Intra-Articular Platelet-Rich Plasma Injections in Knee Osteoarthritis

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Emerito Carlos Rodriguez-Merchan	+ 3260 word(s)	3260	2022-02-11 03:18:11	\|
2	format correction	Peter Tang	Meta information modification	3260	2022-02-28 07:37:45	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms23031301

Primary knee osteoarthritis (OA) continues to be a hard-to-control degenerative disease. Intra-articular corticosteroids are typically advised, but only for short-term pain alleviation, given that their benefits last only a few weeks. The efficacy of hyaluronic acid is controversial. When the aforesaid options fail, total knee arthroplasty is generally recommended as an efficacious treatment. However, it is costly and can involve medical and postoperative complications. Therefore, determining alternate safe and effective treatments for knee OA is paramount. Platelet-rich plasma (PRP) has lately been investigated for the treatment of knee OA.

platelet-rich plasma knee osteoarthritis mechanisms of action efficacy

1. Introduction

Primary knee osteoarthritis (OA) continues to be a hard-to-control degenerative disease. With the increase in average life expectancy and the prevalence of obesity, OA is creating a rising economic and physical burden ^[1]. Knee OA is a chronic musculoskeletal condition that can eventually require surgical intervention. Thus, patients continue to search for potential nonoperative therapies, such as platelet-rich plasma (PRP) injections into the affected knee ^[2]^[3].

According to Jayaram et al., PRP is an emergent therapeutic approach for the treatment of OA; however, there remains a lack of clinical evidence for its effectiveness, and its mechanisms of action are indeterminate ^[4]. Despite promising outcomes reported with regard to PRP utilization in knee OA, crucial issues such as conclusive evidence about its effectiveness, standard dose, and good preparation techniques remain unknown ^[5].

Knee OA is estimated to affect over 10% of the population worldwide ^[6], with a lifetime risk of 45% ^[7]. Contemporary guidelines advise both non-drug (such as exercise) and drug treatments, such as oral non-steroidal anti-inflammatory drugs (NSAIDs) ^[8]^[9]. Nevertheless, these treatments typically have only short-term benefits ^[10]^[11]. Moreover, the use of drugs is restricted in people with comorbidities due to the risk of complications ^[8].

Intra-articular corticosteroids are typically advised only for short-term pain alleviation because their benefits are limited to a few weeks ^[1]^[8]^[12], and repeated injections have been shown to be related to augmented cartilage loss ^[13]. Some authors have stated that the use of hyaluronic acid (HA) is controversial ^[8]^[9]. However, other authors have reported pain reduction after three to five weekly injections of HA lasting between 5 and 13 weeks (sometimes up to 1 year) ^[1].

When the aforementioned alternatives fail, total knee arthroplasty (TKA) is generally recommended as an effective treatment. However, it is costly and can involve medical and postoperative adverse effects ^[14]. Therefore, identifying alternative safe and effective therapies for knee OA is crucial.

Biological therapies have recently been investigated for the treatment of knee OA, such as PRP ^[15]. PRP is an autologous blood product with a high concentration of platelets. PRP’s effectiveness is thought to be related to the liberation of growth factors and other molecules, including platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, type I insulin-like growth factor (IGF-I), and vascular endothelial growth factor (VEGF) ^[16].

Some publications have stated that PRP might be promising for the treatment of knee OA ^[17]^[18]^[19]. Nevertheless, most disagree concerning the best methods and have many limitations that hamper an appropriate analysis of their outcomes, with risk of bias ^[18]^[20]. Heterogeneity in the preparation and injection methods employed by reported studies is a limitation for defining ideal PRP systems. Moreover, most trials have HA as a comparator, which is itself debatable ^[17]. Some trials have compared PRP with placebo, with outcomes showing significantly greater improvement in symptoms over saline at 6 and 12 months ^[21]^[22]^[23]^[24]^[25]. However, these trials had considerable methodological flaws, including lack of appropriate blinding, suggesting that the benefits might have been overvalued ^[17].

The advantages of PRP for the treatment of knee OA are the following: it is reasonably easy to use because its preparation is rapid and it is minimally invasive; it is a relatively affordable technique, thanks to use of existing public health service structures and equipment; and it is likely to be safe because it is an autologous product. Previous publications have reported only minor and transitory complications ^[17].

