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Regenerative Medicine in Pain Management


Regenerative medicine offers an entirely new approach to repairing, replacing, maintaining, or enhancing organ or tissue function that has been lost due to disease, injury, or aging. By combining biomedical, biochemical, and biomechanical technologies, regenerative medicine strives to improve cellular migration, replication, and remodeling.1 Treatment approaches include cell therapies, tissue engineering, gene therapy, immunomodulation therapy, and biomedical engineering.

Presently, clinical practice within the United States focuses mainly on approved autologous therapies utilizing platelet-rich plasma (PRP) or bone marrow aspirate (BMAC). Here, we will review various stem cell therapies for pain management based on in vitro and clinical studies.

Mesenchymal Stem Cells

Adult stem cells are found throughout the body. The primary role of these cells is to maintain and repair the tissue in which they are found. Adult stem cells possess two very important properties— self-renewal and differentiation. Adult stem cells are multipotent, meaning they can be differentiated into subsets of cell types. Stem cells have been used for many different disease states as they also have the capacity to change the local environment via their paracrine effect, which may render them capable of disease modification.

Mesenchymal stem cells (MSCs) arise from pericytes released from broken and inflamed blood vessels. Once released, the MSCs exhibit an immunomodulatory as well as a regeneration zone of influence. Additionally, they have an angiogenic and antibiotic effect. Caplan et al. describe the immunomodulatory zone as a curtain of bioactive molecules that prevent the body from mounting a chronic autoimmune reaction.2-3 MSCs address the regeneration zone, or the damaged tissue, by secreting a different set of bioactive molecules that have trophic functions. This results in four basic actions: apoptosis inhibition, inhibition of scar formation, angiogenesis, and mitogenesis. Lastly MSCs possess antimicrobial properties that can sense and address infection.4-5

Sources of MSCs include bone marrow, adipose, peripheral blood, amniotic, umbilical, and placental tissue. Most clinical studies involve the use of autologous sources of MSCs due to their accessibility and low risk of infection. In terms of clinical practice, the most popular types are derived from bone marrow aspirate or lipoaspirate.

The International Society for Cellular Therapy (ISCT) set forth minimum criteria to define human MSCs: (a) plastic adherence in standard culture; (b) positive for endoglin, CD73, and CD90, and negative for CD45, CD34, CD14 or CD11, CD97-alpha or CD19, and HLADR surface markers; (c) in vitro differentiation into osteoblasts, adipocytes, and chondroblasts.6

Bone Marrow-Derived Stem Cells

Bone marrow-derived stem cells are the most commonly used source and are permitted by the FDA and other governing bodies. Bone marrow aspirate has been approved and used safely for many years for the treatment of blood cancers and other hematological disorders. Bone marrow is the primary site of new blood cell production. Two main cell types are produced in bone marrow: hematopoietic cells (myelopoietic, erythropoietic, lymphocytes, plasma, reticular, monocytes, magakarocytes, hematopoietic stem cells) and stromal cells (fibroblasts, macrophages, adipocytes, osteoblasts, osteoclasts, endothelial cells, MSCs). The frequency of stem cell production decreases proportionately with age.

Bone marrow MSCs are obtained via bone marrow aspiration of the iliac crest (most commonly) under sterile conditions. The aspirate is then typically washed and centrifuged to remove the plasma and buffy coat until the final “cell pellet” is obtained; in some instances, a separation medium may be utilized. This pellet is commonly referred to as bone marrow aspirate concentrate (BMAC). A milliliter of bone marrow aspirate yields approximately 6 x 106 nucleated cells; only 0.01% are bone marrow stem cells.7

Bone marrow MSCs are a population of cells found in bone marrow that are different from blood cells in a variety of ways. They are multipotent stem cells, giving them the ability to differentiate into bone, cartilage, and fat cells. Additionally, they can support the formation of new blood cells. Two types of stem cells originate in bone marrow—hematopoietic stem cells and MSCs. There are also endothelial progenitor cells that have the capacity to form new vasculature. Hence, they have similar capabilities to stem cells.

Bone marrow-derived MSCs regenerate injured or damaged tissue via the following pathways— fibrinogenesis, osteogenesis, adipogenesis, and chondrogenesis.4 Bone marrow-derived MSCs home to injury sites via migratory properties in bone marrow, bone, and cartilage.8 Additionally, BMAC contains the following growth factors—basic fibroblast growth factor (b-FGF), platelet-derived growth factor (PDGF-BB), vascular endothelial growth factor (VEGF), transforming growth factor- beta (TGF-B), and bone morphogenetic protein-2 (BMP-2), to name a few.9

While the number of stem cells found in BMAC is relatively low compared to those found in lipoaspirate, the growth factors and platelets contained in BMAC are believed to enhance their therapeutic ability. A study by Schafer et al. found that BMAC increases the concentration of PDGF-BB and VEGF in mononuclear cells.10 Both PDGF-BB and VEGF contribute to angiogenesis."-12

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