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Platelet-rich plasma injections induce disease-modifying effects in the treatment of osteoarthritis in animal models

Abstract

Purpose

The mechanisms of action and disease-modifying potential of platelet-rich plasma (PRP) injection for osteoarthritis (OA) treatment are still not fully established. The aim of this systematic review of preclinical evidence was to determine if PRP injections can induce disease-modifying effects in OA joints.

Methods

A systematic review was performed on animal studies evaluating intra-articular PRP injections as treatment for OA joints. A synthesis of the results was performed investigating the disease-modifying effects of PRP by evaluating studies that compared PRP with OA controls or other injectable products, different PRP formulations or injection intervals, and the combination of PRP with other products. The risk of bias was assessed according to the SYRCLE’s tool.

Results

Forty-four articles were included, for a total of 1251 animals. The publication trend remarkably increased over time. PRP injections showed clinical effects in 80% and disease-modifying effects in 68% of the studies, attenuating cartilage damage progression and reducing synovial inflammation, coupled with changes in biomarker levels. Evidence is limited on the best PRP formulation, injection intervals, and synergistic effect with other injectables. The risk of bias was low in 40%, unclear in 56%, and high in 4% of items.

Conclusion

Intra-articular PRP injections showed disease-modifying effects in most studies, both at the cartilage and synovial level. These findings in animal OA models can play a crucial role in understanding mechanism of action and structural effects of this biological approach. Nevertheless, the overall low quality of the published studies warrants further preclinical studies to confirm the positive findings, as well as high-level human trials to demonstrate if these results translate into disease-modifying effects when PRP is used in the clinical practice to treat OA.

Level of evidence

Level II.

Introduction

Osteoarthritis (OA) is the most common degenerative joint disease, with a high social and economic impact worldwide, and its incidence and prevalence are rising [63]. OA is characterized by progressive deterioration and loss of articular cartilage with concomitant structural and functional changes in the entire joint, including subchondral bone remodeling, osteophyte formation, and synovial inflammation [49]. These processes are due to a complex interaction of genetic, metabolic, biochemical, and biomechanical factors leading to inflammation and degeneration [50]. Although numerous conservative treatment strategies have been proposed to address OA, ranging from oral medications to intra-articular (i.a.) injection therapies with corticosteroids and hyaluronic acid (HA), these options mainly provide symptom relief rather than delay the progression of cartilage degeneration or enhance the repair processes [26]. Thus, there is a significant need to develop treatments which are able to alter OA progression with a proven disease-modifying effects.

Among the new treatments proposed in the clinical practice, platelet-rich plasma (PRP) has recently emerged as an attractive biological approach to address joint degeneration. It has gained increasing attention due to the high concentration of growth factors, cytokines, and bioactive molecules stored in platelet α-granules, which showed to take part in the homeostasis of joint tissues, being involved in both healing processes and immunoregulation and inflammation modulation [61]. Due to the safety, the low costs, and the simple preparation technique to obtain its biologically active content, PRP is now often considered a suitable option in the clinical practice [40]. The safety and effectiveness of i.a. PRP injections in OA treatment have been investigated in various clinical studies, showing promising results in terms of functional improvement and reduction of pain-related symptoms [3, 14, 22]. Moreover, PRP injections proved better results than saline as well as compared to other injectable options such as corticosteroids and HA for knee OA [28]. However, besides the observed short-term symptom improvement, the mechanisms of action and the disease-modifying potential of this novel OA therapy still have not been fully established [26]. Due to practical and ethical limitations, the evaluation of PRP potential in counteracting OA progression largely relies on animal models, which play a crucial role in the understanding the structural effects of novel therapeutic interventions [41]. Thus, the evaluation of PRP results in animal OA models can help underlining the mechanism of action and disease-modifying effects of this biological approach.

The aim of this systematic review of preclinical evidence was to determine if PRP injections can induce disease-modifying effects in joints affected by cartilage degeneration and OA.