2. Platelet-Rich Plasma’s Molecular Mechanisms of Action

The results of a Cochrane Library and PubMed (MEDLINE) search of studies related to PRI in knee OA were analyzed. The searches were from the beginning of the search engines until 15 December 2021. Only the studies on PRP in knee OA that the author considered to be of most interest were included. PubMed found 454 articles, of which 80 were selected. One article was found in the Cochrane Library, which was also included, for a total of 80 references.

In 2011, a study was published stating that the use of growth factors (members of the TGF-β superfamily, fibroblast growth factor family, IGF-I, and PDGF) in the management of OA appeared promising ^[26].

In 2014, Sundman et al. reported that PRP treatment of OA joint tissues resulted in diminished catabolism; however, PRP caused a significant decrease in matrix metalloproteinase-13, an elevation in hyaluronan synthase-2 expression in synoviocytes, and an increase in cartilage synthetic activity. The findings of this study showed that PRP stimulates endogenous HA production and diminishes cartilage catabolism. PRP also suppressed inflammatory mediator concentration and expression of their genes in synovial and cartilage cells ^[27].

In 2015, a controlled laboratory study showed that PRP significantly stimulates cell proliferation and superficial zone protein secretion in cartilage and synovial cells of the human knee. These observations help explain the biochemical mechanisms related to the effectiveness of PRP in the treatment of knee OA ^[28].

In a murine OA model (controlled laboratory study) reported by Khatab et al. in 2018, multiple PRP releasate injections alleviated pain and synovial thickness, conceivably through the modulation of macrophage subtypes. Consequently, these injections appear to alleviate pain and synovial inflammation and might inhibit OA development in patients with early OA ^[29].

In 2018, a review of the literature on the PubMed database concluded that PRP therapy for OA appeared to exert modulation on the Wnt/β catenin pathway, which could be important in achieving its beneficial clinical effect ^[30].

In 2019, Liu et al., investigated the molecular mechanism of exosomes derived from PRP involved in alleviating OA. It is important to emphasize that exosomes play crucial roles in intercellular communication. In this study, primary rabbit chondrocytes were isolated and treated with interleukin (IL)-1β to establish the OA model in vitro. Proliferation, migration, and apoptosis assays were measured and compared between PRP-derived exosomes and activated PRP to assess the therapeutic effects on OA. The mechanism involving the Wnt/β-catenin signaling pathway was investigated by Western blot analysis. The therapeutic effects of PRP-derived exosomes on OA were found to be similar to or better than those of activated PRP in vitro and in vivo. Liu et al. stated that PRP-derived exosomes acting as carriers containing growth factors derived from PRP present a novel therapy for OA by activating the Wnt/β-catenin signaling pathway ^[31].

In a mouse model of post-traumatic OA reported in 2020, Jayaram et al. suggested that the effects of PRP on OA progression and disease-induced hyperalgesia might be leukocyte dependent. They also mentioned that leukocyte-poor PRP (LP-PRP) and to a lesser extent leukocyte rich-PRP (LR-PRP) protect against volume and surface loss ^[4].

The findings reported by Yang et al. in 2021 indicated that PRP abates IL-1β-induced chondrocyte apoptosis and inflammation at least partly through inhibiting hypoxia-inducible factor 2α ^[32].

In an in vivo OA model using PRP in rats, Sun et al. found that microRNA-337 and microRNA-375 were involved in delaying OA progression by affecting inflammation and apoptosis ^[33].

According to Sheean et al., the biologic activity of PRP is manifold: platelet α granules promote the release of various growth factors, including VEGF and TGF-β, and inflammation is modulated through the inhibition of the nuclear factor-κB pathway ^[34].

Uchiyama et al. studied the concentrations of humoral factors in PRP prepared from two kits and the impact of humoral factors on macrophage phenotypes. They found that the concentrations of cell components and humoral factors differed between PRP purified using the two kits. The autologous protein solution LR-PRP kit had a greater concentration of M1 and M2 macrophage-related factors. The addition of PRP supernatants to the culture media of monocyte-derived macrophages and M1 polarized macrophages showed that PRP suppressed M1 macrophage polarization and promoted M2 macrophage polarization ^[35].

