Platelet Rich Plasma is an autologous blood derived concentrate. It contains a plethora of growth factors and cytokines which induce cellular proliferation, differentiation, angiogenesis and extracellular matrix synthesis.
The functional mechanisms of PRP in knee osteoarthritis are explained by its effect on modulating pro inflammatory mediators and enzymes to maintain joint homeostasis.
The sources of these mediators are the granules contained on the platelets. The primary granule is the alpha granule. Once stimulated, the alpha granule releases platelet derived growth factor, insulin like growth factor, vascular endothelial growth factor, transforming growth factor and many more. The understanding of the overall functions of these growth factors is critical for the explanation as to how PRP works in the disease of osteoarthritis.
Epidermal Growth Factor
- Stimulates the growth, proliferation and differentiation of mesenchymal and epithelial cells, and the mitogenesis of chondrocytes and osteoblasts
- Promotes angiogenesis.
- Regulates the secretion of collagenase.
Platelet Derived Growth Factor
- Increases the synthesis and secretion of collagen as well as regulates the secretion of collagenase.
- Activates the chemotaxis of fibroblasts, macrophages and neutrophils.
- Regulates the proliferation of bone cells.
Transformative Growth Factor Alpha
- Affects the formation, reconstruction and regeneration of bones by inhibiting collagen synthesis and release of calcium.
- Regulates osteogenesis by influencing the formation of osteoblasts and the deposition of bony matrix.
Transformative Growth Factor Beta
- Increases synthesis of type 1 collagen and fibronectin and regulates collagenase.
- Stimulates or inhibits endothelial fibroblastic and osteoblastic mitogenesis.
- Inhibits the formation of osteoclasts and bone reabsorption.
Vascular Endothelial Growth Factor
- Induces neovascularization.
- Promotes angiogenesis.
- Activates the synthesis of metalloproteinases involved in the degradation of interstitial collagen types 1,2,3
Tumor Necrosis Factor
- Stimulates the growth of fibroblasts.
- Promotes angiogenesis.
- Inhibits the proliferation and growth of keratinocytes.
Insulin Like Growth Factor
- Stimulates the growth of myoblasts and fibroblasts.
- Regulates the metabolism of articular cartilage.
- Stimulates cartilage growth.
- Mediates the growth and repair of skeletal muscle.
Interleukin 1B
- In high concentration- activates osteoclastic activity
- In low concentrations- supports the growth of new bone
Platelet Derived Epidermal Growth Factor
- Stimulates endothelial angiogenesis.
- Stimulates epithelial and mesenchymal mitogenesis.
- Supports wound healing.
The above are a few of the major growth factors and interleukins that participate in the healing of damaged tissues. The major role of these growth factors contained in the granules of platelets is to recruit other immune cells or induce the inflammatory response. Additional factors included on the alpha granules are chemokines and cytokines such as platelet factor 4, pro platelet basic protein and P selectin which are involved in stimulating cell chemotaxis, proliferation and maturation.
Dense granules on the platelets contain ADP, ATP, serotonin, dopamine, polyphosphates, histamine and epinephrine. The substances modify platelet activation and thrombus formation. They also have immune cell modifying effects. Histamine and serotonin increase permeability of the capillaries enabling the migration of cells involved in the inflammatory process such as macrophages. This action stimulates fibroblasts, stem cells and chondrocytes.
Cartilage damage leads to inflammation and the inflammatory component plays a critical role in the development of osteoarthritis. Interleukin 1B and tumor necrosis factor are the catabolic cytokines in the OA joint which cause the activity and levels of the metalloproteinases to increase by synovial cells and chondrocytes. This can develop into the overexpression of cartilage degrading proteases and inflammatory factors. This is responsible for the breakdown of the extracellular matrix adding to the inflammatory environment. This triggers osteoarthritis as cartilage repair mechanisms are inhibited.
This catabolic and inflammatory intra and extracellular environment is influenced and modified by the administration of platelet rich plasma. The therapeutic effects of intra articular PRP
treatment is mediated by a protective effect against the cytotoxicity of reactive oxygen species and an anti-inflammatory effect. It has also been found that PRP enhanced a superficial zone protein secretion from synovium and cartilage derived cells. This protein has been found to have lubrication properties similar to that of the bodies own synovial fluid.
Shock Wave Therapy Mechanisms
Extracorporeal shockwave therapy (ESWT) is a popular non-invasive treatment modality for many common musculoskeletal disorders, sexual medicine, aesthetics, wound care and other fields of medicine. Shockwave was first introduced in the 1980’s as a treatment for kidney stones. A focused shockwave was delivered, and the stones were disintegrated. The modality was then applied into cardiac medicine where deposits in the coronary arteries were ablated. It has since been applied in other fields of medicine especially musculoskeletal applications. The application in orthopedics is beneficial due to the ability to cause interstitial and extracellular responses which cause tissue to regenerate.
Mechanism of action
There are four phases of ESWT on tissue.
