Platelet-rich plasma for the treatment of knee osteoarthritis: an expert opinion and proposal for a novel classification and coding system.

INTRODUCTION: Platelet-rich plasma (PRP) is able to modulate the joint environment by reducing the inflammatory distress and promoting tissue anabolism. Therefore, it has gained increasing popularity among clinicians in the treatment of osteoarthritis (OA), and it is currently proposed beside consolidated options such as viscosupplementation. AREAS COVERED: A systematic review of all available meta-analyses evaluating intra-articular PRP injections in patients affected by knee OA was performed, to understand how this biologic treatment approach compares to the traditional injective therapies available in clinical practice. Moreover, a novel coding system and 'minimum reporting requirements' are proposed to improve future research in this field and promote a better understanding of the mechanisms of action and indications. EXPERT OPINION: The main limitation in the current literature is the extreme variability of PRP products used, with often paucity or even lack of data on the biologic features of PRP, which should not be considered as a simple substance, but rather a 'procedure' requiring accurate reporting of the characteristics of the product but also all preparation and application modalities. This approach will aid in matching the optimal PRP product to specific patient factors, leading to improved outcomes and the elucidation of the cost-effectiveness of this treatment.

Optimizing Clinical Use of Biologics in Orthopaedic Surgery: Consensus Recommendations From the 2018 AAOS/NIH U-13 Conference.

Concern that misinformation from direct-to-consumer marketing of largely unproven "biologic" treatments such as platelet-rich plasma and cell-based therapies may erode the public trust and the responsible investment needed to bring legitimate biological therapies to patients have resulted in calls to action from professional organizations and governing bodies. In response to substantial patient demand for biologic treatment of orthopaedic conditions, the American Academy of Orthopaedic Surgeons convened a collaborative symposium and established a consensus framework for improving and accelerating the clinical evaluation, use, and optimization of biologic therapies for musculoskeletal diseases. The economic and disease burden of musculoskeletal conditions is high. Of the various conditions discussed, knee osteoarthritis was identified as a "serious condition" associated with substantial and progressive morbidity and emerged as the condition with the most urgent need for clinical trial development. It was also recognized that stem cells have unique characteristics that are not met by minimally manipulated mixed cell preparations. The work group recommended that minimally manipulated cell products be referred to as cell therapy and that the untested and uncharacterized nature of these treatments be clearly communicated within the profession, to patients, and to the public. Minimum standards for product characterization and clinical research should also be followed. A framework for developing clinical trials related to knee OA was agreed upon. In addition to recommendations for development of high-quality multicenter clinical trials, another important recommendation was that physicians and institutions offering biologic therapies commit to establishing high-quality patient registries and biorepository-linked registries that can be used for postmarket surveillance and quality assessments.

Treatment of medial epicondylar tendinopathy in athletes.

Medial epicondylar tendinopathy, also known as golfer's elbow, is less common than lateral elbow tendinopathy. Overhead throwing athletes and those participating in sports that require repeated forearm pronation and wrist flexion are most commonly affected by this disorder. This problem predominates in amateur as opposed to professional athletes and is also seen more commonly in patients over 40 years of age. This review will begin by outlining the incidence, history, and physical examination of medial epicondylar tendinopathy, including a new clinical test. Imaging modalities, nonoperative, and operative treatments will then be outlined. Finally, future directions will be explored including emerging biological therapies.

Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients.

BACKGROUND: Elbow tenderness and pain with resisted wrist extension are common manifestations of lateral epicondylar tendinopathy, also known as tennis elbow. Previous studies have suggested platelet-rich plasma (PRP) to be a safe and effective therapy for tennis elbow. PURPOSE: To evaluate the clinical value of tendon needling with PRP in patients with chronic tennis elbow compared with an active control group. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 230 patients with chronic lateral epicondylar tendinopathy were treated at 12 centers over 5 years. All patients had at least 3 months of symptoms and had failed conventional therapy. There were no differences in patients randomized to receive PRP (n = 116) or active controls (n = 114). The PRP was prepared from venous whole blood at the point of care and contained both concentrated platelets and leukocytes. After receiving a local anesthetic, all patients had their extensor tendons needled with or without PRP. Patients and investigators remained blinded to the treatment group throughout the study. A successful outcome was defined as 25% or greater improvement on the visual analog scale for pain. RESULTS: Patient outcomes were followed for up to 24 weeks. At 12 weeks (n = 192), the PRP-treated patients reported an improvement of 55.1% in their pain scores compared with 47.4% in the active control group (P = .163). At 24 weeks (n = 119), the PRP-treated patients reported an improvement of 71.5% in their pain scores compared with 56.1% in the control group (P = .019). The percentage of patients reporting significant elbow tenderness at 12 weeks was 37.4% in the PRP group versus 48.4% in the control group (P = .143). Success rates for patients at 12 weeks were 75.2% in the PRP group versus 65.9% in the control group (P = .104). At 24 weeks, 29.1% of the PRP-treated patients reported significant elbow tenderness versus 54.0% in the control group (P = .009). Success rates for patients with 24 weeks of follow-up were 83.9% in the PRP group compared with 68.3% in the control group (P = .037). No significant complications occurred in either group. CONCLUSION: No significant differences were found at 12 weeks in this study. At 24 weeks, however, clinically meaningful improvements were found in patients treated with leukocyte-enriched PRP compared with an active control group.

