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The use of PRP injections in the management of knee osteoarthritis

  • Brendan O’Connell
  • Nicholas Martin Wragg
  • Samantha Louise WilsonEmail author
Open Access
Review

Abstract

Osteoarthritis (OA) is a degenerative disease involving joint damage, an inadequate healing response and progressive deterioration of the joint architecture that commonly affects the knee and/or hip joints. It is a major world public health problem and is predicted to increase rapidly with an ageing population and escalating rate of obesity. Autologous blood-derived products possess much promise in the repair and regeneration of tissue and have important roles in inflammation, angiogenesis, cell migration and metabolism in pathological conditions, including OA. Utilising platelet-rich plasma (PRP) to treat tendon, ligament and skeletal muscle has shown variable results across many studies with the current evidence base for the efficacy of PRP in treating sports injuries remaining inconclusive. More uniformly positive results have been observed by various studies for PRP in OA knee in comparison to hyaluronic acid, other intra-articular injections and placebo than in other musculoskeletal tissue. However, methodological concerns as well as satisfactory PRP product classification prevent the true characterisation of this treatment. Thus, further research is required to investigate how leukocyte inclusion, activation and platelet concentration affect therapeutic efficacy. Furthermore, the optimisation of timing, dosage, volume, frequency and rehabilitation strategies need to be ascertained. For knee OA management, these concerns must be addressed before this promising treatment can be widely implemented.

Keywords

Platelet-rich plasma Osteoarthritis Intra-articular injection Knee Repair and regeneration 

Introduction

Osteoarthritis (OA) is a serious degenerative joint disease resulting from the degradation of articular cartilage, degradation and proliferative reformation of subchondral bone and a low degree of synovitis that leads to a reduced quality of life (QoL). It is a major cause of pain and disability in the elderly population (> 70 years) (Neogi and Zhang 2013). OA alters the normal joint metabolism favouring increased catabolism and decreased anabolism (Dhillon et al. 2017). Inflammation and vascular pathology, in combination with cell death, meniscal changes, bone remodelling and subchondral sclerosis, produces a vicious cycle of progressive joint degeneration. This can be exacerbated by excessive mechanical stress and oxidative damage (Wruck et al. 2011). Moreover, under conditions of metabolic or cytotoxic stress, such as in ageing, autophagy can be upregulated, further decompensating homeostatic mechanisms (Lotz and Caramés 2011).

In OA knees (Fig. 1), chondrocyte senescence and loss of cartilage integrity are major features. There is an increase in the water content of hyaline cartilage, accompanied by corresponding decreases in proteoglycan concentration, length and aggregation, causing reduced cartilage stiffness and fibrillation of the cartilage surface. From this, cartilage proceeds to erode and deep clefts may form. Concurrently, morphological changes in subchondral bone are found. As synovial fluid infiltrates, the formation of subarticular cysts in the subchondral bone also occurs. Osteophytes (bony projections) are characteristic features of knee OA in non-pressure areas, caused by the flattening of bone from pressure in high-wear areas (Adatia et al. 2012).
Fig. 1

Comparison of a healthy (left) and OA knee joint (right)

Many interacting factors have a role in indicating the potential for the development of knee OA, although age is typically highlighted (Blagojevic et al. 2010; Michael et al. 2010; Heidari 2011; Silverwood et al. 2015; Driban et al. 2017) (Table 1). Primary care databases from a variety of countries have shown a higher incidence of knee OA than hip or hand OA and a large increase in new knee OA diagnoses in the past decade, especially in 35–44 year olds (Prieto-Alhambra et al. 2014; Yu et al. 2015). Over a 7-year period, an estimated 13% of older adults (> 50 years) receive a diagnosis of OA with the knee joint implicated in 25% of the population (Jordan et al. 2014). There is also an accompanying socioeconomic burden in terms of cost of medical care for both government and individuals (Xing et al. 2017). It is a major public health problem worldwide (Pereira et al. 2011) and is projected to rapidly increase as the population ages and rates of obesity escalate (Cross et al. 2014).
Table 1

Risk factors for knee OA

Intrinsic

Extrinsic

Age

Previous trauma

• Advancing age effects of both sexes altered locomotor (stereognostic) control of opposing muscle groups

• Macrotrauma

• Repetitive loading (e.g., squatting) causing repetitive microtrauma

• Increases risk 3.86 times

Sex

Co-morbidity

• Females more prone to develop Heberden’s nodes, being female increases risk 1.84 times

• Diseases such as:

▪ Cardiovascular disease

▪ Respiratory illness can contribute/accelerate progression of knee OA

Heredity

Body mass

• Heberden’s nodes inherited as autosomal trait

• Genetically determined metabolic disorders (e.g., ochronosis and Ehler-Danlos syndrome) predispose to OA

• Overweight (BMI > 25)

• Obesity (BMI > 30)

Ethnic origins

 

• Increased incidence in European descent

Resective joint surgery

• Less common in Asians

• Post-menopausal changes

Knee characteristics:

 

▪ Joint laxity

Number of pregnancies (> 6)

▪ Malalignment (femur-tibial angle (FTA))

 

Muscle weakness

Modified from Adatia et al. (2012)

Hip and knee OA has been ranked as the 11th highest contributor to global disability and 38th highest in years lived with disability (Cross et al. 2014). The disability associated with knee OA results in a considerable economic burden, both in direct costs related to treatment, particularly joint replacement surgery and job-related indirect costs, including loss of productivity (Murphy and Helmick 2012). Knee OA affects between 6% and 40% of the general population (Michael et al. 2010) and is significantly increased among retired elite athletes, with prevalence rates as high as 95% (Gouttebarge et al. 2015). The global burden of knee OA, as rated by the World Health Organisation (WHO, 2011), is comparable with that of patients with cardiac dysrhythmias, liver cirrhosis or stage IV kidney disease (Mather III et al. 2013).