In 2021, Szwedowski et al. described the growth factors liberated in the OA knee following PRP injection: tumor necrosis factor (TNF), IGF-1, TGF, VEGF, a disintegrin and metalloproteinase with thrombospondin motifs, interleukin, matrix metalloproteinase, epidermal growth factor, hepatocyte growth factor, fibroblast growth factor, keratinocyte growth factor, and platelet factor 4 ^[36].

Table 1 ^[4]^[27]^[28]^[29]^[30]^[31]^[32]^[33]^[34]^[35]^[36] and Figure 1 summarize the molecular mechanisms of action of PRP intra-articular injections in knee OA.

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Figure 1. A summary of the molecular mechanisms of action of intra-articular injections of platelet-rich plasma (PRP) in knee osteoarthritis (OA) ^[4]^[27]^[28]^[29]^[30]^[32]^[33]^[34]^[35]^[36].

Table 1. Summary of PRP’s molecular mechanisms of action.

Authors	Year	Main Findings
Sundman et al. ^[27]	2014	PRP treatment decreases catabolism and matrix metalloproteinase-13 and increases hyaluronan synthase-2 expression in synoviocytes and cartilage synthetic activity.
Sakata et al. ^[28]	2015	PRP stimulates cell proliferation and superficial zone protein secretion by articular cartilage and synovium of the human knee joint.
Khatab et al. ^[29]	2018	Multiple PRP releasate injections reduce pain and synovial thickness, possibly through modulation of macrophage subtypes.
De Santis et al. ^[30]	2018	PRP therapy for OA exerts modulation on the Wnt/β catenin pathway that might be relevant in achieving its beneficial clinical effect.
Liu et al. ^[31]	2019	The therapeutic effects of exosomes derived from PRP on OA were similar or better compared with those of activated PRP in vitro or in vivo.
Jayaram et al. ^[4]	2020	The effects of PRP therapy on OA progression and disease-induced hyperalgesia might be leukocyte-dependent.
Yang et al. ^[32]	2021	PRP attenuates interleukin-1β, inducing chondrocyte apoptosis and inflammation at least partially through inhibiting hypoxia-inducible factor 2α.
Sun et al. ^[33]	2021	Micro-RNA (miR)-337 and miR-375 are involved in PRP-delayed OA progression by affecting inflammation and apoptosis.
Sheean et al. ^[34]	2021	Platelet α granules promote the release of various growth factors, including vascular endothelial growth factor and tissue growth factor β, and inflammation is modulated through inhibition of the nuclear factor-κB pathway.
Uchiyama et al. ^[35]	2021	The autologous protein solution leukocyte-rich PRP kit has a higher concentration of M1 and M2 macrophage-related factors.
Szwedowski et al. ^[36]	2021	Growth factors released in the OA knee joint after PRP injection: tumor necrosis factor, insulin-like growth factor, transforming growth factor, vascular endothelial growth factor, a disintegrin and metalloproteinase with thrombospondin motifs, interleukin, matrix metalloproteinase, epidermal growth factor, hepatocyte growth factor, fibroblast growth factor, keratinocyte growth factor, and platelet factor 4.

PRP = platelet-rich plasma; OA = osteoarthritis.

3. Efficacy of Intra-Articular Platelet-Rich Plasma Injections in Knee Osteoarthritis

3.1. Placebo-Controlled Trials

In a single-blinded, randomized, placebo-controlled pilot study, Tucker et al. assessed molecular biomarkers and mesenchymal stem cells in synovial fluid during PRP treatment of the osteoarthritic knee joint ^[37]. Seventeen patients with mild-to-moderate knee OA were randomized in a 2:1 placebo-controlled ratio, receiving PRP or saline (placebo) intra-articular injection of the knee. Levels of IL-5, IL-6, IL-10, and TNF-α were measured in synovial fluid 10 days after PRP injection. Altered gene expression profiles in mesenchymal stem cells from patients receiving PRP were found for matrix metalloproteinases and inflammatory markers (IL-6, IL-8, CCL2, TNF-α). Alpha-2-macroglobulin protease was significantly augmented after PRP injection (p = 0.005). Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores decreased for up to 3 months from baseline levels and remained low at 6 and 12 months in the PRP group. However, WOMAC scores for patients who received the saline injection were relatively unchanged for up to 12 months. Tucker et al. postulated that PRP modulates the local knee synovial environment by modifying the inflammatory milieu, matrix degradation, and angiogenic growth factors. The group receiving PRP had less pain and stiffness and improved function scores ^[37].