Platelet-rich plasma in orthopaedic applications: evidence-based recommendations for treatment.

Autologous platelet-rich plasma (PRP) therapies have seen a dramatic increase in breadth and frequency of use for orthopaedic conditions in the past 5 years. Rich in many growth factors that have important implications in healing, PRP can potentially regenerate tissue via multiple mechanisms. Proposed clinical and surgical applications include spinal fusion, chondropathy, knee osteoarthritis, tendinopathy, acute and chronic soft-tissue injuries, enhancement of healing after ligament reconstruction, and muscle strains. However, for many conditions, there is limited reliable clinical evidence to guide the use of PRP. Furthermore, classification systems and identification of differences among products are needed to understand the implications of variability.

Platelet-rich plasma and the upper extremity.

Platelet-rich plasma (PRP) is a fraction of whole blood containing powerful growth factors and cytokines. Preclinical studies suggest PRP may be useful for tendon repair or regeneration. Clinical investigations have focused on the treatment of chronic lateral epicondylar tendinopathy and rotator cuff pathology. Multiple controlled studies support the use of PRP for chronic tennis elbow. Rotator cuff studies, however, have produced conflicting results based on PRP formulation, surgical technique, and size of tendon tear. This article explores the scientific rational for using PRP, its various formulations, and the emerging clinical data. Future potential applications are also explored.

Sports medicine applications of platelet rich plasma.

Platelet rich plasma (PRP) is a powerful new biologic tool in sports medicine. PRP is a fraction of autologous whole blood containing and increased number of platelets and a wide variety of cytokines such as platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGF-B1), fibroblast growth factor (FGF), Insulin-like growth factor-1 (IGF-1) among many others. Worldwide interest in this biologic technology has recently risen sharply. Basic science and preclinical data support the use of PRP for a variety of sports related injuries and disorders. The published, peer reviewed, human data on PRP is limited. Although the scientific evaluation of clinical efficacy is in the early stages, elite and recreational athletes already use PRP in the treatment of sports related injuries. Many questions remain to be answered regarding the use of PRP including optimal formulation, including of leukocytes, dosage and rehabilitation protocols. In this review, a classification for platelet rich plasma is proposed and the in-vitro, preclinical and human investigations of PRP applications in sports medicine will be reviewed as well as a discussion of rehabilitation after a PRP procedure. The regulation of PRP by the World Anti-Doping Agency will also be discussed. PRP is a promising technology in sports medicine; however, it will require more vigorous study in order to better understand how to apply it most effectively.

In search of a consensus terminology in the field of platelet concentrates for surgical use: platelet-rich plasma (PRP), platelet-rich fibrin (PRF), fibrin gel polymerization and leukocytes.

In the field of platelet concentrates for surgical use, most products are termed Platelet-Rich Plasma (PRP). Unfortunately, this term is very general and incomplete, leading to many confusions in the scientific database. In this article, a panel of experts discusses this issue and proposes an accurate and simple terminology system for platelet concentrates for surgical use. Four main categories of products can be easily defined, depending on their leukocyte content and fibrin architecture: Pure Platelet-Rich Plasma (P-PRP), such as cell separator PRP, Vivostat PRF or Anitua's PRGF; Leukocyteand Platelet-Rich Plasma (L-PRP), such as Curasan, Regen, Plateltex, SmartPReP, PCCS, Magellan, Angel or GPS PRP; Pure Plaletet-Rich Fibrin (P-PRF), such as Fibrinet; and Leukocyte- and Platelet-Rich Fibrin (L-PRF), such as Choukroun's PRF. P-PRP and L-PRP refer to the unactivated liquid form of these products, their activated versions being respectively named P-PRP gels and L-PRP gels. The purpose of this search for a terminology consensus is to plead for a more serious characterization of these products. Researchers have to be aware of the complex nature of these living biomaterials, in order to avoid misunderstandings and erroneous conclusions. Understanding the biomaterials or believing in the magic of growth factors ? From this choice depends the future of the field.

