Platelet-rich plasma (PRP) is defined as a platelet-rich concentrate with platelet levels greater than the baseline platelet count in whole blood. This autologous derived substance, also referred to as autologous platelet-derived growth factors (PDGF), platelet gel, platelet-rich concentrate, autogenous platelet gel, plasma rich in growth factors or platelet releasate, has been proposed for the treatment of multiple conditions to enhance healing. Theoretically, these growth factors function as a mitogen for fibroblasts, smooth muscle cells, osteoblasts and vascular endothelial growth factors.1,2 While PRP may work by activating the innate immune response and stimulating tissue anabolism, its precise mechanism of action is still unclear.2 The role that white blood cells (WBCs) may play is particularly unclear, as the immune cells may act as antimicrobial and/or proinflammatory agents. Furthermore, PRP preparations are not standardized and exhibit wide variability in platelet and WBC concentrations and the use of thrombin activators. The way in which variations in PRP composition may impact clinical outcomes is also unclear.3 Mishra et al.4 proposed classifying these types in 3 categories: the presence of WBCs (e.g., leukocyte-rich or -poor), whether the PRP is activated or not, and the concentration of platelets.
A number of factors have contributed to the growing popularity of biologic therapies despite the dearth of high-quality clinical trials supporting their use. Musculoskeletal conditions are both serious and prevalent. Conventional treatment, for the most part, is lacking in success. PRP has the appeal of a simple, minimally invasive treatment with little regulation, which can be easily administered via local injection by clinicians. In addition, the biotechnology companies that manufacture the equipment used to assist in the production of these therapies have conducted nation-wide marketing directly to clinicians and consumers, touting success with high profile professional athletes.
A collection and preparation system is used to collect a small sample of blood at the patient’s point of care or clinical laboratory. The systems used for preparing autologous PDGF are Federal Drug Administration (FDA) approved under the 510(k) process. While the technology to obtain PRP is FDA-approved, PRP itself is currently not indicated for direct injection. Centrifugation of this blood sample separates the denser red cells from the plasma. The plasma components are divided into a buffy coat and an adjacent layer. The buffy coat contains leucocytes and most of the platelets. The adjacent layer of plasma is less rich in platelets and has few leucocytes.5
There are a variety of techniques used to harvest the buffy coat, the adjacent plasma layer, or both. Some methods concentrate the buffy coat further using a "double spin" technique. This process involves a second centrifugation of the supernatant obtained from the initial centrifugation and produces a more concentrated sample. Depending on the method used, the number of platelets in PRP varies between 1 and 9 times that of whole blood. Techniques that produce higher platelet concentrations (e.g., double spin) typically produce higher leucocyte concentrations as well. Hence, PRP is often referred to as leucocyte-rich (LR-PRP) or leucocyte-poor (LP-PRP).6
Some practitioners add exogenous calcium salts to the PRP just prior to administration with the intention of ensuring platelet activation, while others assume that contact with tendon collagen will suffice.7 PRP composition can also differ by donor age, health status, gender and even time of day when collected.8
Administration protocols also vary per type of injury. PRP may be injected using a peppering technique, whereby the PRP is injected with several penetrations of the tendon from a single skin penetration9 or may be injected directly into a joint. Frequency of injections also vary. For tendon conditions, 1 to 4 intratendinous injections are given over 2 weeks. Joint conditions typically have 3 injections given within a 6-month time frame, usually performed 3-4 weeks apart.10 A local anesthetic is often utilized, and an ultrasound (US) may provide guidance. Local anesthetics may compromise the efficacy of the PRP.11 Patients need to refrain from non-steroidal anti-inflammatory medications for 2 weeks prior to harvesting due to the effect on platelet function.12 There are no accepted exercise protocols or return-to-sport guidelines following PRP treatment. The usage of PRP can be broadly separated into 3 categories which will be discussed further: primary treatment for tendinopathies/non-tendon inflammation, surgical augmentation of repairs and primary treatment for osteoarthritis.
Primary Treatment for Tendinopathies/Non-Tendon Inflammation
The evidence regarding PRP treatment of tendinopathies/non-tendon inflammation includes multiple randomized control trials (RCT), as well as systematic reviews with meta-analyses (SR/MA). Typical outcomes are pain relief and functional status. The literature is clustered around usage for the following: lateral epicondylitis (LE), carpal tunnel syndrome (CTS), rotator cuff (RC) tears, plantar fasciitis (PF), Achilles tendinopathy (AT), and patellar tendinopathy (PT).