Materials and methods

Search strategy and article selection

A systematic review was performed on the i.a. use of platelet concentrates as injective treatment for joints affected by OA. The search was conducted on three electronic databases (PubMed, Embase, Web of Science) on February 1, 2021, with no time limitation and without any filters, using the following string: (PRP OR platelet-rich plasma OR plasma rich in growth factors OR PRGF OR platelet-derived growth factor OR platelet-derived OR platelet gel OR platelet concentrate OR PRF OR platelet-rich fibrin OR ACP OR autologous conditioned plasma OR APS OR autologous protein solution OR platelet lysate OR platelet supernatant) AND (cartilage OR chondrocytes OR synoviocytes OR osteoarthritis). According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [44], the screening process and analysis were conducted separately by two authors (GM and MS).

The retrieved articles were first screened by title and abstract. The following inclusion criteria were used: animal studies, written in English language, on blood products based on platelet concentrates as injective treatment for cartilage degeneration or OA. Exclusion criteria were: articles written in other languages, in vitro or clinical studies, literature reviews, congress abstracts, studies on joint diseases different from OA, and studies reporting on the use of PRP without a control group or the combined use of PRP with another product without analyzing the specific contribution of PRP treatment. In the second step, the full texts of the selected articles were screened, with further exclusions according to the previously described criteria. In addition, the reference lists from the selected papers and previously published relevant reviews were also screened. The screening process is detailed in Fig. 1. Two investigators independently reviewed each article (GM and MS), and any discrepancies between them were resolved by discussion and consensus with a third author (AB).

Fig. 1
figure1

PRISMA flowchart of the study selection process

Data extraction and quality assessment

For the included studies, relevant data were extracted from article texts, tables, and figures, and then summarized and analyzed for the purpose of the present work. In particular, the following data were collected for each study: authors and year of publication, number and type of evaluated animals, involved joint, OA model, type of treatment, PRP characteristics and injection schedule, follow-up length, and results. A synthesis of the obtained results was performed investigating the disease-modifying effects of i.a. PRP, intended as evidence of objective elements of effects on OA processes going beyond the mere symptomatic improvement. This was achieved by evaluating the studies that compared animals treated with PRP and controls (saline injection or no treatment). Moreover, other results were analyzed with regard to the benefits provided by different PRP formulations or injection schedules, the effects versus other injectable treatments, and finally the effects derived from the combination of PRP with other products exploring potential synergistic effects.

The risk of bias of the included studies was assessed according to the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE)’s tool [34]. This tool, based on the Cochrane Collaboration RoB Tool [33], contains 10 items related to the types of bias: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases. All items could be judged as ‘yes’ (low risk of bias), ‘no’ (high risk of bias), and ‘unclear’ (unclear risk of bias). Two reviewers (GM and MS) independently evaluated the studies, and discrepancies were resolved through discussion and consensus with a third author (AB).

Results

Study selection and analysis

The initial search identified 3284 articles; the study selection process led to 44 articles included in the qualitative data synthesis (Fig. 1). Since the first report in 2009, the publication trend remarkably increased over time, with three quarters of the studies published in the last 5 years (Fig. 2).

Fig. 2
figure2

Number of animal studies on intra-articular PRP injections to address OA

A total of 1251 animals were assessed, with 32 studies focused on small animals (19 on rodents such as guinea pig, mouse, and rat, and 13 on rabbits) and 12 studies on large animals (7 on dogs, 4 on horses, and one on goats). The evaluated joints were: knee in 36 articles, temporo-mandibular joint in 2 articles, hip, elbow, and distal interphalangeal joint in 1 article each, while 3 studies included various joints in their analysis. The OA animal model was surgically induced in 17 studies (through ligament transection and/or meniscectomy), chemically induced in 15 studies (through i.a. injection of chondrotoxic or pro-inflammatory substances, like mono-iodoacetate, collagenase, formalin, or surgical talc), naturally occurring in 9 studies, weight-induced in 2 studies, and induced by the increase in axial tibial load in one study.

