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Stem Cell Prolotherapy

Adult stem cell therapy holds promise for the treatment of osteoarthritis and joint regeneration.

What if prolotherapy and then platelet rich prolotherapy (PRP) were to fail? What is the next step, short of surgery (if surgery is even an option)? Since the early 1990s there has been an interest in “adult stem cells”—undifferentiated cells that can be isolated from many tissues in all stages of life.1

Difference Between Fetal (Embryonic) and Adult Stem Cells

  • Fetal stem cells are generalized, full of potential, can give rise to any cell type, and therefore deemed “pluripotent”.
  • Adult stem cells, on the other hand, are partially differentiated but can still give rise to cells from multiple lineages, and therefore deemed “multipotent”. These adult stem cells are found throughout the body and exist in order to replenish dying cells and regenerate damaged tissue.
  • Musculoskeletal tissues come from a type of adult stem cell known as the “mesenchymal” stem cell (MSC). MSCs can replicate as undifferentiated cells but also have the potential to differentiate into a variety of connective tissue cells2 including bone, cartilage, fat, tendon, muscle, and adipose tissue.2
  • Adult stem cells also produce useful growth factors and cytokines that may help repair additional tissues.1 The major reservoirs for mesenchymal stem cells are bone marrow and adipose tissue.1

History of Autologous Mesenchymal Adult Stem Cell Therapy
As early as 1993, the existence of mesenchymal stem cells—“non-committed progenitor cells of musculoskeletal tissues”—were known to have an active role in tissue repair.3 These cells, first labeled by Caplan of Case Western University in 1991 as “mesenchymal” stem cells (MSC)4 because of their ability to differentiate to lineages of mesenchymal tissue, are known to be an essential component of the tissue repair process.5

Some researchers believe that stem cells exist in every tissue, with bone marrow serving as one of the bodys main “reservoirs” from which extra stem cells are mobilized when needed.6 It is well known that healing takes place more rapidly in children than adults, a fact credited to the increased number of stem cells in children.

As early as 1998, researchers were studying the use of MSCs in tendon repair,7 and concluded that the use of implanted adult stem cells delivered to tendon defects can “significantly improve the biomechanics, structure, and probably the function of the tendon after injury.”7

MSC were deemed to be safe for human use in 19958 and, once safety was established, research efforts grew. In 1999, an article in Science described how these cells could be extracted from human bone marrow and then selectively induced to differentiate exclusively into either the adipocytic, chondrocytic or osteocytic lineages based on different processing protocols after extraction.2

Autologous Stem Cell Therapy for Osteoarthritis and Joint Regeneration
An interesting observation about MSCs is their ability to “home in” and repair areas of tissue injury, including osteoarthritis9,10 and other injured types of tissue; for example ischemic heart tissue,11,12 graft-vs-host disease,13 and osteogenesis imperfecta.14 In certain degenerative diseases such as osteoarthritis, an individuals stem cell potency appears depleted, with reduced proliferative capacity and ability to differentiate.6,15

Researchers have developed protocols to process extracted autologous stem cells which encourage them to differentiate in the desired direction, whether towards cartilage, tendon, muscle or bone.1 Studies have demonstrated the regeneration of articular cartilage defects with adult stem cell therapy.16,17 In 2003, Murphy et al found significant improvement in medial meniscus and cartilage regeneration with stem cell therapy in an animal model.9 Not only was there evidence of marked regeneration of meniscal tissue, but the usual progressive destruction of articular cartilage, osteophytic remodeling and subchondral sclerosis seen in osteoarthritic disease were reduced in MSC-treated joints compared with controls.9

In 2008, Centeno et al documented significant knee cartilage growth and symptom improvement in a human case report using culture expanded autologous MSCs from bone marrow.10

Bone Marrow Aspirate Concentrate (BMAC)

Bone marrow has classically been the reservoir used to harvest stem cells. Bone marrow aspiration is commonly done in the office setting with local anesthesia and is tolerated well by most patients.1 Once harvested, the stem cells need to be isolated.1 In addition to isolation, concentrating the cells is important and related to effectiveness. Some of the available systems that process PRP, such as Harvests Smart PReP 2, are also FDA-approved to isolate and concentrate the bone marrow aspirate into a bone marrow aspirate concentrate (BMAC).18 Concentration of the bone marrow is an important element of efficacy.19