Andia2 conducted a review of over 1500 patients treated with PRP for tendinopathies in 58 studies, evenly distributed between lower and upper extremities. Six of these were of Level 1 Evidence Quality, mostly utilizing LR-PRP. Given the heterogeneity in tendinopathies and preparation of PRP, they concluded the data was insufficient to make a recommendation for treatment.
A 2014 systematic review (SR) of 19 randomized and quasi-randomized trials of PRP for musculoskeletal soft tissue injuries, involving 1088 participants, noted no difference in clinically important outcomes.13 The quality of these studies was limited by small numbers of participants, non-standardization of treatment preparation and outcome measures that focused on subjective pain scores, rather than more objective measures of tendon tissue healing or improvement in function. Additional limitations were lack of accounting for other confounding factors, such as differentiation between an overuse injury vs. degenerative tendon rupture, and whether or not bursal involvement was present. As previously stated, the role of leukocytes in tendon healing is controversial, but the few randomized trials that differentiated between LR-PRP and LP-PRP suggest that LR-PRP may be more effective in treatment of tendinopathies.14 The evidence, examined in detail below, is insufficient to determine the benefit of PRP on health outcomes for tendinopathies/non-tendon inflammation.
Lateral epicondylitis (LE), commonly known as “tennis elbow”, affects approximately 1-3% of the population with men and women equally represented. An overuse injury is characterized by angiofibroblastic hyperplasia.15 Patients typically complain of pain for 6-12 weeks, but in some cases pain can persist for up to 2 years. Eighty percent recover with no treatment.16 Although self-limiting, this condition still results in disability, lost productivity and health care utilization costs. Conservative efforts include non-steroidal anti-inflammatory drugs, orthotic devices, physical therapy, glucocorticoid injection and extracorporeal shock wave therapy.
The Washington State Health Care Authority17 recently published a comprehensive health technology assessment, in which they examined the efficacy and safety of PRP when used in the patient with recalcitrant LE (> 6 months duration). The authors included 5 RCTs that compared PRP with corticosteroid injection (CS)18-22 and 2 RCTs that compared PRP with anesthetic.9,23 In the short term, neither CS nor local anesthetic differed from PRP regarding pain or function. While in the intermediate term, low quality evidence suggested PRP was superior to CS (P = 0.007) for pain and function, but not local anesthetic (P = 0.08). In the long term, low quality evidence suggested PRP and CS were not different (P = 0.11), but PRP was superior to local anesthetic (P < 0.00001).
Stratification of systematic review/meta-analysis (SR/MA) of 8 RCTs by Mi et al.24 found that treatment with PRP appeared to be more effective than CS at intermediate term (12 weeks) and long term (6 months and 1 year) intervals, whereas CS demonstrated superiority in the short term (2-8 weeks).
Montalvan et al.25 conducted a RCT, which found that 2 US guided PRP injections in 25 patients were no more efficacious than saline injections at 6 and 12 months on either pain score reduction or functional improvement. Mishra et al.9 conducted a RCT of 112 patients with LE comparing LR-PRP and bupivacaine injections, concluding there were no differences in global pain scores at 12 weeks. Schoffl found no significant difference between PRP vs. saline in functional improvement at 3 months in a double-blinded (DB) RCT of 50 patients.26
Linnanmaki et al.27performed a parallel group, randomized, controlled participant- and assessor-blinded study including adults with clinically diagnosed LE. The participants were recruited from a secondary referral center, after not responding to initial nonoperative treatment. One hundred nineteen participants were randomized to receive PRP, saline or autologous blood. Follow-up visits were at 4, 8, 12, 26, and 52 weeks after the injection. The primary outcome measure was improvement in pain, measured with Visual Analog Scale (VAS) in a 0-10 range, without specification as to whether the pain was activity related or at rest, from baseline to 52 weeks. The secondary outcomes were the Disabilities of the Arm, Shoulder and Hand (DASH) score. There were no clinically important differences in the mean VAS pain or DASH scores among the groups at any timepoint. Level of evidence Level II therapeutic study.
