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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Arthroscopy. 2021 Mar 17;37(8):2608–2624. doi: 10.1016/j.arthro.2021.03.010

Platelet-Rich Product Supplementation in Rotator Cuff Repair Reduces Retear Rates and Improves Clinical Outcomes: A Meta-Analysis of Randomized Controlled Trials

James M Ryan 1, Casey Imbergamo 1, Suleiman Sudah 2, Greg Kirchner 3, Patricia Greenberg 1, James Monica 1, Charles Gatt 1
PMCID: PMC8349828  NIHMSID: NIHMS1696805  PMID: 33744318

Abstract

Purpose:

The purpose of this study was to conduct a comprehensive systematic review and meta-analysis to investigate the clinical and imaging outcomes of all four types of platelet-rich therapies [pure platelet-rich plasma (P-PRP), leukocyte and platelet-rich plasma (L- PRP), pure platelet-rich fibrin (P-PRF), and leukocyte and platelet-rich fibrin (L-PRF)] in rotator cuff repairs.

Methods:

A systematic literature search was performed to identify RCTs comparing any of the four types of platelet-rich products (PRP) to a control in rotator cuff repair. Data extracted from the studies included retear rates diagnosed with imaging studies, as well as outcome scores such as Constant, American Shoulder and Elbow Surgeons (ASES), University of California Los Angeles (UCLA), Simple Shoulder Test (SST) and visual analog scale (VAS). Meta-analyses compared postoperative outcome scores and retear rates between the control and study groups.

Results:

Seventeen studies were included in the meta-analysis. When pooling data from all studies, retear rate for the treatment group was 19.3%, compared to 25.4% for the control group (odds ratio [OR] 0.59, p =0.0037). When stratified based on PRP type, only P-PRP resulted in a significant reduction in retear rate (OR 0.26, p=0.0005). Overall, treatment with PRP significantly improved Constant scores when compared to controls (mean difference [MD] 2.41, p = 0.0027), as well as VAS scores (MD −0.12, p = 0.0014), and SST scores (MD 0.41, p = 0.0126). There was no significant difference in ASES scores (MD 0.37, p = 0.7762) or UCLA scores (MD 0.76, p = 0.2447) between treatment and controls when pooling data from all studies.

Conclusions:

This analysis demonstrates significant reductions in retear rates when rotator cuff repair is augmented with PRP. P-PRP appears to be the most effective formulation, resulting in significantly improved retear rates and clinical outcome scores when compared with controls.

Introduction

Despite improvements in the surgical techniques and mechanical constructs used in rotator cuff repairs, high failure rates remain an issue. Documented failure rates following rotator cuff repairs are variable, with some studies reporting rates between 29–94%.1–5 Outcomes are dependent on tear size, surgical technique, age of the patient, and amount of fatty infiltration, among other factors. 6 The rates of success following repair have remained far from consistent. This has created a significant need for methods which can be implemented to improve healing in this setting.

It has been demonstrated that, in comparison to healthy tissue, degenerative rotator cuff tissue has significantly decreased microcirculation.7 Additionally, the fibrovascular scar tissue at the tendon-bone interface following rotator cuff repair has been found to be of inferior quality relative to the native enthesis.8,9 This has been postulated to be the underlying cause of decreased healing capability following attempted repair.10 Given this rationale, there has been a great deal of promise placed in strategies to improve long-term outcomes following rotator cuff repair including biologic augmentation of growth factors and cytokines, gene therapy, and stem cell application.11–15

The use of platelet-rich plasma (PRP) is a particular area of interest in orthopedics.5,16 PRP is a biologically active concentrate produced by the centrifugation of whole blood which has been widely studied for its potential use in tissue healing and reconstruction.17–21 Platelets have been found to play an important role in tissue repair and wound healing by releasing numerous growth factors including transformed growth factor b1 (TGF-b1), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF), and insulin-like growth factor type I (IGF-I).22–24 The local release of these growth factors through the implementation of PRP is thought to potentially improve healing following rotator cuff repair. Animal models have found that the use of local growth factors in rotator cuff repairs was associated with accelerated tendon-to-bone remodeling, an increase in tendon attachment strength, and greater formation of new bone, fibrocartilage, and soft tissue.25,26