The i.a. PRP injection was compared with saline in 28 studies, with no treatment in 14 studies, mesenchymal stem/stromal cells (MSCs) in 6 studies, HA in 3 studies, bone marrow aspirate concentrate (BMAC), alendronate, avastin, HA combined with methylprednisolone, and continuous passive exercise in 1 study each. PRP was evaluated in 15 studies in combination with other products such as MSCs (5 studies), HA (4 studies), alendronate, avastin, caffeic acid phenethyl ester (CAPE), microspheres, and Vitamin C (1 study each), or in combination with continuous passive exercise (1 study). Moreover, 3 studies compared different PRP injection schedules (single versus multiple injections), 3 studies different PRP formulations (based on leukocytes concentration), and 2 studies different activation methods (irradiation or biophysical activation). The most common injection schedule was the single PRP administration (19 studies), followed by a 3-injection protocol (11 studies), 2 injections (6 studies), 4 injections (4 studies), 6 injections (2 studies), 7 injections (1 study), and 10 injections (1 study). For the 25 studies evaluating multiple PRP application cycles, the injective timing ranged from 2 days to 4 weeks, with the majority (17 studies) using a 1 week interval among injections. The follow-up evaluation of the included studies ranged from 1 day to 1 year after PRP injection.

The amount of administered PRP ranged from 5 to 1000 µL in small animal models, and from 1 to 5 mL in large animals. When specified, PRP was autologous in 27 articles, allogenic in 12 articles, and xenogenic in 4 articles. Only one article did not report the PRP origin. PRP activation method was reported in 27 studies, with the calcium chloride solution as the most used one (13 studies), followed by thrombin (3 studies), not activated, calcium gluconate, and combined use of calcium chloride solution and thrombin (2 studies each), irradiation and biophysical activation (1 study each). Three studies specifically reported about relaying on freeze-thawing for activation. The remaining 17 studies did not describe the activation method. Frozen PRP was used in 13 articles, fresh PRP was used in 12 articles, the first injection was fresh and the following ones were frozen in 2 studies, while 17 articles did not specify this aspect. Twenty-four studies (55%) detailed the number of platelets injected and 13 studies (30%) detailed the presence of leukocytes: PRP with leukocytes was documented in 11 study groups, while PRP without leukocytes in 5 study groups. Only 9 (20%) studies investigated the concentration of bioactive molecules in PRP. The analysis of PRP characteristics over time did not show a trend toward improving detail reporting, with missing data also in the most recent publications (for example, platelet concentration was reported in 45% vs 59% in the most recent half of the papers vs the older ones). Further details on the characteristics of the different PRPs used are reported in Table 1.

Table 1 Characteristics of the included studies

Disease-modifying effects of PRP

Thirty-one studies (29 small animals and 2 large animals) investigated the results of PRP injections in comparison to “no treatment” or saline injections to address OA joints performing a statistical analysis to evaluated disease-modifying effects. Out of these, 21 studies (68%) reported overall better results in animals treated with PRP compared to control groups, while 10 studies (32%) revealed no improvement following PRP injection. A more detailed analysis is reported in the following paragraphs and in Fig. 3.

Fig. 3
figure3

PRP effects on OA joints. The bar chart shows the percentage of studies that met the specific effects. Positive effects vs no effects in clinical outcome (10 studies), cartilage macroscopic evaluation (6 studies), cartilage histology (29 studies), cartilage immunohistochemistry (7 studies), synovium histology (6 studies), synovium immunohistochemistry (3 studies), and OA biomarkers (12 studies). IHC, immunohistochemistry. OA, osteoarthritis

Small animal models—cartilage

61% of the 28 studies investigating the disease-modifying effects on cartilage tissue reported positive results. In particular, animals treated with PRP were reported to sustain a marked reduction in the severity of cartilage destruction and surface loss, as well as less fibrillation and irregularity compared to control groups [10, 38, 52, 66, 67, 71, 72]. These findings were confirmed by phase-contrast computed tomography (CT), revealing greater cartilage volume and surface in mice treated with PRP [37]. Histologically, better cellularity was seen following PRP administration, which prevented chondrocyte apoptosis and increased their viability with increased proliferative rate, resulting in higher chondrocyte numbers [6, 9, 10, 18, 35, 68]. Chondrocytes also showed better ultrastructural characteristics with a relatively intact cell membrane, abundant cellular organelles, roughly normal nuclear morphology, and relatively uniform cytoplasmic staining [66]. Accordingly, the cartilage matrix secreted by chondrocytes also presented better characteristics, showing no proteoglycan loss and collagenous fibers uniformly arranged with some fractures, with a strong Type II Collagen expression [19, 66, 68, 72]. One study, apart from reporting several positive findings, also reported a negative effect of PRP on cartilage tissue, documenting an increased extracellular matrix mineralization compared to the OA control group [18].