One small study looked at PRP as an alternative to operative management. Mayo Clinic28 conducted a non-randomized trial where 15 patients were treated with a series of 2 LR-PRP injections, and 18 patients were treated with surgery. Outcome measures included time to pain-free status, time to full range of motion (ROM), the Mayo Elbow Performance Score (MEPS), and the Oxford Elbow Score (OES). Successful outcomes were observed in 80% of patients treated with PRP and 94% of those treated operatively (P = 0.37). A statistically significant improvement was noted in both time to full ROM (42.3 days for PRP vs. 96.1 days for surgery; P < 0.01) and time to pain-free status (56.2 days for PRP vs. 108.0 days for surgery; P < 0.01). No significant difference was found in return-to-activity rates, overall successful outcomes, MEPS scores, or OES scores.
Overall, the current evidence suggests that PRP may yield some long-term benefits that are not apparent before 6 months, particularly when compared with CS. However, analysis of the quality of evidence is limited by sample size too small to be sufficiently powered and lack of correction for multiple comparisons.
Carpal Tunnel Syndrome
Literature reports comparing 5% Dextrose in Water (D5W), CS and PRP injections with non-surgical management of CTS were systematically reviewed by Lin et al.29 Ten studies with 497 patients comparing 5 treatments (D5W, PRP, splinting, CS, and normal saline (NS)) were included. The main outcome was the standardized mean difference (SMD) of the symptom severity and functional status scales of the Boston Carpal Tunnel Syndrome Questionnaire at 3 months after injections. The results showed that D5W injection was likely to be the best treatment, followed by PRP injection, in terms of clinical effectiveness in providing symptom relief. With respect to functional improvement, splinting ranked higher than PRP and D5W injections. Lastly, CS and saline injections were consistently ranked fourth and fifth in terms of therapeutic effects on symptom severity and functional status. D5W and PRP injections are more effective than splinting and CS or saline injection for relieving the symptoms of CTS. Compared with splinting, D5W and PRP injections do not provide better functional recovery.29
In 2009, the UK National Institute for Health and Clinical Excellence (NICE) stated that current evidence on the safety and efficacy of PRP for tendinopathy is inadequate in quantity and quality (NICE 2013). This was reiterated in recent SRs of the evidence.30
Rotator Cuff Tears
Rotator cuff (RC) tears are a common clinical problem in the geriatric population with rates as high as 80% in those over age 80,31 and debate exists over how to best provide pain relief and restore shoulder function. Treatment options can be broadly divided into non-surgical and surgical, with the majority of patients initially placed on a trial of conservative therapy. A major concern with RC repairs in older patients is decreased vascularity and healing potential of the tendons. With poorer healing, there is an increased risk of re-rupture, and older age is associated with higher rates of failure following repair. For those with irreparable RC tears, low functional demand, or interest in nonoperative management, there are a number of non-surgical treatments to consider, including rehabilitation and injections of CS, hyaluronic acid (HA) and PRP.
Several meta-analyses have been published, but none have focused exclusively on level 1 RCTs until Chen’s work.32 Eighteen Level I studies were evaluated. The VAS scores were significantly improved short term (-0.45 [95% CI, -0.75 to -0.15]; P < 0.01). Sugaya grade IV and V retears in PRP-treated patients were significantly reduced long term (odds ratio [OR], 0.34 [95% CI, 0.20-0.57]; P < 0.01). In PRP-treated patients with multiple tendons torn, there were reduced odds of retears (OR, 0.28 [95% CI, 0.13-0.60]; P < 0.01). Long-term odds of retears were decreased, regardless of leukocyte content (LP-PRP: OR, 0.36 [95% CI, 0.16-0.82]; LR-PRP: OR, 0.32 [95% CI, 0.16-0.65]; all P < 0.05) or usage of gel (non-gel: OR, 0.42 [95% CI, 0.23-0.76]; gel: OR, 0.17 [95% CI, 0.05-0.51]; all P < 0.01). The conclusion was that long-term retear rates were significantly decreased in patients with rotator cuff-related abnormalities who received PRP. Significant improvements in PRP-treated patients were noted for multiple functional outcomes, but none reached their respective minimal clinically important differences. Overall, the results suggest that PRP may positively affect clinical outcomes, but limited data, study heterogeneity, and poor methodological quality hinder firm conclusions.