There are four classifications of PRP: pure platelet-rich plasma (P-PRP), leukocyte- and platelet rich plasma (L- PRP), pure platelet- rich fibrin (P-PRF), and leukocyte- and platelet-rich fibrin (L-PRF).27 In order to categorize platelet products, they are separated according to their leukocyte concentration and presence or absence of solid fibrin architecture. Pure platelet-rich plasma (P-PRP) products are preparations with a low-density fibrin network, existing in the form of a liquid solution or activated gel, devoid of leukocytes. 27 Similarly, leukocyte-and platelet-rich plasma (L-PRP) products also exist in liquid or activated gel form, however these products also contain higher concentrations of leukocytes.27,28 In contrast to plasma products, fibrin products exist exclusively as strong fibrin matrices, which can be handled as solid materials rather than liquids or gels. Within this category exists two subsets of platelet-rich fibrin products: pure platelet-rich fibrin (P-PRF) as well as leukocyte- and platelet-rich fibrin (L-PRF) products.27 Due to the polymerization technique of these platelet-rich fibrin products, the stable matrix allows for an extended continuous release of growth factors for up to 28 days, which was thought to theoretically enhance healing.29 Several systematic reviews have been conducted to evaluate the effects of PRP and PRF following rotator cuff repair, with some suggesting a possible benefit in the healing process, while others fail to show benefits.30–37

The objective of this study was to conduct a comprehensive systematic review and meta-analysis of level I and II studies to investigate the clinical and imaging outcomes of all four types of platelet-rich therapies (P-PRP, L-PRP, P-PRF, and L-PRF) in rotator cuff repairs. We hypothesized that the use of both platelet-rich plasma and fibrin products will improve clinical outcomes and decrease retear rates.

Methods

Search Strategy

A systematic literature search was performed up to June 2019 of the Pubmed (Medline) and Cochrane Library databases. The search was repeated in June 2020. The following keywords were used for the query: “augment”, “matrix”, “plasma”, “platelet”, “rich”, “PRP”, “biologic”, “stem cells”, and “rotator cuff.” The Boolean operators “OR” and “AND” were used as indicated to aid the search. Any studies with the keywords “arthroplasty,” “fracture,” or “revision” were excluded. Additional filters included human studies, adult population, and English language.

Eligibility

Studies were retained for review if they were full text studies published in the English language, human studies of intraoperative platelet-rich plasma augmentation during rotator cuff repair, were randomized controlled trials, and followed patients for a minimum of 12 months. Articles were excluded if they were case reports, case series, cohort studies, reviews, meta-analyses, biomechanical studies, studies that only introduced PRP augmentation postoperatively, or studies that described any other primary or concomitant procedures other than rotator cuff repair.

Study Selection

A flow diagram outlining the process for study selection is presented in Figure I. A total of 651 studies were returned by the original search. After duplicates were removed, the remaining 588 studies were screened based on title and abstract. Eligibility of each study was considered using the aforementioned criteria. Each study deemed eligible from the title and abstract then underwent a full text review by three reviewers independently. Additionally, independent searches and the screening of references of included studies resulted in the addition of three studies. Two of these studies were subsequently excluded due to inadequate follow-up or administration of PRP postoperatively, and one was included in the meta-analysis.