Small animal models—synovial membrane

75% of the 8 studies investigating the disease-modifying effects of PRP on the synovial membrane documented positive results after PRP injection, while no negative effects were reported. Thinner synovial membrane and less synovial hyperplasia were observed histologically [2, 37, 65]. PRP reduced the inflammatory reactions caused by OA with less edema, fewer synovial vascularity and fibrosis, and reduced inflammatory cell infiltration compared to controls [4, 10, 38, 39, 70, 71]. In addition, a reduction trend of inflammatory macrophages was seen (iNOS) [39]. Synovium specimens revealed strong platelet-derived growth factor subunit A (PDGF-A) expression in synoviocytes, stromal cells, and vascular endothelium. Likewise, there was a significantly higher immunostained area percentage for vascular endothelial growth factor (VEGF) in synovial membrane from PRP groups specimens compared to controls [2].

Small animal models—biomarker profile

PRP benefits were also assessed through measurement of synovial fluid (SF) or serum biomarkers related to cartilage metabolism or inflammation. SF cartilage oligomeric matrix protein (COMP) was reported to be significantly lower following PRP administration [38]. PRP injections also decreased the serum and SF concentrations of tumor necrosis factor—α (TNF-α), interleukin-1 beta (IL-1β), and prostaglandin E2 (PGE2) [1, 64, 66, 70, 71]. PRP injections also provided a significant increase in serum levels of PDGF-A and VEGF [2]. PRP provided an increase in mRNA expression of Type II Collagen and a decrease in mRNA expression of matrix metalloproteinases (MMP-2, -9, and -13) and inflammatory factors such as IL-18, IL-1β, and TNF-α [5]. Moreover, PRP produced a reduction of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway [67].

Large animal models

Out of 12 articles, only 2 (dog and goat) analyzed experimental models of induced OA by a histologic analysis [64, 74]. Similar to small animal models, large animal joints treated with PRP revealed a reduced depth and area of cartilage damage and a lower osteophyte development, in addition to improved characteristics in terms of chondrocyte density and extracellular matrix quality. No study evaluated the effect of PRP on synovial membrane, while the SF analysis demonstrated lower levels of IL-6 and PGE2 in one study [64].

Clinical effects of PRP

Ten studies quantitatively evaluated the effects of PRP on clinical parameters compared to no treatment. Among these, 8 articles (80%) [4, 5, 37, 55, 60, 65, 67, 72] reported better clinical results in both small and large animals in terms of pain relief, symptoms (lameness grades), weight distribution over the hindlimbs, and thermal hyperalgesia protection, while two studies did not demonstrate significant clinical differences between PRP and saline injections [39, 74].

Different PRP formulations and injective protocols

Different types of PRP were compared in 3 studies [4, 37, 71]. In a rat OA model, Araya et al. compared 3 types of PRP: pure PRP (without leukocytes), leukocyte-poor PRP (LP-PRP), and leukocyte-rich PRP (LR-PRP), reporting better results for pure PRP in reducing the progression of cartilage degeneration and preventing synovitis and infrapatellar fat pad fibrotic changes. Animals treated with pure PRP presented a lower density of calcitonin gene-related peptide (CGRP) positive nerve fibers and α-smooth muscle actin (α–SMA) positive cells, suggesting benefits through inhibiting pain sensitization [4]. In a mouse OA model, Jayaram et al. observed improved protection from cartilage volume loss at phase-contrast CT analysis after LP-PRP versus LR-PRP, although the histologic evaluations did not show differences in terms of cartilage degeneration and synovitis. On the other hand, platelet concentrates protected animals from thermal hyperalgesia in a leukocyte concentration-dependent manner, with better results for LR-PRP [37]. Finally, Yin et al. reported that pure PRP administration in a rabbit OA model achieved better outcomes in preventing cartilage destruction and reducing the concentration of pro-inflammatory cytokines IL-1β and PGE2 versus LR-PRP [71].