Current knee osteoarthritis incidence and management strategies

Knee OA management strategies include improvement in function, reduction in disability, pain relief and hence, improved QoL (Ng et al. 2012; Xing et al. 2017). However, there currently exist no pharmacologic agents that are able to halt OA progression or to reverse existing damage (Kanchanatawan et al. 2016). Existing approaches focus on preventing or delaying progression by developing less invasive procedures or applying interventions earlier in the disease onset (Zhang et al. 2008). Non-operative therapeutic interventions involving intra-articular injection at the knee joint, including hyaluronic acid (HA), corticosteroids, platelet-rich plasma (PRP), non-steroidal anti-inflammatory drugs (NSAIDs), physical therapy and unloaded bracing, play major roles in the management of knee OA (Campbell et al. 2015).

Platelet-rich plasma for inducing regeneration

PRP is an autologous mixture of highly concentrated platelets and associated growth factors and other bioactive components produced by centrifugal separation of whole blood (Fig. 2) that is used in orthopaedic and sports medicine practices to treat bone, tendon and ligament injuries (Fig. 3) (Sundman et al. 2014). The growth factors released by PRP have been discussed in great detail within the literature (Lubkowska et al. 2012; Pavlovic et al. 2016; Fernandes and Yang 2016; Parrish and Roides 2018) and have been shown to promote cell recruitment, proliferation and angiogenesis resulting in a reduction in the critical regulators of the inflammatory process and a decrease in the expression of inflammatory enzymes (Table 2) (van Buul et al. 2011). PRP may induce a regenerative response by improving the metabolic functions of damaged structures (Ficek et al. 2011; Chen et al. 2018) and has been shown to have a positive effect on chondrogenesis and mesenchymal stem cell proliferation (Kabiri et al. 2014).
Fig. 2

PRP preparation process

Fig. 3

Clinical applications of PRP

Table 2

Commonly discussed growth factors and effects associated with PRP

Growth factor

Effect

Platelet-derived growth factor (PDGF)

Angiogenesis; macrophage activation; proliferation and chemotaxis of fibroblasts; collagen synthesis; enhanced proliferation of bone cells

Transforming growth factor-β (TGF-β)

Fibroblasts proliferation; synthesis of type I collagen and fibronectin; deposition of bone matrix; inhibition of bone resorption

Platelet-derived epidermal growth factor (PDGF)

Epidermal regeneration; promotes wound healing through stimulation of keratinocytes and dermal fibroblasts proliferation; enhanced production and effect of other growth factors

Vascular endothelial growth factor (VEGF)

Vascularisation; stimulation of vascular endothelial cells

Insulin-like growth factor 1 (IGF-I)

Fibroblasts chemotaxis; protein synthesis stimulation; enhanced bone formation

Platelet factor 4 (PF4)

Enhanced influx of neutrophils; chemoattractant for fibroblasts

Epidermal growth factor (EGF)

Cellular proliferation and differentiation

Hepatocyte growth factor (HGF)

Inhibition of NF-κB transactivation activity; anti-inflammatory action through inhibition of monocyte-like chemotaxis

Stromal-cell-derived growth factor-1α (SDF-1α)

Supports primary adhesion and migration of progenitor cells

Modified from (Engebretsen et al. 2010)

In clinical practice, PRP is used to enable the application of autologous plasma and platelet-derived proteins to a desired location with the use of an appropriate scaffold to assist in the repair of the injured tissue (Marx 2001). The rationale for PRP in scaffolds is to take advantage of the huge amount of growth factors contained in platelets to promote cartilage regeneration; however, the use of PRP-augmented scaffolds is still in a preliminary state, with a low scientific level of power (Kon et al. 2013). In application to chondrocytes, growth factors promote matrix synthesis, cell growth and migration and facilitate protein transcription. The supra-physiological release of platelet-derived factors directly at the site of cartilage disease, particularly with interest to knee OA, may stimulate the natural regenerative signalling cascade and enhance the healing of tissue with further mediation of the anti-inflammatory response (Mascarenhas et al. 2014). In OA joints, PRP has been shown to affect local and infiltrating cells, mainly synovial cells, endothelial cells, those cells involved in innate immunity (such as macrophages) and cartilage and bone cellular components (Mifune et al. 2013; Dhillon et al. 2017). Additionally, PRP can affect inflammation and angiogenic processes and anabolism and catabolism balance in cartilage formation and alter the existing microenvironment during disease progression (Andia and Maffulli 2013).

