the number and quality of cells necessary to successfully treat the target condition. The advantage of the adult stem cells is in their predictability; there is a much lower probability adult stem cells will develop into an unexpected type of tissue (remains controversial).

Scientific (more detailed) discussion of types of stem cells and their potency:  The following discussion may be difficult for an individual without a science background to absorb. But, this is useful information in the pursuit of a decent understanding of stem cell science.

As stem cells differentiate and become more mature, their developmental potency is reduced. The following is a brief explanation of the sub-types of stem cells that exist in humans, beginning with conception (getting pregnant):

1. Totipotent stem cells. The best example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. When an egg is fertilized by sperm in the fallopian tube (just outside the uterus) it becomes a zygote. The zygote is a single cell that contains all 46 of the chromosomes (DNA) needed to become a fully developed human. A zygote is pretty much the first stage of human life. Totipotent cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential (ability to sub-specialize into different types of cells) and allows cells to form both embryo and extra-embryonic structures. This type of stem cell is not commonly discussed in context of treating common musculoskeletal injuries. {totipotent cells are mentioned to avoid voids in the basic science education}

2. Pluripotent stem cells (PSCs) are almost as “powerful” as totipotent stem cells. PSCs can also form cells of all germ layers (all types of human tissue), with the exception of the placenta.

Embryonic stem cells (ESCs) are an example. Reminder to science students: The zygote undergoes some evolution (cell division) in the first few days the zygote will become an embryo, then a morula, then a blastocyst. When the embryo grows to the level of blastocyst, it is ready for implantation in the uterus. ESCs are derived from the inner cell mass of preimplantation embryos (blastocyst).

Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. iPSCs are artificially generated (an individual’s cells are modified in a lab) similarly to PSCs. iPSCs are promising for the future regenerative medicine, but are not currently the standard of care.

3. Multipotent stem cells have a narrower range of differentiation (ability to specialize) than PSCs, but they still have significant capacity. They can specialize into cells of specific cell lineages (cells of one germ layer). For example, a multipotent blood stem cell can differentiate itself into several types of blood cells; red blood cells (RBCs) and different types of white blood cells (WBCs).

Most stem cells used for the experimental treatment of osteoarthritis are adult mesenchymal stem cells (MSCs). These cells are typically collected from fat or bone marrow. MSCs are multipotent, capable of specializing into cartilage, bone, muscle, tendon, ligaments, or fat. Which tissue they differentiate into depends upon their environment (type of tissue cells are inserted into).

The influence of MSCs on joint disease (e.g. osteoarthritis) is not fully understood. Beyond the hope of tissue regeneration, there are other potentially beneficial effects. The injection of MSCs can be associated with the release anti-inflammatory factors. Some believe the benefits of MSCs relates to the enhancement of the wound healing cascade, similar to PRP.

4. Oligopotent stem cells can differentiate into sub-types of particular lineage. Using the same example of blood cells; a lymphoid cell can give rise to various blood cells such as B and T cells, however, not to a different blood cell type like a red blood cell

5. Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type. So, their use can be focused.

Stem Cell Therapy for Osteoarthritis (OA).

Most injection-based treatments use a patient’s own MSCs (called autologous MSCs) taken from their bone marrow or fat. The odds of this type of intervention resulting in the stem cells developing into an unintended tissue type, is extremely low.

Despite the fact research to date shows that stem cell treatments using a patient’s own cells tend to be safe for OA, the Health Canada has not approved stem cell therapy at this time.

Critics of stem cell intervention emphasize that there have been no large-scale, prospective, double-blind research studies to support stem cell therapy for arthritis. Critics are also concerned that the assumption that adult stem cells are safe and will develop into the target issue without incident is a premature conclusion.

It is likely, in the near future, enough support for the safety and efficacy of stem cell treatment in well selected osteoarthritis patients will be published to restart this type of care for Canadian patients. In the short term, stem cell intervention is not available in Canada.

Regenerative Medicine and Wound Healing

Regenerative medicine

Regenerative medicine is the field of study which involves the process of replacing or “regenerating” human cells, tissues or organs to restore or establish normal function. This field holds the promise of repairing damaged tissues and organs in the body.