PRP injection protocols were investigated in 6 studies. Three studies compared the efficacy of single versus 2- or 3-injection protocols, reporting controversial results. Multiple injections provided better results in terms of synovial and total articular scores in a guinea pig early knee OA model and in terms of clinical improvement and biomarker profile in dogs with naturally occurred knee OA [19, 55]. Conversely, Coskun et al. could not demonstrate such differences in a rabbit temporo-mandibular joint OA [20]. Yan et al. investigated different doses of platelet concentrates in a rat knee OA model, showing a dose-dependent efficacy in relieving symptoms and preventing cartilage degeneration [68]. Finally, two studies evaluated different activation methods, showing better results for biophysical activation compared to no activation in dogs, and lower results for irradiated PRP compared to non-irradiated PRP in rats [36, 55].

Comparison with other injectables

Thirteen studies evaluated the efficacy of PRP in comparison to other injectable products. In particular, 4 studies compared PRP injection with adipose-derived MSCs, reporting controversial results. Two studies demonstrated lower results for PRP in terms of macroscopic and histological findings in a rat OA model and in terms of clinical improvement in a RCT on dogs with naturally occurred OA [21, 32]. Conversely, two studies showed similar histological and immunohistochemical results between the two treatments in surgically induced OA models (rats and dogs) [1, 74]. Two studies did not show differences between PRP and muscle-derived MSCs in terms of histologic findings in a rat OA model, and between PRP and blood-derived MSCs in terms of clinical findings in horses with naturally occurred OA [15, 48]. PRP was also compared with BMAC injections, reporting less favorable macroscopic and histological findings in a goat OA model, with the BMAC group showing greater cartilage protection and less extracellular matrix loss compared to the PRP group [64].

PRP efficacy and possible complications were compared with HA in 3 studies (mouse models). Overall, no differences were found in terms of complications. Among these studies, one reported better cartilage quality in animals treated with PRP, one showed similar histological improvement, while one study observed scarce results for both treatments in terms of protective response on cartilage proteoglycan loss or chondrocyte apoptosis, as well as in resolving synovitis [17, 18, 23]. A RCT on dogs with naturally occurred elbow OA compared a single PRP injection to a single injection of HA combined with methylprednisolol showing comparable clinical results up to 24 weeks [29]. Finally, two studies showed similar benefits between PRP injection and avastin or alendronate in OA small animal models (rabbits and rats, respectively) [67, 72].

PRP augmentation

In 5 studies, PRP was combined with MSCs. The combined use of PRP and adipose-derived MSCs showed a synergistic effect in two OA models (rats and dogs, respectively) with higher extracellular matrix synthesis, chondrocyte proliferation, and anti-inflammatory effects [1, 74]. In a rat OA model, the addition of PRP to muscle-derived MSCs significantly improved macroscopic and histologic results of articular cartilage repair, with higher numbers of cells producing Type II Collagen and lower levels of chondrocyte apoptosis [48]. In a rabbit OA model, PRP combined with undifferentiated MSCs or MSCs subjected to chondrogenic differentiation offered better histological results compared to the saline and PRP alone group, although the combined therapy was not compared with cell treatment alone [32]. Conversely, in horses with naturally occurred knee OA, the addition of PRP to blood-derived MSCs did not provide a significant clinical improvement in comparison to MSCs alone [15].

PRP combination with HA was explored in 4 animal models with positive effects versus HA alone in three of these studies (one dog and two mouse OA models): less cartilage damage, reduced matrix degradation and mineralization, and a significant reduction of serum white blood cells and lymphocytes [17, 18, 43]. On the other hand, in the fourth study, the combination with HA did not provide effects in reversing/protecting the pathological events in cartilage and synovium in a mouse post-traumatic OA model [23]. PRP has been also combined with other products or treatments, showing potential synergistic effects with alendronate, CAPE, gelatin hydrogel, Vitamin C, or continuous passive exercise, while it did not demonstrate particular advantages when used with avastin [9, 58, 67, 71, 72, 75].