- Physical Phase- shockwaves cause a positive pressure and transmission of energy to cells. This increases the permeability of cell membranes.
- Physicochemical Phase- the stimulus causes biochemical reactions and cell signaling pathways are activated.
- Chemical Phase- The shockwaves alter the functions of ion channels in cell membranes and calcium is mobilized.
- Biological Phase- ESWT modulates angiogenesis, anti-inflammatory effects and healing of tissues.
Shockwave therapy stimulates a phenotype change in macrophages from M1 to M2. M1 is the inflammatory phenotype of a macrophage and M2 is the anti-inflammatory phenotype. The M2 phenotype stimulates interleukins and are directly involved in the regenerative process. The M1 type on the other hand displays microbial activity and inhibits cell proliferation releasing inflammatory IL-6 and tumor necrosis cytokines.
After a shockwave is directed into an area of damaged tissue, this M1 to M2 shift changes the microenvironment and proliferation and subsequent remodeling can take place.
Pain relief is one of the biological effects of ESWT. There are two theories to explain this action.
- SWs degenerate nerve fibers from small neurons and this action decreases the pro-inflammatory mediators.
- SW’s trigger the release of endorphins and other analgesic molecules. Pain generated by the first stimulus will be reduced by the second and so on.
Tissue regeneration is stimulated by ESWT. This is due to the down regulation of the pro-inflammatory cytokines and matrix metalloproteinases. These inflammatory cytokines restart cell growth and protein synthesis. Therefore, the reduction of these cytokines stimulates the regenerative cascade in tissue.
ESWT induces neovascularization and improvement of blood flow. This has been proven by doppler testing and post treatment, the blood flow is increased in damaged tissues.
ESWT preserves the neuronal and vascular function and suppress apoptosis in these tissues. It can promote regeneration of nerve function by the stimulation of new growth in nerve cells.
Chondroprotection and bone healing has been proven in lab studies. Wang et al demonstrated that osteoporosis increased the severity of chondral damage in knee OA. Upon application of ESWT as a treatment modality, effectiveness in the reduction of osteoporotic osteoarthritis of the knee in rat models was demonstrated. This study showed that early intervention with moderate energy ESWT significantly reversed osteoarthritic alterations and resulted in chondroprotective effects in the knee model.
The question is” what treatment is best?” Both would be excellent modalities for the treatment of osteoarthritis of the knee. Why not both?
Recent published study:
Pak J Med Sci 2024 Jan-Feb;40(3Part-11):382-397 PMID 38356839
Objective: To determine the efficacy of extracorporeal shock wave combined with platelet rich plasma therapy on knee osteoarthritis with meniscus injury in terms of pain relief, functional outcome and complications.
Conclusion: Compared with PRP or ESWT treatment alone, ESWT combined with PRP for KOA with meniscus injury can better alleviate pain, achieve faster functional recovery and significantly reduce complications.
Juventix Regenerative Medical is an industry leader in the regenerative medical field. Our Platelet Rich Plasma Kits are FDA cleared and designed for safety, sterility and effectiveness. Our kits are scientifically manufactured to produce a platelet concentrate, devoid of red blood cells with a minimum number of leukocytes, critical to the regenerative process.
Juventix Regenerative Medical offers a LED Activator to activate the platelets and begin the regenerative process. The activation is a critical step in the release of cytokines, growth factors and bioactive proteins from the alpha granules on the platelets and is accomplished with LED light. This negates the use of chemical additives such as Calcium Chloride, Thrombin of Collagen. This mode of activation by LED light provides sustained growth factor release versus older methods of activation while adhering to the minimal manipulation standards recently released by the FDA.
Juventix Regenerative Medical supplies a Bio-Incubator to transform the Platelet Rich Plasma into an Injectable Platelet Rich Fibrin. The Platelet Rich Fibrin, commonly called the “second generation of platelet products” has different cytokines and growth factors than the original PRP. These different cytokines provide and anti-inflammatory environment and can be used confidently in inflammatory conditions.
Juventix Regenerative Medical in collaboration with Oceanus are proud to offer the PhysioPRO shockwave system. This radial shockwave device is a clinical grade shockwave system that induces intracellular and extracellular tissue regeneration. The technology activates regenerative cells and increases blood flow to the damaged tissues. This reduces pain and increases recovery time. The PhysioPRO is simple to use and low cost. This will enhance your treatment of musculoskeletal conditions, wound care, aesthetics, erectile dysfunction and many other conditions encountered by the medical professional.
Regenerative Regards,
Dr. Robert McGrath
Studies
Medicine 2023 Nov;102(46):e36117 PMID 37986308
- The Anti-Inflammatory and Matrix Restorative Mechanisms of Platelet Rich Plasma in OsteoarthritisAm J Sports Med 2014 Jan;42(1):36-41 PMID 24192391
- The Effect of Platelet Rich Plasma on the Intra-Articular Microenvironment in Knee OsteoarthritisInt J Mol Sci 2021 May 23;22(11):5492 PMID 34071037