The combined effects of PRP make it a potential option for management of knee OA, especially as a primary analgesic agent (Meheux et al. 2016). This is due to an increase in proliferation of tenocytes, osteoblasts, mesenchymal stem cells resulting in decreased pain levels postoperatively (Ogino et al. 2006). Despite encouraging preclinical results and increasing clinical interest, there remain multiple questions regarding the clinical application and efficacy of PRP, not least in the production of PRP, which can cause wildly varying characteristics. A simple classification was first proposed in 2009 following the fibrin architecture and cell content (pure PRP: leukocyte-poor PRP, leukocyte- and platelet-rich plasma; pure platelet-rich fibrin: leukocyte-poor platelet-rich fibrin, leukocyte- and platelet-rich fibrin). Each of these classifications had different growth factor release profiles (time, concentration) but studies found additional biological signatures and mechanisms within each family (Dohan Ehrenfest et al. 2014). A further classification can be included in the method of application (e.g., injections, glues) and the area of application (e.g., oral/maxillofacial surgery, skin wound healing). A more recent classification system called PAW (platelet, activation, white blood cells) is based upon absolute number of platelets, activation method and presence or absence of white blood cells (DeLong et al. 2012). According to the authors, the specific determination of the components of the PRP is vital in allowing comparisons between studies. In 2016, a further classification was proposed. Magalon et al. (2016) suggested that the dose of injected platelets, the efficiency of the production (percentage of platelets recovered), the purity of the PRP (ratio of platelets, leucocytes and red blood cells) and the activation process were overall termed the DEPA (dose, efficiency, purity, activation) system. Whilst each of these systems has their merits, as a product for application in the clinic, they must be able to be characterised by the administrator or be detailed on the product, in which case, the effect of storage/transport should be disclosed in studies and discussed further in the literature.

Current use of PRP in musculoskeletal tissues

PRP has been proposed as a promising biologic treatment with a wide range of applications in sports medicine (Lansdown and Fortier 2017). Injury type is significant, with benefits shown in the treatment of patella tendinopathy (Dragoo et al. 2014) and OA (Laudy et al. 2015) but not in Achilles tendinopathy or hamstring injuries (Manduca and Straub 2018). The available clinical studies on PRP as a treatment option suggest a good potential in favouring pain reduction and improved function for articular injuries to the ankle, knee and hip (Engebretsen et al. 2010). The evidence base for PRP across different injury types has been criticised for being inconsistent and uncertain (McNamee et al. 2018). In a meta-analysis, Grassi et al. (2018) advocated PRP treatment as a safe procedure with negligible adverse effects that is readily available and has a minimal risk of reactivity compared to other exogenous compounds owing to the autologous nature of PRP injections. However, existing large and indiscriminate use of PRP injections for the treatment of acute muscle injuries in clinical practice is not justified by evidence (Grassi et al. 2018). Thus, caution should be applied to use in knee OA.

In muscle strain and tendon injuries, no statistical or clinically significant differences were found for RTP duration and re-injury rate, leading to the conclusion that PRP is no more effective than a placebo injection or intensive rehabilitation (de Vos et al. 2010, 2014; Creaney et al. 2011; de Jonge et al. 2011; Thanasas et al. 2011; Krogh et al. 2013; Hamilton et al. 2015; Reurink et al. 2015; Liddle and Rodríguez-Merchán 2015); however, other studies have pointed to enhanced recovery (A Hamid et al. 2014; Chen et al. 2018). Between these reports, significant differences in the quality of the study are noted and should be used as a guide when analysing knee OA efficacy.

In knee OA, PRP injections aim to stimulate cartilage repair and offer relief to other osteoarthritic symptoms, potentially delaying the need for joint replacement surgery. PRP injections have shown to influence the entire joint environment, leading to a short-term clinical improvement (Filardo et al. 2012a, b) with PRP injections being considered a safe procedure with more favourable outcomes when compared to alternative treatments (Laver et al. 2017). PRP is relatively easy to use due to its simple and rapid preparation and the minimally invasive administration requiring a simple intra-articular injection. Adverse effects are likely to be reduced due to the patient’s own protein use and bioactive molecules can be concentrated to achieve the desired dosage, also eliminating potential drug interactions (Zhu et al. 2013). Without a synthetic element, PRP is, for the most part, not considered to be a drug or therapeutic substance and does not therefore need to fulfil the regulatory requirements needed for other biologic therapies.

PRP use in knee osteoarthritis

The use of PRP in the treatment of degenerative knee OA has increased in recent years given its apparent high margin of safety and ease of production and administration (Smith 2016). Contrasting scientific evidence exists regarding PRP injections for knee OA, with the efficacy of PRP injections widely reported (Rahimzadeh et al. 2018). The enhanced effectiveness of PRP for pain treatment and knee joint function in comparison to HA or placebo and positive outcomes in all stages of knee OA (early, middle and late), have all been reported (Kanchanatawan et al. 2016; Dai et al. 2017; Cole et al. 2017). In addition, the effects of PRP seemingly last longer and are superior in comparison with intramuscular injection therapies (Prieto-Alhambra et al. 2014). Comparisons between intra-articular injection of PRP and placebo and HA therapy in mild and moderate knee OA have generally shown higher clinical outcome scores with PRP use (Filardo et al. 2012a, b). Similarly, using meta-analysis to compare the efficacy of PRP injections against placebo or other therapeutic means for the treatment of knee OA (Bennell et al. 2017) has reported greater pain reduction (Laudy et al. 2015) and functional improvement (Chang et al. 2014) with the use of PRP. However, this is at the expense of an increase in nonspecific adverse events (Khoshbin et al. 2013).