Figure 1:

Figure 1:

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Flow diagram outlining process of study selection

Data Extraction

Each study was reviewed and data was extracted for number of participants, mean follow-up, tear size, and PRP type. Data on surgical outcomes was also extracted, which included retear rate as determined by postoperative ultrasound or magnetic resonance imaging, UCLA shoulder score, Constant-Murley shoulder outcome score, simple shoulder test (SST), the American Shoulder and Elbow shoulder (ASES) score, and visual analog scale (VAS). A retear was defined as Sugaya type IV or V appearance (if provided) or any lack of continuity in the repaired rotator cuff at final follow up.6

Best Evidence Synthesis

Each article’s level of evidence was evaluated with the American Academy of Orthopedic Surgeon’s levels of evidence system. Thirteen RCTs included in this study are Level I evidence, and four are Level II evidence.

Statistical Analysis

All statistical analyses were performed using R: A language and environment for statistical computing (R Foundation for Statistical Computing, Vienna, Austria). More specifically, the “esc”, “metafor”, “meta”, and “rmeta” R packages were used. Primary results were analyzed to compare treatment (PRP/PRF) versus control for: (1) post-operative tendon retear rates, (2) Constant score, (3) visual analog scale (VAS) score for pain, (4) American Shoulder and Elbow Surgeons (ASES) score, (5) Simple Shoulder Test (SST) score, and (6) University of California, Los Angeles (UCLA) score. Continuous outcomes were analyzed as both mean differences (MD) and standardized mean differences (SMD) with 95% confidence intervals (CI), while dichotomous outcomes were analyzed as odds ratios (OR) with 95% CI. Similar to Hurley et al., heterogeneity between studies was quantified using the statistic, where an I2 value of <25% indicated low study heterogeneity and an I2 value of <75% indicated high study heterogeneity.37 Random-effects models were used for all analyses and continuous measure diagnostics included both numeric (AIC, BIC) and visual methods (funnel plots, boxplots). Subgroup analyses were also performed for outcomes where there were more than 3 studies available for (1) leukocyte-rich vs. leukocyte-poor treatment, (2) liquid vs. solid treatment, and (3) more specific treatment types (P- PRP, P-PRF, L-PRP, L-PRF). All p-values are two-sided and a value of < 0.05 was considered statistically significant.

Quality Appraisal

Each study included in this analysis underwent a thorough risk-of-bias assessment to identify factors that may have potentially altered the results. The investigators evaluated each included study and documented their potential for selection bias, performance bias, detection bias, attrition bias, and reporting bias using the Cochrane tool for assessing risk of bias in randomized clinical trials.38

Results

Study Characteristics

All of the included studies were level I or II RCTs.39–55 There were 17 RCTs comparing 553 patients treated with PRP to 551 patients treated with a control. Six studies compared 184 patients treated with leukocyte poor PRP (P-PRP) to 182 treated with a control.43–48 Two studies compared 56 patients treated with leukocyte rich PRP (L-PRP) to 57 treated with a control.39,40 Seven studies compared 257 patients treated with leukocyte poor PRF (P-PRF) to 257 treated with a control.49–55 Two studies compared 56 patients treated with leukocyte rich PRF (L-PRF) to 55 treated with a control.41,42

Overall, 8 studies compared 240 patients treated with a liquid formulation of PRP (L-PRP or P-PRP) to 239 treated with a control39,40,43–48, and 9 studies compared 313 patients treated with a solid formulation of PRF (L-PRF or P-PRF) to 312 treated with a control.41,42,49–55 When categorizing studies by the leukocyte content of the platelet products, 4 studies compared 112 patients treated with a leukocyte rich formulation (L-PRP or L-PRF) to 112 treated with a control39–42, and 13 studies compared 441 patients treated with a leukocyte poor formulation (P-PRP or P-PRF) to 439 treated with a control.43–55 See Table I for a summary of included studies.

