Advances in Regenerative Medicine: High-density Platelet-rich Plasma and Stem Cell Prolotherapy For Musculoskeletal Pain
Prolotherapy is a method of regenerative injection treatment designed to stimulate healing.1 Prolotherapy is used for the treatment of chronic musculoskeletal pain, inclucing ligament, tendon and joint injuries, as well as osteoarthritis. The term prolotherapy is short for proliferation therapy, as it stimulates the proliferation and repair of injured tissue.
Traditional dextrose prolotherapy originated in the 1930s and continues to be used successfully. In the 2000s, in-office platelet-rich plasma (PRP) prolotherapy was introduced. This method uses a patient’s own blood, centrifuged to concentrate growth factor–rich platelets as the proliferation formula. In the past few years, physicians have began using adult stem cells, harvested from an individual’s fat tissue or bone marrow during an in-office procedure, then combined with the individual’s PRP as the proliferation formula for injection into injured musculoskeletal tissue.
This newest form of prolotherapy, known as stem cell prolotherapy, is used in difficult cases or where accelerated musculoskeletal healing is desired. Popular media reports have been emerging that cite the use of stem cell prolotherapy in professional athletes such as Bartolo Colon, starting pitcher for the New York Yankees, who had the procedure successfully done for a rotator cuff injury earlier this year.2 Our article will review the history, science, methodology, and evidence for these types of prolotherapy, and offer a treatment algorithm.
Prolotherapy: The Original Regenerative Medicine
Prolotherapy was “discovered” in the 1930s by Dr. Earl Gedney, an osteopathic surgeon, before the term regenerative medicine existed. However, prolotherapy is a true regenerative medicine, working by locally raising growth factor levels to promote tissue repair and regeneration.3-5
Multiple studies confirm the effectiveness of prolotherapy in the resolution of musculoskeletal pain, including low back pain,6,7 neck pain, and whiplash injuries8; chronic sprains and/or strains; tennis and golfer’s elbow9; plantar fasciitis10; knee,11 ankle, shoulder pain, coccyxdynia12; chronic tendonitis/tendonosis,13 including Achilles tendonitis/tendonosis14; and other joint pain or musculoskeletal pain related to osteoarthritis.4
How Prolotherapy Works
Prolotherapy is based on the premise that chronic musculoskeletal pain is caused by an inadequate repair of fibrous connective tissue, resulting in ligament or tendon weakness and relaxation (laxity),1 also known as connective tissue insufficiency.15 Weak connective tissue results in insufficient tensile strength or tightness,16 causing excessive “loading” of the tissues that stimulates pain mechanoreceptors.15 As long as connective tissue remains functionally insufficient or ineffective, these pain mechanoreceptors continue to fire with use, causing significant pain and limitation of function.17 If the laxity or tensile strength deficit is not corrected sufficiently to stop pain mechanoreceptor stimulation, chronic sprain/strain, and pain results.3
Prolotherapy works by stimulating a temporary, low-grade inflammation at the site of ligament or tendon weakness, “tricking” the body into initiating a new healing cycle cascade.3 A common formula used in classic prolotherapy is dextrose, however, the choice of solution varies depending on practitioner preference and may contain sarapin, morruate, zinc, or other natural ingredients, combined with a local anesthetic.
Platelet-rich Plasma Prolotherapy
In the 1990s, the use of PRP to accelerate healing gained acceptance in surgical circles. However, the machines were large, expensive, and only used in hospital operating rooms. By the 2000s, the machines were smaller and available for use in an office setting.
Prolotherapists, and other physicians in the orthopedic and sports medicine fields, began using PRP injections to stimulate musculoskeletal connective tissue repair.18-20 PRP prolotherapy is based on the same theory as traditional dextrose prolotherapy, however, the formula used is a high-density concentration of the patient’s circulating platelet levels isolated and concentrated by bidirectional centrifugation. Enhanced healing capability is possible when platelet concentrations are increased within injured or damaged tissue.21
High-density PRP (HD-PRP) is defined as autologous blood with concentrations of platelets at no less than four times the circulating baseline levels,22 and which increases the important bioactive protein load (growth factors) in a direct correlative fashion.23 Cell ratios in average circulating whole blood contain only 6% platelets. In true HD-PRP preparations, the concentration achieved is 94%.22 An average patient platelet count is 250,000 platelets/dL. Four times this is 1 million platelets/dL, which is considered the desired benchmark for therapeutic PRP (Figure 1).24
Circulating platelets, when activated, begin a degranulation process that secretes a variety of important growth factors and cytokines/chemokines, such as platelet-derived growth factor (PDGF; stimulates cell replication, angiogenesis), transforming growth factor β-1 (TGF-β1; angiogenesis), vascular endothelial growth factor (VEGF; angiogenesis), fibroblast growth factor (FGF; proliferation of myoblasts and angiogenesis), and insulin-like growth factor-1 (ILGF-1; mediates growth and repair of skeletal muscle), among others.25 Activated platelets also secrete stromal cell–derived factor 1-α (SDF-1α), which supports primary adhesion and migration of mesenchymal stem/stromal cells (Table, page 58).22
Platelets contain a significant number of key signal proteins, growth factors, chemokines, cytokines, and other proinflammatory bioactive factors that initiate and regulate basic aspects of the inflammatory cascade resulting in natural wound healing.26 Elevated platelet concentrations are known to stimulate the proliferation, differentiation, and migration of needed mesenchymal and stromal repair cells to an injury site.27
Similar to dextrose prolotherapy, the addition of HD-PRP concentrates results in an inflammatory and proliferative response that enhances healing and promotes tissue regeneration.28 The use of clinically proven devices to obtain this degree of concentration is considered essential. Various portable commercial centrifugation units exist that can process blood samples, resulting in PRP concentrates, however only a few have been shown to concentrate platelets to therapeutic levels as does the FDA cleared Harvest Technologies' SmartPrep2 system.