PRP use has been advocated as a treatment option in all stages of knee OA. Intra-articular PRP injections in active patients with knee OA show significant improvements in pain reduction, improved symptoms and QoL (Gobbi et al. 2012). This could be due to the immediate and sustained release of growth factors over a prolonged period, which enhances healing resulting in sustained clinical effects (Dhillon et al. 2017). Symptomatic relief for up to 12 months with increased benefits to patients with early knee degenerative changes has been found (Campbell et al. 2015) with significant improvements in function and reductions in pain with three injections per month yielding significantly better outcomes in the short-term (Huang et al. 2017). Improved pain outcomes after 3 months with a greater effect in lower OA grades have been reported (Montañez-Heredia et al. 2016). In moderate knee OA, functional status and pain have improved with a minimum of two injections (Kavadar et al. 2015). In late-stage knee OA, it may be that only a single PRP intra-articular injection is required to provide effective pain relief, thus improving activities of daily living and QoL (Joshi Jubert et al. 2017).

Research into the efficacy of PRP has focused on comparing the effects of intra-articular PRP injections to other injection therapies. In many studies, PRP injections have improved functional outcomes when compared to HA and placebo controls and appear more efficacious in reducing symptoms and improving QoL (Raeissadat et al. 2015; Kanchanatawan et al. 2016). Kon et al. (2011) examined three homogenous groups of patients treated with three injections of PRP, low molecular weight HA and high molecular weight HA and concluded that autologous PRP injections have longer efficacy than HA injections and enhance articular function. The results showed improved outcomes for the PRP group at 6 months with younger and more active patients achieving better results with a low degree of cartilage degeneration (Meheux et al. 2016). Conversely, PRP causes a significantly greater acute inflammatory response and an increase in synoviocyte cell death (Braun et al. 2014) and induces more transient reactions than HA (Riboh et al. 2016). Spaková et al. (2012) compared three PRP injections with three HA injections in a randomised controlled trial (RCT) on 120 patients and discovered better Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores and Numerical Rating Scale (NRS) in the PRP group compared to the HA group (Table 3). In a separate RCT with 120 patients, Cerza et al. (2012) compared four PRP injections at 1-week intervals with low molecular weight HA and observed better improvement of WOMAC scores at 24 weeks in the PRP group. No correlations with the grade of OA were found in either study. Additionally, better WOMAC scores were achieved at 24 weeks using PRP by Sánchez et al. (2012) who examined 126 patients in a RCT with different grades of OA and compared three PRP injections at 1-week intervals with HA. Similarly, better outcomes have been documented when comparing PRP to HA groups at 6 months (Li et al. 2011; Say et al. 2013). Patel et al. (2013) compared normal saline with PRP and demonstrated that PRP significantly improved WOMAC scores following 6 months in comparison to the placebo groups, with patients experiencing benefits as early as 18 days. In a follow-up study, Patel and Dhillon (2014) hypothesised that the anti-inflammatory effect and chondral remodelling induced by PRP could be the reason for the improved clinical effects.
Table 3

Methods to assess impact of clinical intervention

Outcome measure

Function

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)

Assesses pain, stiffness and physical function. Consists of 24 items divided into 3 subscales:

• Pain (5 items): during walking, using stairs, in bed, sitting or lying and standing

• Stiffness (2 items): following waking and later in the day

• Physical function (17 items): stair use, rising from sitting, standing, bending, walking, getting in/out of a car, shopping, putting on removing socks, rising from bed, lying in bed, getting in/out of bath, sitting, getting on/off toilet, heavy household duties, light household duties

Lequesne

Assesses the effectiveness of therapeutic interventions.

Sections for index:

1. Pain or discomfort

2. Maximum distance walked

3. Activities of daily living

EQ-VAS

Patients’ self-evaluation of overall health. 0 (worst possible health) to 100 (best possible health)

International Knee Documentation Committee (IKDC) Questionnaire

Subjective overall function score. Questionnaire looks at 3 categories:

• Symptoms

• Sports activity

• Knee function

Symptom subscale assists evaluation of pain, stiffness, swelling and giving-way of the knee. Sports activity subscale focuses on functions such as ascending and descending stairs, rising from a chair, squatting and jumping.