In their double-blind, RCT of 40 patients (average age 51) with RC tears, Kesikburun et al.33 randomized patients to a single 5-mL injection of either PRP or saline, in addition to a standard 6-week exercise program. At 1-year follow-up, the authors found that PRP was no better than placebo at improving quality of life, pain, disability, and shoulder ROM. In contrast, positive results were reported by Rha et al.34 in their study of 39 patients (average age 45) with tendinosis or partial RC tears. Patients were randomized to either 2 injections of PRP or dry needling spaced 4 weeks apart. At the 6-month follow-up, those treated with PRP had superior results in terms of pain, function, and ROM.
Singh et al.35 conducted a SR/MA study comparing PRP injections and CS injections for plantar fasciopathy (PF). Studies were assessed using the Cochrane Risk of Bias Tool and the Newcastle Ottawa Scale (NOS). The primary endpoint was pain and function score at 3- and 6-month follow-up. Ten studies with a total of 517 patients were included. Seven studies were randomized. Studies reported outcomes using the VAS and American Orthopedic Foot and Ankle Score (AOFAS). At 3-month follow-up, PRP injections were associated with improved VAS scores (standard mean difference [SMD], -0.66; 95% CI, -1.3 to -0.02; p = 0.04) and AOFAS scores (SMD, 1.87; 95% CI, 0.16-3.58; p = 0.03). However, by the 6-month follow-up, there was no difference in VAS score (SMD, -0.66; 95% CI, -1.65 to 0.3; p = 0.17) or AOFAS scores (SMD, 1.69; 95% CI, -1.06 to 4.45; p = 0.23).
Sarah Johnson-Lynn et al.36 randomized 28 patients35 with 6 months or more of magnetic resonance imaging (MRI)-proven PF to PRP or saline. Using the VAS, both treatments resulted in a similar, significant improvement in symptoms at 6 months. Levels of Evidence: Level II.
A larger, randomized trial of 115 patients37 compared CS to PRP using Foot Function Index pain score (FFI). In the control group, FFI pain scores decreased quickly, and then remained stable during follow-up. In the PRP group, FFI pain reduction was more modest, but reached a lower point after 12 months than the control group. After adjusting for baseline differences, the PRP group showed significantly lower pain scores at the 1-year follow-up than the control group (mean difference, 14.4; 95% CI, 3.2-25.6). The number of patients with at least 25% improvement (FFI pain score) between baseline and 12-month follow-up differed significantly between the groups. Of the 46 patients in the PRP group, 39 (84.4%) improved at least 25%, while only 20 (55.6%) of the 36 in the control group showed such an improvement (P = 0.003). The PRP group showed significantly lower FFI disability scores than the control group (mean difference, 12.0; 95% CI, 2.3-21.6).
RCTs of 24 patients with injection of PRP vs. saline into Achilles tendon (AT) demonstrated no significant difference at 3 months in Victorian Institute of Sports Assessment-Achilles (VISA-A) score.38 A 1-year follow-up of 54 patients in a similar trial also found no improvement.39
Patellar tendinopathy is a condition characterized by anterior knee activity related pain, most commonly found in athletes who engage in jumping sports. A well-designed multisite single-blind study randomized 57 athletes with patellar tendinopathy to LR-PRP, LP-PRP, and saline ultrasound guided injections. All participants received 1 injection followed by 6 weeks of supervised rehabilitation training 3 times per week. Study retention was 93% at 12 weeks and 79% after 1 year. Using the outcome measure, Victorian Institute of Sport Assessment-patellar (VISA-P), there was no significant difference in mean change in VISA-P score, pain, or global rating of change among the 3 treatment groups at 12 weeks or any other time point.40 A SR/MA addressed 70 studies of treatment of patellar tendinopathy involving 2530 patients, reported in 22 studies on eccentric exercise, extracorporeal shockwave therapy (ESWT), and PRP. Eccentric exercise therapies obtained the best results (P < 0.05) at short-term (< 6 months, mean 2.7 +/- 0.7 months). However, multiple injections of PRP obtained the best results (P < 0.05), followed by ESWT and eccentric exercise, at long-term follow-up (>/=6 months, mean 15.1 +/- 11.3 months).41
A different SR looked at 15 studies comparing eccentric training, PRP, CS and ESWT. Eccentric training, with or without core stabilization or stretching, improved symptoms by 61% in the VISA-P score with a 95% confidence interval. Results from ESWT demonstrated 54% improvement and PRP studies 55% improvement with similar confidence intervals. Finally, CS injection provided no benefit.42
In summary, findings from RCTs and SR/MA have been mixed and have generally found that PRP did not have a statistically and/or clinically significant impact on pain or functional outcomes. In RCTs that have found significantly improved pain outcomes for PRP injections, important relevancy gaps and study conduct limitations preclude reaching strong conclusions based on their findings. The evidence is insufficient to determine the benefit of PRP on health outcomes for patellar tendinopathy.