What regenerative medicine treatments are available for musculoskeletal injuries (joints, tendon, ligament)?

The most commonly discussed regenerative therapies for musculoskeletal injuries are:

  • Stem cell therapy
  • Platelet rich plasma (PRP)

Stem cell therapy and platelet rich plasma are not the same. However, there is overlap with how these two treatments influence the body’s efforts to repair musculoskeletal injuries.

  • PRP primarily works to boost the body’s natural healing mechanisms.
  • Stem cells, theoretically, have the ability to “regenerate” tissue. Realistically, when discussing the current available stem cell treatments for musculoskeletal injury, stem cells carry out their primary effect by enhancing our natural healing mechanisms (similar to PRP). In medicine, we refer to this repair process as wound healing.
  • “Regeneration” of new tissue with stem cell technology is likely within our grasp. In fact, in animal studies, regeneration of soft tissues has been demonstrated. However, it is not clear that the benefits we are seeing in real life (injured humans) are related to “regeneration” in the strictest definition of the term. More likely than not, stem cell treatments with autologous stem cells (harvested from your own body) exert their influence by enhancing our natural healing mechanisms.
  • Because the assumed benefits of both PRP and stem cells are understood to relate to enhancement of our natural healing processes, it makes sense to discuss the basic science of wound healing to improve our understanding of this type of medicine…

Wound Healing

Wound healing is a dynamic physiological process for restoring the normal architecture and functionality of damaged tissue. A highly detailed discussion of the steps involved in wound healing is beyond the goals of this website. However, a grasp of the basic science may be useful to the patient, therapist or family physician to improve communication surrounding treatment options. To comprehend wound healing, one must have a basic understanding of the components of our blood.

In other words…

  • One needs to know the basic science of blood components to understand wound healing.
  • One needs to know the basic science of wound healing to understand the current state of regenerative medicine.

Understanding the components of blood

  1. Plasma: The blood that runs through our veins, arteries, and capillaries is known as whole blood, a mixture of about 55 percent plasma and 45 percent blood cells. The liquid component of blood is called plasma, a mixture of water, sugar, fat, protein, and salts. The main job of the plasma is to transport blood cells throughout your body along with nutrients, waste products, antibodies, clotting proteins, chemical messengers such as hormones, and proteins that help maintain the body’s fluid balance.
  2. Red Blood Cells (erythrocytes): Red blood cells (RBCs) are the most abundant cell in the blood. RBCs contain a special protein called hemoglobin (Hgb), which helps carry oxygen (O2) from the lungs to the rest of the body and then returns carbon dioxide (CO2) from the body to the lungs so it can be expelled. Blood appears red because of the large number of red blood cells, which get their color from the hemoglobin.
  3. White Blood Cells (leukocytes): White blood cells (WBCs) protect the body from infection. They are much fewer in number than red blood cells, accounting for about 1% of your blood.
    • The most common type of white blood cell is the neutrophil (a granulocyte), which is the “immediate response” cell and accounts for 55 to 70 percent of the total white blood cell count.
    • The other major types of white blood cells are the monocytes and lymphocytes. Both monocytes and lymphocytes are important in immune function. Monocytes also have a major role in wound healing, which will be discussed, below.
    • Lymphocytes are less involved in the wound healing response. However, to complete the educational discussion…There are two main populations of lymphocytes. T lymphocytes help regulate the function of other immune cells and directly attack various infected cells and tumors. B lymphocytes make antibodies, which are proteins that specifically target bacteria, viruses, and other foreign materials.
  4. Platelets (thrombocytes): Unlike RBCs and WBCs, platelets (plts) are not actually cells but rather small fragments of cells. Platelets help the blood clotting process by gathering at the site of an injury, sticking to the lining of the injured blood vessel, and forming a platform on which blood coagulation (clotting) can occur. This results in the formation of a fibrin clot (like a nutritious, sticky plug), which covers the wound and prevents blood from leaking out. This fibrin clot forms the initial scaffolding upon which new tissue forms, thus promoting healing.