RevaTen platelet-rich plasma improves cardiac function after myocardial injury.

OBJECTIVE: Cell therapy is an exciting area of investigation for repair of injured myocardial tissue. Platelet-rich plasma (PRP) is an autologous fractionation of whole blood containing high concentrations of growth factors including vascular endothelial growth factor and insulin-like growth factor, among many others. PRP has been shown to safely and effectively enhance healing of musculoskeletal tissue primarily by reparative cell signaling. Despite a growing body of evidence on PRP's safety and efficacy, limited studies have been performed using PRP in cardiovascular tissues. Utilizing a murine myocardial permanent ligation and ischemia/reperfusion model, this study sought to determine whether RevaTen PRP (Menlo Park, CA, USA), a proprietary formulation of PRP, improves cardiac function as measured by left ventricular ejection fraction (LVEF). METHODS: Via thoracotomy, the left anterior descending arteries (LAD) of 28 mice were occluded by suture either permanently or for 45 min to induce ischemic injury and then reperfused. Mice undergoing permanent ligation had intramyocardial injections of either RevaTen PRP (n=5) or phosphate-buffered saline (PBS; n=4). Magnetic resonance (MR) imaging was performed to calculate LVEF at 7 days. Mice undergoing ischemia and reperfusion had intramyocardial injections of either PRP (n=10) or PBS (n=9) and underwent MR imaging to calculate LVEF at 21 days. Hearts were harvested for histologic examination following imaging. RESULTS: Compared with PBS controls, RevaTen PRP-treated animals that underwent LAD ligation had a 38% higher LVEF 7 days after injury (PRP=36.1±6.1%; PBS=26.4±3.6%, P=.027). Compared with PBS controls, PRP-treated animals who underwent ischemia-reperfusion of the LAD had a 28% higher LVEF 21 days after injury (PRP=37.6±4.8%, control=29.3±9.7%, P=.038). Histologic analysis suggested the presence of more scar tissue in the control group compared to the PRP-treated animals. CONCLUSION: MR imaging demonstrated a positive effect of RevaTen PRP on left ventricular function in both a ligation and ischemia-reperfusion murine model. Our results suggest RevaTen PRP should be investigated further as a potential point-of-care biologic treatment following myocardial injury.

Buffered platelet-rich plasma enhances mesenchymal stem cell proliferation and chondrogenic differentiation.

The success of tissue engineering applications can potentially be dramatically improved with the addition of adjuncts that increase the proliferation and differentiation of progenitor or stem cells. Platelet-rich plasma (PRP) has recently emerged as a potential biologic tool to treat acute and chronic tendon disorders. The regenerative potential of PRP is based on the release of growth factors that occurs with platelet rupture. Its autologous nature gives it a significant advantage in tissue engineering applications. To test whether PRP may be useful specifically for cartilage regeneration, a cell culture experiment was devised in which mesenchymal stem cells (MSCs) were grown in control media or media enhanced with inactivated, buffered PRP. Proliferation 7 days after PRP treatment was increased: 1.041 versus 0.199 for the control media cells ( p<0.001). The messenger RNA (mRNA) level of the osteogenic marker RUNX2 was 52.84 versus 26.88 for the control group ( p<0.005). Likewise the mRNA level of the chondrogenic markers Sox-9 and aggrecan was 29.74 versus 2.29 for the control group ( p<0.001) and 21.04 versus 1.93 ( p<0.001), respectively. These results confirm that PRP enhances MSC proliferation and suggest that PRP causes chondrogenic differentiation of MSC in vitro.

Treatment of tendon and muscle using platelet-rich plasma.

Tendon and muscle injuries are common in elite and weekend athletes. Treatment of these injuries in both groups is rapidly evolving. Sports medicine patients are demanding better and less invasive solutions for all types of musculoskeletal disorders. In this context, platelet-rich plasma (PRP) has emerged as a potential solution. PRP is a fraction of whole blood containing concentrated growth factors and proteins. These cytokines direct tissue healing through autocrine and paracrine effects. The number of basic science, animal, and human investigations of PRP for tendon and muscle injuries worldwide has risen sharply in recent years. These studies are helping clinicians better understand the mechanisms of PRP and are guiding novel treatment protocols. In this paper, the value of PRP as a treatment for acute or chronic tendon and muscle disorders is explored.

Selecting and starting an orthopaedic surgery practice.

Every new surgeon is faced with the same question as their residency or fellowship draws to a close: What is next? Few residents or fellows are as well prepared to answer that question as they could be. Most programs do not teach residents how to choose a practice type and location. After formal orthopaedic training, new surgeons must make decisions about their careers that can be nearly as complex and difficult as the decisions they make in the operating room. Career choices have both significant and long-term effects on the physician's financial situation, career satisfaction, and personal life. The physician should be aware of key non academic issues that arise when completing a residency program or just beginning the practice of orthopaedic surgery.