Study quality assessment

A summary of the risk of bias assessment of all included studies is illustrated in Fig. 4. Due to poor reporting, most items (56%) were viewed as unclear, while low and high risk of bias were observed in 40% and 4% of items, respectively. In assessing the selection bias (items 1–3), 33 studies used a random allocation to the treatment, 27 studies reported similar baseline characteristics between groups, while only 7 studies adequately described the allocation concealment. As for the performance bias assessment (items 4 and 5), no studies clearly described a random housing, while the investigators were blinded from intervention knowledge in only 3 studies. For the detection bias, the outcome assessor was blinded in 22 studies, while only one study reported a random selection of animals for outcome assessment. Low risk of attrition bias was described in 18 studies and low risk of reporting bias was described in 33 studies. Finally, 34 studies were apparently free from other problems. The analysis of risk of bias assessment over time did not show a trend toward improving the quality of the included studies, with low-risk items reported in 41% vs 39% in the most recent half of the papers vs the older ones. There was a 91% agreement between the two authors involved in the evaluation of the risk of bias.

Fig. 4
figure4

Risk of bias assessments for the included studies according to the SYRCLE's risk of bias tool. The bar chart shows the percentage of all studies that met each quality item, scored as “Low risk”, “High risk”, or “Unclear”

Discussion

The main finding of this systematic review is that i.a. PRP injections showed disease-modifying effects in most animal OA models, attenuating the progression of cartilage tissue damage and reducing the inflammatory reaction of the synovial membrane. These effects were confirmed by serum and SF biomarker measurements, revealing changes in cartilage metabolism and inflammatory biomarkers levels, and were also reflected in the clinical improvement of the investigated animals.

This study confirmed the increasing interest in PRP as an injective treatment for OA, with a growing number of animal studies published over time. PRP has gained increasing attention as a promising treatment modality in the management of OA, thanks to its benefits described in the clinical practice in reducing pain and improving joint function [25]. Positive outcomes are attributed to the high concentrations of growth factors, cytokines, and bioactive molecules in PRP. Nevertheless, many controversies around its use are still present due to the large placebo effect attributed to i.a. injections, in particular when associated with new orthobiologic treatment such as PRP [28, 56]. Moreover, there is still limited knowledge regarding its direct and indirect local effects on the joint’s tissues when applied into the joint, and some in vitro findings remain controversial as well.

Several in vitro studies analyzed the effects of PRP on chondrocytes and cartilage tissue, showing various and heterogeneous mechanisms of action, including chondrocyte proliferation, inflammation modulation, and matrix production stimulation [51, 54]. However, recent conflicting results showed that PRP was unable to inhibit the inflammatory response in OA chondrocytes and did not promote their regeneration [57]. Controversies of in vitro studies can be overcome by considering PRP effects in the complexity of the articular joint through in vivo preclinical studies. Most animal studies reported positive effects of PRP on cartilage and chondrocytes in OA models, demonstrating benefits in macroscopic, histological, immunohistochemical, and ultrastructural evaluations. These results could derive from the direct anabolic effect of PRP on cartilage, as well as from the indirect effects of the platelet concentrates in reducing the synovial inflammation, thus positively modulating the joint environment.

The synovial membrane plays an important role in OA pathogenesis [59]. Alterations in the synovial membrane observed in OA joints can result in decreased concentrations of cartilage-protecting factors and in the increased production of factors that contribute to the degradation of the articular matrix and to pain development in OA. Therefore, a considerable part of the symptomatic improvement obtained with PRP injections could likely derive from an interaction between the released bioactive molecules and the synovial tissue. In fact, PRP may significantly enhance HA secretion by synoviocytes and alter synovial angiogenesis to a more balanced status [8]. PRP may also promote the production of hepatocyte growth factor (HGF) by synoviocytes, which is known to limit the inflammatory response within the synovial membrane [11]. These findings were confirmed by the in vivo studies of this systematic review, showing overall positive results with a significant reduction of synovial inflammation and vascularity in animals treated with i.a. PRP injections.