Limitations and recommendations for further research

Despite the apparent positivity in the use of PRP for treatment of knee OA, methodological concerns and considerable heterogeneity between studies are evident (Rodriguez-Merchan 2013b). Large RCTs are needed to further assess the efficacy and duration of PRP treatment for patients with knee OA (Rodriguez-Merchan 2013a; Lai et al. 2015). When planning or analysing treatments, frequency and number of injections, as well as the activation methods (in the case of anticoagulated PRP), storage aspects, time from plasma isolation and accompanying therapy should be considered as at present they vary widely between groups. The greatest limiting factor for PRP use is the lack of standardisation with further research required to investigate how leukocyte inclusion, activation and platelet concentration affect therapeutic efficacy (Chen et al. 2018). Potential classification systems are discussed in depth by Dohan Ehrenfest et al. (2014), Lana et al. (2017) and Alves and Grimalt (2018). The cost-effectiveness of PRP, the demographic most likely to benefit and the optimal PRP protocol must all be researched further (Bennell et al. 2017). To this end, optimisation is still required regarding timing, dosage, volume, frequency, composition and post-injection rehabilitation (Engerbresten et al. 2010) and a unified classification needs to be agreed before this promising treatment can be widely implemented.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. A Hamid MS, Mohamed Ali MR, Yusof A et al (2014) Platelet-rich plasma injections for the treatment of hamstring injuries. Am J Sports Med 42:2410–2418Google Scholar
  2. Adatia A, Rainsford KD, Kean WF (2012) Osteoarthritis of the knee and hip. Part I: aetiology and pathogenesis as a basis for pharmacotherapy. J Pharm Pharmacol 64:617–625Google Scholar
  3. Alves R, Grimalt R (2018) A review of platelet-rich plasma: history, biology, mechanism of action, and classification. Ski Appendage Disord 4:18–24Google Scholar
  4. Andia I, Maffulli N (2013) Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol 9:721–730Google Scholar
  5. Bennell KL, Hunter DJ, Paterson KL (2017) Platelet-rich plasma for the management of hip and knee osteoarthritis. Curr Rheumatol Rep 19:24Google Scholar
  6. Blagojevic M, Jinks C, Jeffery A, Jordan KP (2010) Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthr Cartil 18:24–33Google Scholar
  7. Braun HJ, Kim HJ, Chu CR, Dragoo JL (2014) The effect of platelet-rich plasma formulations and blood products on human synoviocytes. Am J Sports Med 42:1204–1210Google Scholar
  8. Campbell KA, Saltzman BM, Mascarenhas R et al (2015) Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A systematic review of overlapping meta-analyses. Arthrosc J Arthrosc Relat Surg 31:2213–2221Google Scholar
  9. Cerza F, Carnì S, Carcangiu A et al (2012) Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med 40:2822–2827Google Scholar
  10. Chang K-V, Hung C-Y, Aliwarga F et al (2014) Comparative effectiveness of platelet-rich plasma injections for treating knee joint cartilage degenerative pathology: a systematic review and meta-analysis. Arch Phys Med Rehabil 95:562–575Google Scholar
  11. Chen X, Jones IA, Park C, Vangsness CT (2018) The efficacy of platelet-rich plasma on tendon and ligament healing: a systematic review and meta-analysis with bias assessment. Am J Sports Med 46:2020–2032Google Scholar
  12. Cole BJ, Karas V, Hussey K et al (2017) Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med 45:339–346Google Scholar
  13. Creaney L, Wallace A, Curtis M, Connell D (2011) Growth factor-based therapies provide additional benefit beyond physical therapy in resistant elbow tendinopathy: a prospective, single-blind, randomised trial of autologous blood injections versus platelet-rich plasma injections. Br J Sports Med 45:966–971Google Scholar
  14. Cross M, Smith E, Hoy D et al (2014) The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 73:1323–1330Google Scholar
  15. Dai WL, Zhou AG, Zhang H, Zhang J (2017) Efficacy of platelet-rich plasma in the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trials. Arthrosc J Arthrosc Relat Surg 33:659–670.e1Google Scholar
  16. de Jonge S, de Vos RJ, Weir A et al (2011) One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy. Am J Sports Med 39:1623–1630Google Scholar
  17. de Vos RJ, Weir A, van Schie HTM et al (2010) Platelet-rich plasma injection for chronic Achilles tendinopathy. JAMA 303:144Google Scholar
  18. de Vos R-J, Windt J, Weir A (2014) Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med 48:952–956Google Scholar
  19. DeLong JM, Russell RP, Mazzocca AD (2012) Platelet-rich plasma: the PAW classification system. Arthrosc J Arthrosc Relat Surg 28:998–1009Google Scholar
  20. Dhillon MS, Patel S, John R (2017) PRP in OA knee – update, current confusions and future options. Sicot-J 3:27Google Scholar