Table 1:

Summary of included studies

L-PRP Level of Evidence N Follow up
(Imaging/Clinical)		 Tear size Outcomes Significant difference No significant difference
Randelli et al(2011) 1 53 (26 PRP, 27 control) 24 months <6mm SST, UCLA, Constant scores, strength in ER higher in the treatment group at 3 months postoperatively. No difference after 6, 12, and 24 months. MRI showed no significant difference in the healing rate of the rotator cuff tear. Pain score in the treatment group was lower than the control group at 3, 7, 14, and 30 days after surgery. Pain up to 30 days, SST, UCLA, Constant, ER strength at 3 months Retear rates, SST, UCLA, Constant ER strength beyond 3 months
Zhang et al(2016) 1 60 (30 PRP, 30 control) 12 months >1cm DASH, Constant, VAS, ROM (FF, IR, ER), MRI. No differences in any clinical outcomes between groups, but the retear rate was significantly lower in the PRP group compared to the controls. Retear rates DASH, Constant, VAS, ROM
L-PRF N Follow up Tear size Outcomes Significant difference No significant difference
Zumstein (2016) 1 35 (17 PRP, 18 control) 12 months N/A (mean size 2.14cm PRP, 1.61 control) L-PRF yielded no beneficial effect in clinical outcome, anatomic healing rate, mean postoperative defect size, and tendon quality at 12 months follow-up. Constant score and active flexion at 6mo postoperatively, (neither of these metrics at 12mo latest timepoint) Subjective Shoulder Value, patient satisfaction, VAS, SST, Constant, MRI healing rate
Gumina et al(2012) 1 76 (39 PRP, 37 control) 12 months 2–4 cm No differences in pain or Constant scores. Repair integrity significantly improved compared to control group. Repair integrity/Retear rates Pain, Constant
P-PRP N Follow up Tear size Outcomes Significant difference No significant difference
Auuna et al(2013) 1 28 (14 PRP, 14 control) 12 months / 24 months >5cm No significant difference between PRF and control groups for Constant, DASH, VAS scores. Retear rate similar between groups. None Retear rate, Constant, DASH, VAS
Ebert et al(2017) 1 60 (30 PRP, 30 control) 36 months <2cm No difference in PROM, Constant (although strength subscore differed significantly), or retear rate. Strength subset of Constant score Retear rate, Constant, PROM
Pandey et al (2016) 1 102 (52 PRP, 50 control) 24 months 1–5 cm VAS was better in the PRP group at all time points except for 24 months. For the PRP group, Constant scores were greater at 12 and 24 months, and UCLA scores were significantly higher at 6 and 12 months, but not 24 months. No difference in ASES. Retear in the PRP group was significantly lower than in the control group, significant only for large tears. Retear rates specifically in large tears, VAS at all time points except 24 months, Constant score, UCLA at 6 and 12 months, vascularity ASES Scores, 24 month VAS and UCLA scores
Jo et al(2015) 1 74 (37 PRP, 37 control) 9 months / 12 months 1–5 cm Constant, VAS, ROM, strength, satisfaction, functional scores, retear rate, and change in cross-sectional area. All results were not singificantly different between groups with the exception of retear rate and 12-month difference in cross-sectional area. Retear Rates, cross sectional area of repair Constant, VAS, ROM, Strength, Satisfaction
Jo et al(2013) 1 48(24 PRP, 24 control) 5 years >3cm Retear rate, cross-sectional area, pain, range of motion, muscle strength, overall satisfaction, ASES, Constant, UCLA, DASH, SST, and SPADI scores. The retear rate of the PRP group was significantly lower than the conventional group. Clinical outcomes showed no statistical difference except for the overall function. The change in postoperative CSA was significantly different between the two groups. Retear rates, cross sectional area of repair, overall function Pain, range of motion, muscle strength,
ASES, Constant, UCLA, DASH, SST, and SPADI scores
Malavolta (2018) 2 51 (26 PRP, 25 control) 12 months / 24 months <3cm Retear rate (reported as Sugaya type IV or V), UCLA, Constant, VAS. None of the clinical assessments in either grouP-PRoduced statistically significant differences. The overall number of retears did not differ between groups. None Retear rate (reported as Sugaya type IV or V), UCLA, Constant, VAS
P-PRF N Follow up Tear size Outcomes Significant difference No significant difference
Catricini et al(2011) 1 88 (43 PRP, 45 control) 16 months <3cm There was no statistically significant difference in total Constant score between the two groups. There was no statistically significant difference in MRI tendon score when comparing arthroscopic repair with or without PRFM. None MRI, Constant
Flury et al (2016) 1 120 (60 PRP, 60 control) 24 months N/A (mean size 2.35cm PRP, 2.0cm control) No significant differences in Constant, OSS, ASES, qDASH, EuroQol 5 dimensions. No significant difference in pain between groups. No difference in retear rate between the PRP and control groups. None Constant score, OSS (Oxford Shoulder Score), ASES, DASH, EuroQol 5 dimensions, pain score, MRI or U/S
Rodeo et al(2012) 2 79 (40 PRP, 39 control) 12 months <5cm PRF had no demonstrable effect on tendon healing, tendon vascularity, manual muscle strength, or clinical rating scales. The regression analysis suggested that PRF may have a negative effect on healing. Retear rate; When comparing PRF versus control for each repair type, there was a significantly higher failure rate in the PRF, double-row/transosseousequivalent repairs at 12 weeks ASES, L’Insalata, U/S (no difference in overall intact repair rate between the two groups), vascularity, strength
Ruiz-Moneo et al(2013) 1 63 (32 PRP, 31 control) 12 months All tear sizes
(<1cm to >5cm)		 No differences in rotator cuff healing or improvements in function were observed in the 1-year postsurgical clinical and radiological follow-up assessments. None UCLA, MRI (arthro-MRI)
Walsh et al(2018) 2 76 (38 PRP, 38 control) 6 months / 24 months N/A (mean size
PRP: AP 2.3cm, ML
1.9. Control: AP
2.3, ML 2.1)		 Results showed no benefit from PRPFM used for rotator cuff repair according to the WORC Index, SST, shoulder strength index, MRI assessment. None WORC (Western Ontario RC), SST, shoulder strength index, MRI
Weber et al(2013) 1 60 (30 PRP, 30 control) 3 months / 12 months N/A (mean size 1.77 PRP, 1.72cm control) Platelet-rich fibrin matrix was not shown to significantly improve clinical outcomes or structural integrity. UCLA ROM, VAS, narcotic consumption, SST, ASES, MRI
Márquez (2011) 2 28 (14 PRP, 14 control) 12 months >5cm No significant differences in Constant scores between both groups. No differences were found in the number of re-tears between the study and control groups. None Constant, MRI
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Bias assessment