Surgical Augmentation of Repairs
The majority of RCTs with surgical repair of RC or AT have not demonstrated any clinically significant benefit.43-46 A MA of 8 Level I or Level II studies of RC surgery comparing preoperative and postoperative risk for retears, as well as, gain in functional outcome showed no statistically significant differences between those treated with PRP and those without such an intervention.47 An additional MA of Level II and Level III studies by Saltzman et al.48 came to similar conclusions. A Cochrane review by Moraes et al.13 on platelet-rich therapies for musculoskeletal soft tissue injuries identified 2 RCTs and 2 quasi-randomized studies (total n = 203 patients) specifically on PRP used in conjunction with anterior cruciate ligament (ACL) reconstruction. Pooled data found no significant difference in International Knee Documentation Committee (IKDC) scores between the PRP and control groups. The evidence is insufficient to determine the benefit of PRP on health outcomes for surgical augmentation of repairs.
Primary Treatment for Osteoarthritis
Osteoarthritis (OA) is a common disease involving joint damage, an inadequate healing response and progressive deterioration of the joint architecture. Presently, intra-articular injections of CS or viscosupplementation with HA remain the mainstay of conservative treatment. The evidence for using PRP for this condition includes multiple RCTs and SRs. Most trials have compared PRP with HA for knee OA, though HA as a comparator is questionable, because the evidence demonstrating the benefit of HA for OA is not robust.
SRs have generally found that PRP was more effective than placebo or HA in reducing pain and improving function. However, SR authors have noted that their findings should be interpreted with caution due to important limitations, including significant statistical heterogeneity, questionable clinical significance, and high risk of bias in study conduct.49 One retrospective study compared PRP to HA in 190 patients between January 2014 and October 2017. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), VAS, and ROM were measured before injection, at 15 days, 6 months, 12 months, and at last follow-up. HA treated patients experienced a higher arthroplasty rate (36.0% vs 5.3%, p < 0.001), lower ROM, worse VAS and WOMAC score, and increased risk of any arthroplasty occurrence (log-rank < 0.001) than PRP patients.49
A 2014 SR of 10 randomized and non-randomized trials of PRP for OA of the knee found intra-articular PRP injections were more effective for pain reduction (mean difference (MD) -2.45; 95% CI -2.92 to -1.98; p value < 0.00001 and MD -2.07; 95% CI -2.59 to -1.55; p value < 0.00001, single and double PRP injections, respectively) compared with placebo at 6 months post injection. Intra-articular PRP injections were compared with HA and showed a statistically significant difference in favor of PRP on pain reduction based on the VAS and numeric rating scale (standardized mean difference -0.92; 95% CI -1.20 to -0.63; p value <0.00001) at 6 months post injection. Almost all trials revealed a high risk of bias.50
A similar SR/MA in 2020 of 18 studies (all level 1) met inclusion criteria, including 811 patients undergoing intra-articular injection with PRP (mean age, 57.6 years) and 797 patients with HA (mean age, 59.3 years). The mean follow-up was 11.1 months for both groups. Mean improvement was significantly higher in the PRP group (44.7%) than the HA group (12.6%) for WOMAC total scores (P < 0.01). Of 11 studies based on the VAS, 6 reported PRP patients to have significantly less pain at latest follow-up when compared with HA patients (P < 0.05). Of 6 studies based on the subjective IKDC outcome score, 3 reported PRP patients to have significantly better scores at latest follow-up when compared with HA patients (P < 0.05). Finally, LP-PRP was associated with significantly better subjective IKDC scores vs. LP-PRP (P < 0.05).51