  21. Dohan Ehrenfest DM, Andia I, Zumstein MA et al (2014) Classification of platelet concentrates (platelet-rich plasma-PRP, platelet-rich fibrin-PRF) for topical and infiltrative use in orthopedic and sports medicine: current consensus, clinical implications and perspectives. Muscles Ligaments Tendons J 4:3–9Google Scholar
  22. Dragoo JL, Wasterlain AS, Braun HJ, Nead KT (2014) Platelet-rich plasma as a treatment for patellar tendinopathy. Am J Sports Med 42:610–618Google Scholar
  23. Driban JB, McAlindon TE, Amin M, Price LL, Eaton CB, Davis JE, Lu B, Lo GH, Duryea J, Barbe MF (2017) Risk factors can classify individuals who develop accelerated knee osteoarthritis: data from the osteoarthritis initiative. J Orthop Res 36:876–880Google Scholar
  24. Engebretsen L, Steffen K, Alsousou J, Anitua E, Bachl N, Devilee R, Everts P, Hamilton B, Huard J, Jenoure P and Kelberine F, (2010) IOC consensus paper on the use of platelet-rich plasma in sports medicine. British Journal of Sports Medicine 44(15):1072–1081Google Scholar
  25. Fernandes G, Yang S (2016) Application of platelet-rich plasma with stem cells in bone and periodontal tissue engineering. Bone Res 4:16036Google Scholar
  26. Ficek K, Kamiński T, Wach E, Cholewiński J, Cięszczyk P (2011) Application of platelet rich plasma in sports medicine. J Hum Kinet 30:85–97Google Scholar
  27. Filardo G, Kon E, Di Martino A, Di Matteo B, Merli ML, Cenacchi A, Fornasari PM, Marcacci M (2012a) Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord 13:229Google Scholar
  28. Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A, Fornasari P, Marcacci M, Kon E (2012b) Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med 43:1575–1582Google Scholar
  29. Gobbi A, Karnatzikos G, Mahajan V, Malchira S (2012) Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis. Sport Health A Multidiscip Approach 4:162–172Google Scholar
  30. Gouttebarge V, Inklaar H, Backx F, Kerkhoffs G (2015) Prevalence of osteoarthritis in former elite athletes: a systematic overview of the recent literature. Rheumatol Int 35:405–418Google Scholar
  31. Grassi A, Napoli F, Romandini I, Samuelsson K, Zaffagnini S, Candrian C, Filardo G (2018) Is platelet-rich plasma (PRP) effective in the treatment of acute muscle injuries? A systematic review and meta-analysis. Sport Med 48:971–989Google Scholar
  32. Hamilton B, Tol JL, Almusa E, Boukarroum S, Eirale C, Farooq A, Whiteley R, Chalabi H (2015) Platelet-rich plasma does not enhance return to play in hamstring injuries: a randomised controlled trial. Br J Sports Med 49:943–950Google Scholar
  33. Heidari B (2011) Knee osteoarthritis prevalence, risk factors, pathogenesis and features: part I. Casp J Intern Med 2:205–212Google Scholar
  34. Huang PH, Wang CJ, Chou WY, Wang JW, Ko JY (2017) Short-term clinical results of intra-articular PRP injections for early osteoarthritis of the knee. Int J Surg 42:117–122Google Scholar
  35. Jordan KP, Jöud A, Bergknut C, Croft P, Edwards JJ, Peat G, Petersson IF, Turkiewicz A, Wilkie R, Englund M (2014) International comparisons of the consultation prevalence of musculoskeletal conditions using population-based healthcare data from England and Sweden. Ann Rheum Dis 73:212–218Google Scholar
  36. Joshi Jubert N, Rodríguez L, Reverté-Vinaixa MM, Navarro A (2017) Platelet-rich plasma injections for advanced knee osteoarthritis: a prospective, randomized, double-blinded clinical trial. Orthop J Sport Med 5:232596711668938Google Scholar
  37. Kabiri A, Esfandiari E, Esmaeili A, Hashemibeni B, Pourazar A, Mardani M (2014) Platelet-rich plasma application in chondrogenesis. Adv Biomed Res 3:138Google Scholar
  38. Kanchanatawan W, Arirachakaran A, Chaijenkij K, Prasathaporn N, Boonard M, Piyapittayanun P, Kongtharvonskul J (2016) Short-term outcomes of platelet-rich plasma injection for treatment of osteoarthritis of the knee. Knee Surgery, Sport Traumatol Arthrosc 24:1665–1677Google Scholar
  39. Kavadar G, Demircioglu DT, Celik MY, Emre TY (2015) Effectiveness of platelet-rich plasma in the treatment of moderate knee osteoarthritis: a randomized prospective study. J Phys Ther Sci 27:3863–3867Google Scholar
  40. Khoshbin A, Leroux T, Wasserstein D, Marks P, Theodoropoulos J, Ogilvie-Harris D, Gandhi R, Takhar K, Lum G, Chahal J (2013) The efficacy of platelet-rich plasma in the treatment of symptomatic knee osteoarthritis: a systematic review with quantitative synthesis. Arthrosc J Arthrosc Relat Surg 29:2037–2048Google Scholar
  41. Kon E, Filardo G, Di Martino A, Marcacci M (2011) Platelet-rich plasma (PRP) to treat sports injuries: evidence to support its use. Knee Surgery, Sport Traumatol Arthrosc 19:516–527Google Scholar
  42. Kon E, Filardo G, Di Matteo B, Perdisa F, Marcacci M (2013) PRP-augmented scaffolds for cartilage regeneration: a systematic review. Oper Tech Sports Med 21:108–115Google Scholar
  43. Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T (2013) Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. Am J Sports Med 41:625–635Google Scholar