The risk of bias was found to be high for 6 of 17 (35.5%) studies regarding randomization procedures or allocation concealment (selection bias), and for 12 of 17 (70.6%) studies regarding participant and investigator blinding procedures (performance bias). In 4 of 17 (23.5%) studies, completeness of reported data was unclear because of the lack of either an intention to treat analysis or Consolidated Standards of Reporting Trials statement. The results of the bias assessment are demonstrated in Figure II.

Figure II:

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Bias assessment of included studies

Outcomes

Retear Rates

Retear rates were recorded in all studies. Of the 1,104 patients included in all studies, 1,009 (91.4%) completed postoperative imaging, with 503 patients in study groups and 506 controls. Retears were assessed by MRI in 830 patients (82.3%) and ultrasound in 179 patients (17.7%). When pooling data from all studies, treatment with PRP significantly reduced retear rates in the study population. The retear rate for the treatment group was 19.3%, compared to 25.4% for the control group (OR 0.59, p =0.0037). When stratified based on leukocyte concentration, leukocyte poor PRP resulted in a significant reduction in retear rate (OR 0.61, p = 0.0146) while leukocyte rich PRP did not (p=0.16). When stratified based on liquid and solid formulations, liquid formulations of PRP resulted in a reduction in retear rate (OR 0.32, p=0.0003), while solid formulations did not (p=0.46). When further stratified based on PRP type, only P-PRP resulted in a significant reduction in retear rate (OR 0.26, p=0.0005), while P-PRF, L-PRP, and L-PRF did not (p=0.63, p=0.25, p=0.60, respectively). See Figure III for analysis of retear rates.

