Yingtai: PRP Treatment for Osteoarthritis Pain (Part 1)
Introduction
In the past two decades, autologous blood products such as Platelet-Rich Plasma (PRP) have been widely used in clinical fields including orthopedics, spine surgery, dentistry, periodontology, cosmetic surgery, and maxillofacial surgery. The term PRP originated in the 1970s to describe plasma with a platelet count higher than that of peripheral blood. Platelets, which are anucleated discoid cells derived from megakaryocytes, primarily function in hemostasis to maintain the integrity of damaged vascular systems. Recent studies have found that platelets also play significant roles in regulating inflammation, angiogenesis, wound healing, and cancer metastasis. These functions are associated with the presence of over 300 bioactive molecules in the granules secreted by platelets.
Platelets contain three main types of secretory granules: alpha granules, dense granules, and lysosomes. Alpha granules are the most abundant and contain membrane proteins, adhesion molecules (such as von Willebrand factor and fibrinogen), clotting factors, various chemokines, cytokines, and growth factors. Dense granules contain small molecules such as adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin, epinephrine, calcium, pyrophosphate, and polyphosphate. Lysosomes contain acidic hydrolases like cathepsins, hexosaminidases, beta-galactosidases, arylsulfatases, beta-glucuronidases, and acid phosphatases. In summary, platelets function as unique "secretory machines" with various secretory granules, ribosomes, signaling pathways, and receptors.
Due to the differences in the activation-dependent synthesis pathways and release dynamics of various platelet cytokines, the presence of different platelet activators at various tissue injury sites may lead to variations in platelet cytokine secretion or composition patterns. Ehrenfest et al. classified PRP products into four categories based on platelet count, the presence of leukocytes, and fibrin structure: leukocyte-poor PRP, leukocyte-rich PRP, leukocyte-poor PRF, and leukocyte-rich PRF. Magalon et al. proposed the DEPA classification for PRP: D (dose) represents the dose of platelets injected; E (efficiency) represents the preparation efficiency (the percentage of platelets recovered from the blood); P (purity) represents the purity of PRP (the relative composition of platelets, leukocytes, and red blood cells); A (activation) represents the activation process (whether exogenous coagulation factors are used to activate the platelets). Current research has identified key variables that may affect the efficacy of PRP preparations, including PRP composition, PRP activation mode, and PRP application method. However, due to the lack of standardized procedures for PRP preparation, delivery, and activation, it is challenging to compare clinical efficacy evaluations.
PRP contains various autologous bioactive proteins, such as immune mediators, chemokines, growth factors, enzymes, and their inhibitors, giving it natural tissue healing potential. Particularly, the presence of various growth factors in PRP, such as Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor beta (TGF-β), Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor, Insulin-like Growth Factor 1 (IGF-1), Vascular Endothelial Growth Factor (VEGF), and Epidermal Growth Factor (EGF), along with adhesion molecules (such as fibrin, fibronectin, and vitronectin) involved in wound healing, has made PRP a hot topic in clinical applications. Additionally, autologous PRP minimizes potential side effects and the risk of disease transmission, leading to high clinical acceptance. In orthopedics, the evaluation of PRP as an adjunctive treatment has primarily focused on promoting bone and soft tissue regeneration. Recent studies have indicated that PRP injections can also alleviate pain in patients with musculoskeletal disorders such as osteoarthritis. This chapter will overview the potential of intra-articular PRP injection for treating osteoarthritis pain.
PRP Treatment for Osteoarthritis Pain
Osteoarthritis (OA) is a degenerative disease involving joint damage and progressive deterioration of joint structures, primarily affecting the knees and hips, with joint pain as a hallmark symptom. The imbalance in the synthesis and degradation activities within cartilage leads to cartilage loss, resulting in joint degeneration and causing pain and related physical disabilities, severely impacting the quality of life of patients. Among all joints, the knee is the most commonly affected and is a leading cause of disability. In the United States, the prevalence of OA has been steadily increasing. A recent epidemiological survey indicated that the incidence of OA has doubled since the mid-20th century. It is estimated that by 2030, the number of OA patients may reach 70 million.