  44. Lai LP, Stitik TP, Foye PM, Georgy JS, Patibanda V, Chen B (2015) Use of platelet-rich plasma in intra-articular knee injections for osteoarthritis: a systematic review. PM&R 7:637–648Google Scholar
  45. Lana JFSD, Purita J, Paulus C, Huber SC, Rodrigues BL, Rodrigues AA, Santana MH, Madureira JL Jr, Malheiros Luzo AC, Belangero WD, Annichino-Bizzacchi JM (2017) Contributions for classification of platelet rich plasma – proposal of a new classification: MARSPILL. Regen Med 12:565–574Google Scholar
  46. Lansdown DA, Fortier LA (2017) Platelet-rich plasma: formulations, preparations, constituents, and their effects. Oper Tech Sports Med 25:7–12Google Scholar
  47. Laudy ABM, Bakker EWP, Rekers M, Moen MH (2015) Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med 49:657–672Google Scholar
  48. Laver L, Marom N, Dnyanesh L, Mei-Dan O, Espregueira-Mendes J, Gobbi A (2017) PRP for degenerative cartilage disease: a systematic review of clinical studies. Cartilage 8:341–364Google Scholar
  49. Li M, Zhang C, Ai Z, Yuan T, Feng Y, Jia W (2011) Therapeutic effectiveness of intra-knee-articular injection of platelet-rich plasma on knee articular cartilage degeneration. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 25:1192–1196Google Scholar
  50. Liddle AD, Rodríguez-Merchán EC (2015) Platelet-rich plasma in the treatment of patellar tendinopathy. Am J Sports Med 43:2583–2590Google Scholar
  51. Lotz MK, Caramés B (2011) Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol 7:579–587Google Scholar
  52. Lubkowska A, Dolegowska B, Banfi G (2012) Growth factor content in PRP and their applicability in medicine. J Biol Regul Homeost Agents 26:3–22Google Scholar
  53. Magalon J, Chateau AL, Bertrand B, Louis ML, Silvestre A, Giraudo L, Veran J, Sabatier F (2016) DEPA classification: a proposal for standardising PRP use and a retrospective application of available devices. BMJ Open Sport Exerc Med 2:e000060Google Scholar
  54. Manduca ML, Straub SJ (2018) Effectiveness of PRP injection in reducing recovery time of acute hamstring injury: a critically appraised topic. J Sport Rehabil 27:480–484Google Scholar
  55. Marx RE (2001) Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent 10:225–228Google Scholar
  56. Mascarenhas R, Saltzman B, Fortier L, Cole B (2014) Role of platelet-rich plasma in articular cartilage injury and disease. J Knee Surg 28:003–010Google Scholar
  57. Mather RC III, Koenig L, Kocher MS, Dall TM, Gallo P, Scott DJ, Bach BR Jr, Spindler KP (2013) Societal and economic impact of anterior cruciate ligament tears. J Bone Joint Surg Am 95:1751–1759Google Scholar
  58. McNamee MJ, Coveney CM, Faulkner A, Gabe J (2018) Ethics, evidence based sports medicine, and the use of platelet rich plasma in the English premier league. Health Care Anal 26:344–361Google Scholar
  59. Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD (2016) Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: a systematic review. Arthrosc J Arthrosc Relat Surg 32:495–505Google Scholar
  60. Michael JW-P, Schlüter-Brust KU, Eysel P (2010) The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee. Dtsch Aerzteblatt Online 107:152–162Google Scholar
  61. Mifune Y, Matsumoto T, Takayama K, Ota S, Li H, Meszaros LB, Usas A, Nagamune K, Gharaibeh B, Fu FH, Huard J (2013) The effect of platelet-rich plasma on the regenerative therapy of muscle derived stem cells for articular cartilage repair. Osteoarthr Cartil 21:175–185Google Scholar
  62. Montañez-Heredia E, Irízar S, Huertas PJ, Otero E, del Valle M, Prat I, Díaz-Gallardo MS, Perán M, Marchal JA, Hernandez-Lamas MD (2016) Intra-articular injections of platelet-rich plasma versus hyaluronic acid in the treatment of osteoarthritic knee pain: a randomized clinical trial in the context of the Spanish national health care system. Int J Mol Sci 17:1064Google Scholar
  63. Murphy L, Helmick CG (2012) The impact of osteoarthritis in the United States. Orthop Nurs 31:85–91Google Scholar
  64. Neogi T, Zhang Y (2013) Epidemiology of osteoarthritis. Rheum Dis Clin N Am 39:1–19Google Scholar
  65. Ng NTM, Heesch KC, Brown WJ (2012) Strategies for managing osteoarthritis. Int J Behav Med 19:298–307Google Scholar
  66. Ogino Y, Ayukawa Y, Kukita T, Koyano K (2006) The contribution of platelet-derived growth factor, transforming growth factor-β1, and insulin-like growth factor-I in platelet-rich plasma to the proliferation of osteoblast-like cells. Oral Surgery, Oral Med Oral Pathol Oral Radiol Endodontol 101:724–729Google Scholar
  67. Parrish WR, Roides B (2018) Platelet rich plasma in osteoarthritis: more than a growth factor therapy. Musculoskelet Regen 3:e1518Google Scholar
  68. Patel S, Dhillon MS (2014) The anti-inflammatory and matrix restorative mechanisms of platelet-rich plasma in osteoarthritis: letter to the editor. Am J Sports Med 42:NP30–NP31Google Scholar
  69. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A (2013) Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis. Am J Sports Med 41:356–364Google Scholar