Figure III:

Figure III:

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Analysis of retear rates

Constant Score

Constant scores were reported in 11 studies, comparing 382 patients to 381 controls. Two studies compared 56 patients treated with leukocyte rich PRP (L-PRP) to 57 treated with a control. One study compared 39 patients treated with leukocyte rich PRF (L-PRF) to 37 treated with a control. Five studies compared 170 patients treated with leukocyte poor PRP (P-PRP) to 168 treated with a control. Three studies compared 117 patients treated with leukocyte poor PRF (P-PRF) to 119 treated with a control.

Overall, 7 studies compared 226 patients treated with a liquid formulation of PRP (L-PRP or P-PRP) to 225 treated with a control, and 4 studies compared 156 patients treated with a solid formulation of PRF (L-PRF or P-PRF) to 156 treated with a control. When categorizing studies by the leukocyte content of the platelet products, 3 studies compared 95 patients treated with a leukocyte rich formulation (L-PRP or L-PRF) to 94 treated with a control, and 8 studies compared 287 patients treated with a leukocyte poor formulation (P-PRP or P-PRF) to 287 treated with a control.

When pooling data from all studies, treatment with PRP significantly improved Constant scores [(MD 2.41 [95% CI, 0.83–3.98]; I2 = 36.01%; p = 0.0027), (SMD 0.28, [95% CI, 0.09–0.47]; I2 = 40.12%; p = 0.0047)]. When stratified based on leukocyte concentration, leukocyte rich PRP resulted in significantly improved Constant scores [(MD 2.98 [95% CI, 1.01–4.94]; I2 = 0%; p = 0.003), (SMD 0.42 [95% CI, 0.12–0.71]; I2 = 0%; p = 0.0054)], while leukocyte poor PRP did not significantly affect Constant scores [(MD 2.11 [95% CI, −0.06–4.29]; I2 = 44.62%; p = 0.0567), (SMD 0.23 [95% CI, −0.01–0.47]; I2 = 47.59%; p = 0.0607)].

When stratified based on liquid and solid formulations, liquid PRP resulted in significantly improved Constant scores [(MD 3.25 [95% CI, 1.32–5.18]; I2 = 22.45%; p = 0.0009), (SMD 0.35 [95% CI, 0.11–0.58, I2 33.61%;p=0.0039)] while solid PRP did not [(MD 1.34 [95% CI, −1.18–3.87]; I2 = 44.57%; p = 0.1863),(SMD 0.17 [95% CI −0.16–0.50, I2 48.2%;p=0.3156)]

When further stratified based on PRP type, only P-PRP resulted in a significantly improved Constant score [(MD 3.73 [95% CI, 1.36–6.10]; I2 = 21.76%; p = 0.002), (SMD 0.36 [95% CI, 0.05–0.67]; I2 = 48.2%; p = 0.0219)], while P-PRF [(MD −0.04 [95% CI, −2.32–2.25]; I2 = 0%; p = 0.9738), (SMD 0.00 [95% CI, −0.26–0.27]; I2 = 0%; p = 0.9711)] and L-PRP did not [(MD 2.10 [95% CI, −0.82–5.02]; I2 = 0%; p = 0.1583), (SMD 0.28 [95% CI, −0.11–0.66]; I2 = 0%; p = 0.1569)]. See Figure IV for analysis of Constant scores.