3.2. Randomized Controlled Trials

In a randomized controlled trial with level of evidence I, Yurtbay et al. observed that compared with placebo (sodium saline), LR-PRP injections were efficacious in the management of OA ^[38]. Multiple doses of PRP augmented the treatment efficacy and duration. The best results of PRP treatment were attained by patients aged 51–65 years, with a lower mechanical axis angle, and with Kellgren and Lawrence (K/L) grade 2 OA. The better group scores were found at 3 and 6 months. Patients who received PRP injections maintained better scores at 3, 6, and 12 months compared with the placebo group (p < 0.05). Multiple doses of PRP were found to be more efficacious than single-dose PRP at 6 and 12 months (p < 0.05). At 24 months, no significant score difference was found between groups. The most positive change in scores was found in those with K/L grade 2 OA, and the most positive change in range of motion (ROM) was found in those with K/L grade 3 OA. In the PRP groups, knee circumference diminished more at 1 and 6 months (p < 0.05) ^[38].

In a randomized, two-group, placebo-controlled, participant-, injector-, and assessor-blinded clinical trial reported in 2021, 288 individuals aged 50 years or older with symptomatic medial knee OA (K/L grade 2 or 3) were analyzed by Bennell et al. They used three intra-articular injections at weekly intervals of either LP-PRP (n = 140 participants) or saline placebo (n = 140 participants). Patients with symptomatic mild-to-moderate radiographic knee OA who had intra-articular injections of PRP were not found to have improved symptoms or joint structure at 12 months. Therefore, the authors did not support use of intra-articular injections of PRP for the treatment of knee OA ^[39].

Dório et al. evaluated the efficacy of intra-articular PRP and plasma to ameliorate pain and improve function in patients with knee OA over 24 weeks ^[40]. They performed a randomized, double-blind, placebo-controlled trial with three groups (n = 62): PRP (n = 20), plasma (n = 21), and saline (n = 21). Two ultrasound-guided knee injections were performed, with a 2-week interval. The primary parameter was visual analog scale (VAS) 0–10 cm for overall pain at week 24, with intermediate evaluations at weeks 6 and 12. The main secondary parameters were Knee Injury and Osteoarthritis Outcome Score (KOOS), Osteoarthritis Research Society International criteria, and timed up and go test (TUGT). At baseline, 92% of the participants were women, with a mean age of 65 years, mean body mass index (BMI) of 28 Kg/m², and mean VAS pain of 6.2 cm. Changes in pain from baseline at week 24 were −2.9, −2.4, and −3.5 cm for PRP, plasma, and saline, respectively (p intergroup = 0.499). There were no differences among the three groups at weeks 6 and 12. Similarly, there were no differences among the groups regarding secondary outcomes. The PRP group showed a higher frequency of complications (65% versus 24% for plasma and 33% for saline, p 0.02), mostly a mild transitory increase in pain. The conclusion of this study was that PRP and plasma were not better than placebo for pain reduction and function improvement in the knee with OA longer than 24 weeks. The PRP group had a greater frequency of mild transitory pain augmentation ^[40].

3.3. Systematic Reviews and Meta-Analyses

In 2021, Kim et al. performed a systematic review and meta-analysis (level of evidence IV) to assess the complications and clinical results of LP-PRP versus LR-PRP in knee OA. Intra-articular PRP injection resulted in improvements above the minimal clinically important difference in terms of pain and function in patients with knee OA up to 12 months. The risk of local complications appeared to be augmented following LR-PRP compared with LP-PRP injection. The findings of this study supported the use of intra-articular PRP injection for the management of knee OA ^[41].

A systematic review (level of evidence I) performed in 2021 by Nie et al. stated that PRP injections were beneficial for pain alleviation and functional improvement in patients with knee OA. However, they also stated that larger, randomized, high-quality studies were required to compare the effects of LP-PRP and LR-PRP ^[42].

Another review of the literature reported in 2021 by Li et al. included 959 patients with knee OA (1070 knees). The follow-up was between 3 and 12 months. PRP total knee scores were significantly better than baseline at 1, 2, 3, 6, and 12 months following PRP injection. Regarding complications, PRP did not increase the risk of adverse events compared with HA. Compared with many other treatment methods, the intra-articular injection of PRP was proven to be a safe and effective means of improving the quality of life of patients with knee OA ^[43].