  70. Pavlovic V, Ciric M, Jovanovic V, Stojanovic P (2016) Platelet rich plasma: a short overview of certain bioactive components. Open Med 11:242–247Google Scholar
  71. Pereira D, Peleteiro B, Araujo J, Branco J, Santos RA, Ramos E (2011) The effect of osteoarthritis definition on prevalence and incidence estimates: a systematic review. Osteoarthr Cartil 19:1270–1285Google Scholar
  72. Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK (2014) Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis 73(9):1659–1664Google Scholar
  73. Raeissadat SA, Rayegani SM, Hassanabadi H, Fathi M, Ghorbani E, Babaee M, Azma K (2015) Knee osteoarthritis injection choices: platelet- rich plasma (prp) versus hyaluronic acid (a one-year randomized clinical trial). Clin Med Insights Arthritis Musculoskelet Disord 8:CMAMD.S17894Google Scholar
  74. Rahimzadeh P, Imani F, Faiz SH, Entezary SR, Zamanabadi MN, Alebouyeh MR (2018) The effects of injecting intra-articular platelet-rich plasma or prolotherapy on pain score and function in knee osteoarthritis. Clin Interv Aging 13:73–79Google Scholar
  75. Reurink G, Goudswaard GJ, Moen MH, Weir A, Verhaar JA, Bierma-Zeinstra SM, Maas M, Tol JL (2015) Rationale, secondary outcome scores and 1-year follow-up of a randomised trial of platelet-rich plasma injections in acute hamstring muscle injury: the Dutch hamstring injection therapy study. Br J Sports Med 49:1206–1212Google Scholar
  76. Riboh JC, Saltzman BM, Yanke AB, Fortier L, Cole BJ (2016) Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis. Am J Sports Med 44:792–800Google Scholar
  77. Rodriguez-Merchan EC (2013a) Intra-articular injections of hyaluronic acid and other drugs in the knee joint. HSS J 9:180–182Google Scholar
  78. Rodriguez-Merchan EC (2013b) Intraarticular injections of platelet-rich plasma (prp) in the management of knee osteoarthritis. Arch Bone Jt Surg 1:5–8Google Scholar
  79. Sánchez M, Fiz N, Azofra J, Usabiaga J, Recalde EA, Gutierrez AG, Albillos J, Gárate R, Aguirre JJ, Padilla S, Orive G (2012) A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthrosc J Arthrosc Relat Surg 28:1070–1078Google Scholar
  80. Say F, Gürler D, Yener K, Bülbül M, Malkoc M (2013) Platelet-rich plasma injection is more effective than hyaluronic acid in the treatment of knee osteoarthritis. Acta Chir Orthop Traumatol Cechoslov 80:278–283Google Scholar
  81. Silverwood V, Blagojevic-Bucknall M, Jinks C, Jordan JL, Protheroe J, Jordan KP (2015) Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthr Cartil 23:507–515Google Scholar
  82. Smith PA (2016) Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis. Am J Sports Med 44:884–891Google Scholar
  83. Spaková T, Rosocha J, Lacko M, Harvanová D, Gharaibeh A (2012) Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil 91:411–417Google Scholar
  84. Sundman EA, Cole BJ, Karas V, Della Valle C, Tetreault MW, Mohammed HO, Fortier LA (2014) The anti-inflammatory and matrix restorative mechanisms of platelet-rich plasma in osteoarthritis. Am J Sports Med 42:35–41Google Scholar
  85. Thanasas C, Papadimitriou G, Charalambidis C, Paraskevopoulos I, Papanikolaou A (2011) Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis. Am J Sports Med 39:2130–2134Google Scholar
  86. van Buul GM, Koevoet WL, Kops N, Bos PK, Verhaar JA, Weinans H, Bernsen MR, van Osch GJ (2011) Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med 39:2362–2370Google Scholar
  87. Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T (2011) Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 70:844–850Google Scholar
  88. Xing D, Wang B, Zhang W, Yang Z, Hou Y, Chen Y, Lin J (2017) Intra-articular platelet-rich plasma injections for knee osteoarthritis: an overview of systematic reviews and risk of bias considerations. Int J Rheum Dis 20:1612–1630Google Scholar
  89. Yu D, Peat G, Bedson J, Jordan KP (2015) Annual consultation incidence of osteoarthritis estimated from population-based health care data in England. Rheumatology 54:2051–2060Google Scholar
  90. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M (2008) OARSI recommendations for the management of hip and knee osteoarthritis, part ii: OARSI evidence-based, expert consensus guidelines. Osteoarthr Cartil 16:137–162Google Scholar
  91. Zhu Y, Yuan M, Meng HY, Wang AY, Guo QY, Wang Y, Peng J (2013) Basic science and clinical application of platelet-rich plasma for cartilage defects and osteoarthritis: a review. Osteoarthr Cartil 21:1627–1637 QSAGoogle Scholar

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Authors and Affiliations

  • Brendan O’Connell
    • 1
  • Nicholas Martin Wragg
    • 2
  • Samantha Louise Wilson
    • 2
    Email author
  1. 1.National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health SciencesLoughborough UniversityLoughboroughUK
  2. 2.Centre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing EngineeringLoughborough UniversityLoughboroughUK

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