Currently, there are various treatment methods for OA, including non-pharmacological interventions, pharmacological treatments, minimally invasive intra-articular injections, and invasive surgeries. Non-pharmacological interventions for OA include dietary supplements, exercise, and physical therapy. Pharmacological treatment, primarily involving non-steroidal anti-inflammatory drugs (NSAIDs), is the first-line treatment for OA pain. However, the cardiovascular, gastrointestinal, and renal side effects associated with these medications greatly limit their application in OA treatment. Opioids have also been used for OA pain management, but they exhibit poor efficacy and are associated with serious side effects, including addiction.
Minimally invasive intra-articular injection therapies are generally safer than systemic medications, particularly in patients with comorbidities, and offer higher bioavailability. Intra-articular injections of corticosteroids combined with local anesthetics are frequently used to treat knee pain. However, recent studies have indicated potential complications with intra-articular corticosteroid injections, necessitating the exploration of alternative methods. Intra-articular injections of hyaluronic acid (HA) are another common approach and have been shown to have short-term effects in alleviating pain in early to mid-stage knee OA patients. The exact mechanism of HA injections remains unclear but is thought to be related to the ability of HA to increase the viscoelasticity of synovial fluid and protect chondrocytes.
New alternative treatment strategies are under investigation to improve intra-articular therapy for OA, reduce joint pain, and slow cartilage degeneration. Given its potential to accelerate wound healing, promote cell proliferation, and enhance chondrogenesis, intra-articular PRP injections for OA are gaining traction. Furthermore, PRP is relatively safe, easy to prepare, and simple to administer, leading to an increase in clinical applications of intra-articular PRP injections for degenerative OA. The following sections will review recent preclinical and clinical studies evaluating the efficacy of intra-articular PRP injections in alleviating OA pain and discuss the currently known mechanisms of action.
Mechanisms of Action of Intra-Articular PRP Injections
Although the exact mechanisms of action of intra-articular PRP injections remain unclear, preclinical and clinical studies suggest that they have the potential to alleviate OA pain. Proposed mechanisms may include direct inhibition of tissue injury receptors, suppression/reduction of intra-articular inflammation, stimulation of endogenous HA production, and reduction of metabolic activity through the inhibition of matrix metalloproteinases (MMPs).
Dount et al. found that adding PRP significantly improved the survival and proliferation rates of chondrocytes subjected to corticosteroid or local anesthetic-induced cell death, demonstrating the cytoprotective effect of PRP. These protective effects are associated with the high levels of IGF-1 and TGF-β in PRP, which play beneficial roles in regulating cell proliferation and extracellular matrix deposition. One study investigated the effects of PRP-derived products (PRPr, obtained by centrifuging PRP after two freeze-thaw cycles) on human articular chondrocytes. The study found that PRPr significantly enhanced the mitotic and differentiation potential of human chondrocytes in both monolayer and three-dimensional cultures.
Zaky et al. discovered that PRPr could enhance the proliferation and chondrogenic differentiation of human bone marrow-derived stem cells (BMScs), suggesting that PRPr may serve as a potential substitute for fetal bovine serum in promoting BMSc chondrogenic differentiation. Drengk et al. confirmed these findings, showing that PRP promotes the proliferation and chondrogenesis of mesenchymal stem cells. However, exposure to PRP reduced the chondrogenic phenotype of autologous chondrocytes as the proliferative activity increased. Given that the concentration and activation state of growth factors influence the synthetic metabolism and chondrogenic activity of PRP, and the lack of standardized PRP preparation protocols often leads to discrepancies between preclinical results and actual clinical efficacy.
Khatab et al. utilized a collagenase-induced OA mouse model to study the effects of PRPr on pain, cartilage damage, and synovitis. They found that following three consecutive intra-articular injections of PRPr or saline (control), the PRPr group showed increased weight-bearing distribution in the affected limb, indicating a positive impact on pain relief. Histologically, on day 21, the PRPr group exhibited thinner synovium and less cartilage damage compared to the saline group. By day 28, cartilage degeneration was significantly greater in the saline group. The data also indicated that the PRPr group showed a significant reduction in joint inflammation, characterized by an increase in CD206+ and CD163+ anti-inflammatory macrophages, suggesting a regulatory effect of PRPr on macrophage subtypes.
The lower the number of pro-inflammatory macrophages in the joint, the less Prostaglandin E2 (PGE2) is produced, as PGE2 is a mediator of inflammatory pain. Therefore, the improvement in pain with PRPr may.
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