Figure IV:

Figure IV:

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Analysis of Constant scores

VAS Score

VAS Scores were reported in 5 studies, comparing 170 patients to 168 controls. One study compared 30 patients treated with leukocyte rich PRP (L-PRP) to 30 treated with a control, and 4 studies compared 140 patients treated with leukocyte poor PRP (P-PRP) to 138 treated with a control. All five studies utilized a liquid formulation of PRP (L-PRP or P-PRP).

When pooling data from all studies, treatment with PRP significantly improved VAS score compared to controls [(MD −0.12 [95% CI, −0.19- −0.05; I2 = 0.03%; p = 0.0014), (SMD −0.36 [95% CI, −0.57- −0.14; I2 = 0%; p = 0.0012)]. When stratified based on leukocyte concentration, P-PRP resulted in a significantly improved VAS score compared to controls [(MD −0.19 [95% CI, −0.36- −0.03; I2 = 0%; p = 0.0218), (SMD −0.30 [95% CI, −0.54- −0.06; I2 = 0%; p = 0.013)]. When stratified based on PRP type, P-PRP resulted in a significantly improved VAS score compared to controls [(MD −0.19 [95% CI, −0.36- −0.03; I2 = 0%; p = 0.0218), (SMD −0.30 [95% CI, −0.54- −0.06; I2 = 0%; p = 0.013)]. See Figure V for analysis of VAS scores.

Figure V:

Figure V:

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Analysis of VAS scores

ASES Score

ASES Scores were reported in 6 studies, comparing 243 patients to 240 controls. Three studies each compared 113 patients treated with P-PRP to 111 patients treated with a control, and 130 patients treated with P-PRF to 129 patients treated with a control. Notably, all six studies utilized leukocyte poor products.

When pooling data from all studies, there was no significant difference in ASES scores between treatment and controls. [(MD 0.37 [95% CI, −2.20 – 2.95; I2 = 40.86%; p = 0.7762), (SMD 0.07 [95% CI, −0.17– 0.30; I2 = 30.78%; p = 0.5846)]. When stratifying based on leukocyte concentration, there was no significant difference based on PRP composition [(MD 0.37 [95% CI, −2.20 – 2.95; I2 = 40.86%; p = 0.7762), (SMD 0.07 [95% CI, −0.17– 0.30; I2 = 30.78%; p = 5846)]. When stratified based on liquid or solid formulations, liquid PRP resulted in significantly improved ASES scores when compared to controls [(MD 2.17 [95% CI, 0.06 – 4.29; I2 = 0%; p = 0.0439), (SMD 0.28 [95% CI, 0.02 – 0.55; I2 = 0%; p = 0.0346)], while solid formulations did not [(MD −1.99 [95% CI, −5.23 – 1.25; I2 = 19.82%; p = 0.2293), (SMD −0.17 [95% CI, −0.50 - −0.16; I2 = 27.03%; p = 0.3213)]. When stratified based on PRP type, P-PRP resulted in significantly improved ASES scores when compared to controls [(MD 2.17 [95% CI, 0.06 – 4.29; I2 = 0%; p = 0.0439), (SMD 0.28 [95% CI, 0.02 – 0.55; I2 = 0%; p = 0.0346)] while P-PRF did not [(MD −1.99 [95% CI, −5.23 – 1.25; I2 = 19.82%; p = 0.2293), (SMD −0.17 [95% CI, −0.50 - −0.16; I2 = 27.03%; p = 0.3213)]. See Figure VI for analysis of ASES scores.

Figure VI:

Figure VI:

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Analysis of ASES scores

SST

SST Scores were reported in 4 studies, comparing 126 patients to 125 controls. One study each compared 26 patients treated with leukocyte rich PRP (L-PRP) to 27 treated with a control, and 39 patients treated with leukocyte rich PRF (L-PRF) to 37 treated with a control. Two studies compared 61 patients treated with P-PRP to 61 treated with a control. Overall, 3 studies compared 87 patients treated with a liquid formulation of PRP (L-PRP or P-PRP) to 88 treated with a control, and one study compared 39 patients treated with a solid formulation of PRF (L-PRF) to 37 treated with a control. When categorizing studies by the leukocyte content of the platelet products, 2 studies compared 65 patients treated with a leukocyte rich formulation (L-PRF or L-PRF) to 64 treated with a control, and 2 studies compared 61 patients treated with a leukocyte poor formulation (P-PRP) to 61 treated with a control.