Once concentrated, BMAC has been shown to have comparable cell counts as allograft, with less morbidity. This autologous bone marrow aspirate contains not only mesenchymal stem cells but also accessory cells that support angiogenesis and vasculogenesis by producing growth factors and cytokines. There is increasing evidence that combined use of bone marrow aspirate and PRP show equivalence to autologous bone grafting.20 BMAC has also been shown to be a safe and effective treatment for tibial nonunion, metatarsal non-unions and Jones fracture,21 osteonecrosis of the hip,22,23 osteochondral defect repair,24 and limb ischemia.25

Results of a huge five year study in India for non-reconstructable critical limb ischemia demonstrated that BMAC provided an amputation-free survival of 90%, with pain reduction of over 90%.26 Other musculoskeletal applications also exist27 with more studies planned.

Adipose-Derived Stem Cells
Human adipose tissue has been shown to be an abundant and rich source of adult stem cells with a population of cells that possesses extensive proliferative capacity, and the ability to differentiate into multiple cell lineages.28 Most people do not mind giving up a little fat and, in fact, many electively undergo liposuction procedures, which yield large volumes of useable adipose tissue.29 Adipose-derived stem cells can differentiate towards osteogenic, adipogenic, myogenic and chondrogenic, and neurogenic lineages.1

Fat grafting has been popular in cosmetic procedures for the last several years and adipose-derived mesenchymal stem cells (AD-MSCs) are now beginning to be used in musculoskeletal medicine—either with or without PRP—to create a gel matrix or bioactive scafford to hold the essential “inflammatory boost” in a joint area.29 AD-MSCs are similar but not identical to bone marrow mesenchymal stem cells (BM-MSCs).1

Additionally, AD-MSCs can be easily isolated from the adipose tissue in significant numbers, are easy to process, and have low donor morbidity. AD-MSCs have been used with PRP and BMAC in the treatment of many musculoskeletal and vascular disorders. It is believed that the PRP fat graft is inducted by its environment to form the type of cell which surrounds it. For example, if it is placed with muscle cells it was differentiate into muscle and be incorporated there.29

Because of the increased simplicity of fat harvesting versus bone marrow aspiration, the use of autologous adipose tissue is gaining popularity for office use. Also, the yield of stem cells from adipose tissue is higher than with bone marrow, with typical MSC yield for bone marrow between 1 in 50,000 and 1 in 1 million in a skeletally mature adult compared to adipose tissue which yields 1 in 30 and 1 in 1,000 active undifferentiated stem cells.1 Studies show that human AD-MSCs may be promising for neurological autoimmune disorders30 musculoskeletal autoimmune issues such as rheumatoid arthritis,31 for disc regeneration,32 and chronic osteoarthritis33 in animal models. Inevitably the use of AD-MSCs in musculoskeletal medicine will continue to grow.

FDA Considerations
Controversy over the use of fetal stem cells are eliminated with the use of autologous adult stem cells, but regulation still exists in terms of how these cells are used. Autologous adult stem cells are considered “Human Cells, Tissues and Cellular-Based Products (HCT/Ps)” and thus regulated by the FDA.34 However, exemption from regulation exists if the physician “removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure.”35

To be considered as occurring “during the same surgical procedure” the cells must be “autologous,” “minimally manipulated,” and “used within a short period time.”36 “Minimally manipulated” is defined as “processing that does not alter the relevant biological characteristics of cells or tissues.”37 “Short period of time” is not exactly defined but per the “FDA Guidance for Industry” is considered to be “a matter of hours (or less), without the need for shipping.”36 “More than minimal” manipulation involves: “the use of drugs, biologics, and/or additional devices that warrants regulation of the manufacturing process and the resulting cells as biological products.” This is where the culture expansion of cells comes into question. In fact, the FDA defines cultured bone marrow cells as “combination products” which “may be regulated as devices or biological products” and indicates that “these products are currently under review.”38

Therefore, the culture expansion of stem cells, while delivering higher yields, is problematic in terms of FDA requirements. For now it is clear that harvesting of autologous stem cells—either with BMAC or fat extraction—at the point of care, does not pose any problem as far as FDA regulation is concerned as long as exemption criteria are met.


Last updated on: July 8, 2020
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Advances in Regenerative Medicine: High-density Platelet-rich Plasma and Stem Cell Prolotherapy For Musculoskeletal Pain
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