Hong et al. compared the safety and effectiveness of PRP with placebo or other conservative treatments for knee OA (literature review and meta-analysis) ^[44]. Compared with placebo, PRP had a lower VAS score and a higher International Knee Documentation Committee (IKDC) subjective score at the sixth month following PRP injection and a significantly lower WOMAC score during the follow-up period. Compared with oral NSAIDs, PRP had a lower WOMAC score at the sixth month after injection. There were no significant differences in complications comparing PRP with placebo or HA. Different PRP applications did not show significant differences in VAS score in the first month or WOMAC score in the third month after treatment. There were no significant differences between triple PRP injection and single PRP injection in the short-term curative effect ^[44]. In a systematic review reported by Aiyer, they only recommended PRP for patients with early-stage OA (1 or 2) and who were aged younger than 65 years ^[45].

3.4. Case Series

Table 2 summarizes the efficacy of intra-articular PRP injections in knee OA ^[37]^[38]^[39]^[40]^[41]^[42]^[43]^[44]^[45]^[46]^[47]^[48]^[49]^[50]^[51].

Table 2. Summary of the efficacy of intra-articular PRP injections in knee OA.

Authors	Year	Type of Study	Main Findings
Tucker et al. ^[37]	2021	Single-blinded, randomized, placebo-controlled pilot study	The PRP treatment group had less pain and stiffness and improved function scores than the placebo (saline) group
Yurtbay et al. ^[38]	2021	Randomized, double-blind, placebo-controlled clinical trial	Compared with placebo (sodium saline), LR-PRP treatment was effective in the treatment of OA. Multiple doses of PRP increased the treatment efficacy and duration. Patients aged 51–65 years scored better at 6 months
Bennell et al. ^[39]	2021	Randomized, 2-group, placebo-controlled, participant-, injector-, and assessor-blinded clinical trial	Among patients with symptomatic mild-to-moderate radiographic knee OA, intra-articular PRP injection, compared with injection of saline placebo, did not result in a significant difference in symptoms or joint structure at 12 months.
Dório et al. ^[40]	2021	Randomized, double-blind, placebo-controlled trial of 3 groups of patients: PRP, plasma, and saline.	There were no differences among the 3 study groups at weeks 6 and 12.
Kim et al. ^[41]	2021	Systematic review and meta-analysis (level of evidence IV)	Intra-articular PRP injection resulted in improvements above the minimal clinically important difference in terms of pain and function up to 12 months.
Nie et al. ^[42]	2021	Meta-analysis of randomized controlled clinical trials (level of evidence I)	PRP injections were beneficial for pain alleviation and functional improvement in knee OA.
Li et al. ^[43]	2021	Literature review	Compared with many other treatment methods, intra-articular injection of PRP proved to be safe and effective to improve the quality of life of patients with knee OA.
Hong et al. ^[44]	2021	Systematic review and meta-analysis	Compared with placebo, PRP had a lower VAS score and higher IKDC subjective score at 6 months after treatment and a significantly lower WOMAC score during the follow-up period.
Aiyer et al. ^[45]	2021	Systematic review of clinical studies	These authors recommended PRP for patients with early-stage OA (I or II) and who are aged younger than 65.
Moton et al. ^[46]	2021	Prospective case series	PRP injections for treating OA (grade 1 to 3) proved to be successful in terms of improving functional outcomes and reducing pain intensity.
Sun et al. ^[47]	2021	Case series	One injection of PRP improved pain and function for 6 months for patients with early knee OA.
Bec et al. ^[48]	2021	Case series (retrospective study)	A single injection of pure PRP resulted in significant clinical improvement in the management of knee OA.
Hegaze et al. ^[49]	2021	Prospective case series	Intra-articular injections gave significant pain and flexion improvement in patients with grades II, III, and IV OA, especially with multiple injections in the short-term follow-up.
Rai et al. ^[50]	2021	Case series	PRP was a safe and effective therapy for early OA knees. It provided a significant clinical improvement in patients, with some loss of improvement with time.
Jayaram et al. ^[51]	2021	Case series	LR-PRP demonstrated efficacy in meaningful end points for functional and patient-reported outcomes at early time points in patients with knee OA.

PRP = platelet-rich plasma; LR-PRP = leukocyte rich PRP; OA = osteoarthritis; VAS = visual analog scale; IKDC = International Knee Documentation Committee; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

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