A recent prospective study compared the efficacy of intra-articular injections of PRP and HA with a control group of NS solution for knee OA. This was a randomized, dose-controlled, placebo-controlled, double-blind, triple-parallel clinical trial. A total of 87 osteoarthritic knees (53 patients) were randomly assigned to 1 of 3 groups receiving 3 weekly injections of either LP-PRP (31 knees), HA (29 knees), or NS (27 knees). WOMAC score and IKDC subjective score were collected at baseline and at 1, 2, 6, and 12 months after treatment. All 3 groups showed statistically significant improvements in both outcome measures at 1 month; however, only the PRP group sustained the significant improvement in both the WOMAC score (63.71 ± 20.67, increased by 21%) and IKDC score (49.93 ± 17.74, increased by 40%) at 12 months. The conclusion was that intra-articular injections of LP-PRP can provide clinically significant functional improvement for at least 1 year in patients with mild to moderate OA of the knee.52
However, evidence is still limited due to overall high risk of bias in previous trials and great variability between studies regarding the number of injections (generally 1 to 4), interval between injections, preparation of the PRP, and volume injected. Furthermore, the typical length of follow up was only 1 year or less. There is also uncertainty regarding whether individuals with less severe OA may benefit more from this intervention compared with individuals with more advanced structural damage. Additionally, it is unclear as to whether LR-PRP or LP-PRP should be utilized, though the latter appears to have an advantage. Larger controlled studies comparing PRP with placebo and alternatives other than HA are needed to determine the efficacy of PRP for knee OA. Further studies are also needed to determine the optimal protocol for delivering PRP. At the present time, the evidence is insufficient to determine the effects of PRP on health outcomes for OA.
Primary Treatment for Chronic Low Back Pain
Low back pain (LBP) is now regarded as the first cause of disability worldwide, causing morbidity and socioeconomic loss.53 Conventional treatments include physical therapy, CS injection, medial bundle branch block (MBBB) and surgery. Intervertebral disc (IVD) degeneration is an important pathogenesis of LBP. Several animal studies have shown that the injection of PRP into degenerated IVDs is effective in restoring structural changes (IVD height) and improving the matrix integrity of degenerated IVDs as evaluated by MRI and histology.54 Recently, a small number of studies have promoted PRP injection as a relatively safe means of treating patients with degenerative disc disease, who have failed other means of managing their LBP. A small number of prospective trials have suggested there may be some benefit to using PRP injection in the treatment of pain or functional decline caused by facet joint arthropathy.55
Forty-seven adults with chronic (≥ 6 months), moderate-to-severe lumbar discogenic pain unresponsive to conservative treatment were randomized to receive intradiscal PRP or contrast agent after provocative diskography. Data on pain, physical function, and participant satisfaction were collected at 1 week, 4 weeks, 8 weeks, 6 months, and 1 year utilizing Functional Rating Index (FRI), Numeric Rating Scale (NRS) for pain, the pain and physical function domains of the 36-item Short Form Health Survey, and the modified North American Spine Society (NASS) Outcome Questionnaire. Over 8 weeks of follow-up, there were statistically significant improvements in the 29 participants who received intradiscal PRP with regards to pain (NRS Best Pain) (P = 0.02), function (FRI) (P = 0.03), and patient satisfaction (NASS Outcome Questionnaire) (P = 0.01) compared with controls.56
A non-randomized comparator study by Bise et al.57 looked at the efficacy of interlaminar computed tomography (CT) guided epidural PRP and CS injections in 60 patients. Utilizing the NRS and for function with the Oswestry Disability Index (ODI) before and 6 weeks after treatment. At 6 weeks there was found to be no statistical difference between the 2 groups.
The American Society of Interventional Pain Physicians reviewed the evidence for PRP usage in LBP. They found Level III evidence for intradiscal injections of PRP, whereas the evidence is considered Level IV for lumbar facet joint, lumbar epidural, and sacroiliac joint injections of PRP, (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis.53 The evidence is insufficient to determine the benefit of PRP on health outcomes for chronic LBP.