Cellular effects of platelet rich plasmainterleukin1 release from prp treated macrophages.

The therapeutic use of Platelet Rich Plasma (PRP) as a biological tool to enhance soft tissue and bone healing has recently yielded encouraging results in many areas of clinical medicine. PRP is a specific portion of whole blood that contains a high concentration of platelets. The local treatment of bone and soft tissue injuries with this autologous blood product has become increasingly common in recent years. There is still little known about the mechanism by which PRP acts at the cellular level. The macrophage cell has been shown to be critical in the healing of tissues. In this study the macrophage release of a specific pro-inflammatory factor, interleukin-1 (IL-1), was evaluated in macrophage cells activated and treated with platelets as compared to control macrophages in culture. The results show that platelets caused an initial suppression of IL-1 release from activated macrophage compared to controls. The initial suppression was followed by an increase in IL-1 release at day seven over control and activated macrophages that had ceased release of IL-1 at day seven. The initial suppression of the inflammatory response to activation during days 1, 2 and 3 could have broad implications in the explanation of a mechanism by which PRP acts. If PRP can truly be used as a transient anti-inflammatory agent that initially suppresses inflammation and then stimulates a late healing response, then indications for use of PRP may expand beyond the current scope of treatment.

Cellular effects of platelet rich plasma: a study on HL-60 macrophage-like cells.

Healing injured tissue in the body is a complex process which consists of four distinct phases: hemostasis, inflammation, proliferation, and remodeling. Each of these phases is coordinated by growth factor release and cell to cell interactions. Platelet rich plasma (PRP) is a fraction of plasma that has been isolated and used to enhance regeneration in bone and soft tissues. The healing potential of PRP has been attributed to the release of multiple growth factors from the highly concentrated platelets. While there is strong evidence of the pro-stimulatory effect on the cellular proliferation phase of healing, there is little evidence of the effects of PRP on the inflammatory phase of healing. In this study we investigate the effect that PRP has on macrophage cells in culture and the implications this has on the healing process. We investigate specifically the effects of the separate cellular components of PRP, as a whole and individually, on cell proliferation in human macrophage cells in culture. In contrast to the pro-stimulatory effect that PRP has on cells such as osteoblasts, fibroblasts, and tendon cells; our results show a suppression ofmacrophages by PRP as early as 24 hours after treatment. This suppression was statistically significant (p=0.002) and continued to be significant for the duration of the study. The cell viability results of PRP compared to platelet poor plasma (PPP) and individual components of PRP showed that PRP resulted in a steady increase in viability following the initial insult to the macrophage cells, while the viability of other treatment groups seemed to plateau.

Treatment of chronic elbow tendinosis with buffered platelet-rich plasma.

BACKGROUND: Elbow epicondylar tendinosis is a common problem that usually resolves with nonoperative treatments. When these measures fail, however, patients are interested in an alternative to surgical intervention. HYPOTHESIS: Treatment of chronic severe elbow tendinosis with buffered platelet-rich plasma will reduce pain and increase function in patients considering surgery for their problem. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: One hundred forty patients with elbow epicondylar pain were evaluated in this study. All these patients were initially given a standardized physical therapy protocol and a variety of other nonoperative treatments. Twenty of these patients had significant persistent pain for a mean of 15 months (mean, 82 of 100; range, 60-100 of 100 on a visual analog pain scale), despite these interventions. All patients were considering surgery. This cohort of patients who had failed nonoperative treatment was then given either a single percutaneous injection of platelet-rich plasma (active group, n = 15) or bupivacaine (control group, n = 5). RESULTS: Eight weeks after the treatment, the platelet-rich plasma patients noted 60% improvement in their visual analog pain scores versus 16% improvement in control patients (P =.001). Sixty percent (3 of 5) of the control subjects withdrew or sought other treatments after the 8-week period, preventing further direct analysis. Therefore, only the patients treated with platelet-rich plasma were available for continued evaluation. At 6 months, the patients treated with platelet-rich plasma noted 81% improvement in their visual analog pain scores (P =.0001). At final follow-up (mean, 25.6 months; range, 12-38 months), the platelet-rich plasma patients reported 93% reduction in pain compared with before the treatment (P <.0001). CONCLUSION: Treatment of patients with chronic elbow tendinosis with buffered platelet-rich plasma reduced pain significantly in this pilot investigation. Further evaluation of this novel treatment is warranted. Finally, platelet-rich plasma should be considered before surgical intervention.