PRP effects on cartilage and synovial membrane are reflected by the biomarker levels detected in serum and SF. Biomarkers can reflect dynamic quantitative changes in joint remodeling and therefore disease progression or response to a specific treatment [13]. Nevertheless, only few animal studies performed biomarker evaluations. The analysis of COMP levels, a cartilage metabolism marker, demonstrated a significant reduction following PRP injection [38]. This finding supports the chondroprotective effect of PRP toward reducing cartilage degradation and OA progression. Biomarker analysis also supported PRP anti-inflammatory effects, with a significant reduction of pro-inflammatory biomarkers such as TNF-α, IL-1β, and PGE2 in the SF [67, 70, 71]. Increasing evidence supports the complex role of PRP in modulating inflammation in the joint environment [53]. In vitro studies supported an attenuation of the inflammatory response largely due to a decrease in the deleterious pro-inflammatory effects of IL-1β [11, 48]. The anti-inflammatory effect may be related to the inhibition of the NF-κB pathway, one of the key pathways involved in OA pathogenesis [62]. This effect may be promoted by the increased production of Insulin-Like Growth Factor 1 (IGF-1) and HGF by synoviocytes, which are potent NF-κB pathway inhibitors [45].

An important observation in the current study is that the anti-inflammatory effect of PRP seems to depend on the presence or absence of leukocytes, one of the most discussed aspects of PRP. Some in vitro experiments reported deleterious effects of leukocytes in PRP, since these cells can release pro-inflammatory and catabolic molecules. PRP with high concentrations of both platelets and leukocytes resulted in vitro in significantly greater synoviocyte death, higher production of pro-inflammatory mediators, and a down-modulation of anti-catabolic mediators, even though it also showed the highest level of growth factors and cytokines and a higher hyaluronan production by synoviocytes compared to LP-PRP [8, 16]. On the other side, while some evidence showed that PRP with a relatively low concentration of platelets and very few leukocytes led to greater cell growth and anabolism [16], other findings showed similar results with respect to platelet-poor plasma, thus suggesting that the lower concentration of platelets in LP-PRP may lead to a significant lower secretion of bioactive molecules and, therefore, to lower overall effects [8].

The few animal studies in this systematic review evaluating the influence of leukocytes reported overall better results for pure-PRP or LP-PRP compared to LR-PRP in terms of prevention of cartilage destruction, preservation of cartilaginous matrix, and reduction of IL-1β and PGE2 concentrations [4, 37, 71]. Nevertheless, Jarayam et al. did not report significant differences in a mouse OA model between LR-PRP and LP-PRP in terms of cartilage degeneration protection and synovitis, while observed better results for LR-PRP in terms of improved latency to response to thermal hyperalgesia [37]. Moreover, even though the preclinical findings seem to favor the use of platelet concentrates without leukocytes, the clinical evidence on the use of different PRP approaches as i.a. injection for OA remains equivocal and still limited. Yaradilmis et al. demonstrated the superiority of LR-PRP in terms of clinical improvement and recurrence rate of symptoms, even though the mild adverse events were lower for LP-PRP [69]. On the other hand, Filardo et al. [27] showed comparable clinical results up to 12 months between the two treatment groups, although a higher number of minor adverse events was observed after the injections in the LR-PRP group also in this study, thus supporting a possible negative role played by leukocytes. Still, the analysis of the SF one week after the injection of LR-PRP did not show an increase in terms of inflammatory cytokines, leaving the task to clearly demonstrate the role of leukocytes in affecting the final clinical results to further clinical high-level studies [47].