Understanding the phases of wound healing

Now that we have been introduced the components of our blood, we can begin to understand how those blood components are vital to the wound healing process. A relatively simple example to help absorb the basic fundamentals of wound healing, is falling and cutting the skin over your knee. What happens in the body to heal that cut or scrape?

…There are four stages of wound healing that the body carries out from the time you scrape your knee, until the formation of the mature scar, months later…

  1. Clotting
    • Clotting is formally known as hemostasis. This is the initial clotting of the scrape to stop the bleeding. The process takes seconds to minutes.
    • Adhesion: Platelets are our “clotting” cells (or cell fragments), that stick to the injured site.
    • Activation: After adhesion, platelets change shape and release natural chemical signals to promote clotting (they call in their teammates). When the specialized proteins (enzymes) are activated, a complex cascade of events takes place and, in the end, the glycoprotein fibrinogen is converted into fibrin. The fibrin then forms a mesh and acts as “glue” to bind platelets to each other. The result is a fibrin “clot”, which acts as a scaffold for other cells to attach to (infiltrate or invade) and build upon (proliferate or grow).
  2. Inflammation
    • This process takes hours to days. This involves recruitment of the second and third wave of cells in the blood to a) clean up the work site and b) start building a stronger, more complex clot or scab.
    • As per the title, the next cells to get involved are your inflammatory cells, your white blood cells (WBCs). One type of WBC is a neutrophil. Neutrophils “kill and clean”. In the clean-up process, neutrophils will recruit more WCBs (they call in their cousins). The neutrophils will send out more chemical messengers which call in the second line of WCBs called monocytes (cousins).
      1. *For those reading this article who have a science background; the neutrophils release inflammatory mediators TGF-B1, IL-1, IL-4 in order to call in the monocytes
    • Monocytes will change into macrophages (the medical term is “differentiate” which means to become more specialized), which are like little Pac-Man messengers that eat up (the medical term is “phagocytosis”) damaged/dead cells and clear them out, along with bacteria and other debris.
    • There is a third wave of recruitment: More chemical messengers are released and proteins called growth factors (GFs) are released into wound.
    • Growth factors are vital to the healing process!! These growth factors have two important jobs:
      1. GFs promote further migration of cells to the area (even more recruitment of important teammates!)
      2. GFs promote division of cells during proliferative phase (I.e. GFs promote the actual process of cell division for REGENERATION).
  3. Proliferation (Replication and division of cells for “growth”)
    • This phase takes days to weeks. Proliferation is complex. There are many different processes going on at the same time.
    • The WBCs are still important. The macrophages keep releasing chemical messengers (the medical term is “cytokines”) and GFs to boost the process of building new blood vessels (the medical term is “angiogenesis”) and the building of the fresh fibrous tissue (the medical term is “fibroplasia”).
    • The collagen cells (fibroblasts) replicate and then synthesize new components of scar tissue (called the extracellular matrix – ECM). Simply put…the scaffolding that was initiated with the fibrin clot gets reinforced and replaced with higher quality tissue.
    • The blood vessels that have been growing into the fresh tissue start to help out with the process. They bring oxygen and nutrients necessary for the metabolism and growth of cells into the tissue.
    • Essentially, the wound is being filled in by fresh scab tissue. Doctors call this “granulation tissue”. Granulation tissue is new connective tissue (fibrous tissue) and microscopic blood vessels that form on the surfaces of a wound during the healing process (the weak scab, the fibrin clot gets replaced with a strong scab, granulation tissue). 
  4. Maturation/Remodeling
  5. The scab matures. Depending on the regenerative capacity of the tissue (location and type of injury in the body) the body will achieve various outcomes:
    1. The scab may begin its journey to becoming a mature scar.
    2. If the tissue environment is suitable, the scab may be replaced by new tissue, identical to the original cells in the region.
  6. During this final stage, blood vessels formed in the scab (granulation tissue) are no longer required and are removed by apoptosis (organized cell death and removal).
  7. The body begins to remove the less useful collagen and replace it with stronger, more structured collagen.