Leukocyte presence is currently a debated topic, but PRPs actually differ for several factors. Additional variables include: the use of fresh or freeze-thawed products, the activation by different substances and the timing of activation, which could influence PRP physical state and also the kinetic of growth factors’ release, the number and time interval between injections etc. Even platelet characteristics should be better studied: for example, platelet volume (MPV) could reflect the ‘storage capability’ of platelets: larger MPV could, therefore, mean higher content of bioactive molecules. Unresolved issues related to each of these parameters must be addressed to optimize the use of PRP, starting from the possibility to properly understand what is injected and to compare results of different studies based on PRP properties. To this aim, a coding system with ‘minimum reporting requirements’ have been recently proposed as a tool to help researchers in delineating more precise information [40]. Unfortunately, preclinical literature is still scarce in terms of PRP characterization, with no improvement over time and a lack of proper data also in the most recent studies. This is a major limitation of this field, which urges more efforts toward better PRP characterization, from the cellular to the molecular composition.

This systematic review has several limitations that reflect those of the included studies and their limited quality. These studies focused on different animal models, with different follow-ups and different platelet concentrate characteristics and formulations. Some studies compared PRP vs other treatments, others their combined use, all different scenarios where no focus was often placed on reporting adverse events, while outcomes were evaluated with sereval approaches. This heterogeneity clearly represents the complexity of this field and explains the difficulties in the literature analysis, challenging study comparisons and the understanding of some contradictory results. Moreover, preclinical studies do not exactly represent the unique human pathophysiology, and the biological effects reported in animal OA models might not necessarily occur in humans. Thus, the objective findings documented in terms of disease-modifying effects in animals should be verify with specifically designed studies in the clinical settings with evaluation targeted to quantify changes at the tissue level. Nevertheless, animal models of OA have proven to be similar to human OA, and they could thus be able to partially reproduce the effects of PRP in human OA joints [73]. Finally, animal experiments have an advantage versus human trials in terms of impact of the placebo effect on the study findings, which makes the clinical improvement documented in animals a meaningful outcome of this systematic review. Worthy of notice, 80% of the clinical studies documented a significant clinical improvement, either in terms of lameness grades, weight distribution over the hindlimbs, and thermal hyperalgesia protection, which supports the effect of PRP going beyond the molecular and tissue levels up to meaningful symptomatological benefits.

Further clinical studies are required to confirm these results also in humans, trying to elucidate if the effect of blood derivatives goes beyond a mere symptomatological improvement with changes at the tissue level and, overall, an improvement of joint homeostasis. Moreover, several aspects still need to be investigated in preclinical studies to better understand the mechanism of action of different types of PRP, give more suitable treatment indications, and possibly to optimize the product characteristics and improve the potential of this biological minimally invasive approach for the treatment of cartilage degeneration and OA. Nevertheless, while more studies are needed, the analysis of the current preclinical literature showed overall positive findings and the potential of PRP injections to foster disease-modifying effects in OA joints.

Conclusions

Most animal OA models studying the potential of PRP underlined the disease-modifying effects, with i.a. injections attenuating the progression of cartilage tissue damage, reducing the inflammation of the synovial membrane, and improving clinical outcome. Evidence for the best PRP formulation and injection schedule, as well as for the synergistic effect with other injectable options are still limited and inconsistent. The risk of bias and overall low quality of the published studies warrant further preclinical studies to confirm the available positive findings, as well as high-level human trials to demonstrate whether the disease-modifying effects observed in animal studies also translate when PRP is used in the clinical practice for the treatment of OA.

Availability of data and material

Not applicable.

Code availability

Not applicable.

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Acknowledgements

Authors GF, LDG, LL, JM, MS and TT are members of the Orthobiologics Initiative (ORBIT) by the European Society of Sports Traumatology, Knee Surgery & Arthroscopy (ESSKA).

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Correspondence to Giulia Merli.

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JM is a co-founder of Remedex and received honoraria from Fidia Pharmaceuticals, Horiba, and Macopharma. The manufactures had no role in the redaction of this manuscript of its decision for publication. The other authors declare no conflict of interest.

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Boffa, A., Salerno, M., Merli, G. et al. Platelet-rich plasma injections induce disease-modifying effects in the treatment of osteoarthritis in animal models. Knee Surg Sports Traumatol Arthrosc (2021). https://doi.org/10.1007/s00167-021-06659-9

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Keywords

  • Platelet-rich plasma (PRP)
  • Intra-articular
  • Injection
  • Disease-modifying
  • Osteoarthritis
  • Cartilage