When pooling data from all studies, treatment with PRP resulted in significantly improved SST scores when compared to controls [(MD 0.41 [95% CI, 0.09 – 0.73; I2 = 0%; p = 0.0126), (SMD 0.30 [95% CI, 0.04 – 0.55; I2 = 0%; p = 0.0212)]. When stratified based on leukocyte concentration, leukocyte rich PRP resulted in improved SST scores when compared to controls [(MD 0.40 [95% CI, 0.05 – 0.75; I2 = 0%; p = 0.0254), (SMD 0.40 [95% CI, 0.04 – 0.76; I2 = 0%; p = 0.0299)], while leukocyte poor PRP did not [(MD 0.47 [95% CI, −0.36 – 1.30; I2 = 0%; p = 0.2642), (SMD 0.20 [95% CI, −0.16 – 0.55; I2 = 0%; p = 0.2737)]. When stratified based on liquid or solid concentration, liquid PRP did not result in any statistically significant differences in SST when compared to controls [(MD 0.43 [95% CI, −0.10 – 0.96; I2 = 0%; p = 0.1109), (SMD 0.23 [95% CI, −0.07 – 0.54; I2 = 0%; p = 0.1312)]. When stratified based on PRP type, P-PRP did not result in statistically significant differences in SST when compared to controls [(MD 0.47 [95% CI, −0.36 – 1.30; I2 = 0%; p = 0.2642), (SMD 0.20 [95% CI, −0.16 – 0.55; I2 = 0%; p = 0.2737)] See Figure VII for analysis of SST scores.

Figure VII:

Figure VII:

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Analysis of SST scores

UCLA Score

UCLA Scores were reported in 7 studies, comparing 228 patients to 226 controls. One study compared 26 patients treated with leukocyte rich PRP (L-PRP) to 27 treated with a control. Four studies compared 140 patients treated with leukocyte poor PRP (P-PRP) to 138 treated with a control. Two studies compared 62 patients treated with leukocyte poor PRF (P-PRF) to 61 treated with a control. Overall, 5 studies compared 166 patients treated with a liquid formulation of PRP (L-PRP or P-PRP) to 165 treated with a control, and 2 studies compared 62 patients treated with a solid formulation of PRF (P-PRF) to 61 treated with a control. When categorizing studies by the leukocyte content of the platelet products, 1 study compared 26 patients treated with a leukocyte rich formulation (L-PRP) to 27 treated with a control, and 5 studies compared 202 patients treated with a leukocyte poor formulation (P-PRP or P-PRF) to 201 treated with a control.

When pooling data from all studies, there was no significant difference in UCLA scores between treatment and controls. [(MD 0.76 [95% CI, −0.52 – 2.04; I2 = 64.18%; p = 0.2447), (SMD 0.21 [95% CI, −0.16 – 0.58; I2 = 72.68%; p = 0.2616)]. When stratifying based on leukocyte concentration, treatment with leukocyte poor PRP provided no significant difference when compared to controls [(MD 0.51 [95% CI, −0.94 – 1.97; I2 = 66.16%; p = 0.4907), (SMD 0.15 [95% CI, −0.26 – 0.56; I2 = 75.39%; p = 0.4654)]. When stratified based on liquid or solid formulations, liquid PRP resulted in significantly improved UCLA scores when compared to controls [(MD 1.56 [95% CI, 0.49 – 2.63; I2 = 38.96%; p = 0.0044), (SMD 0.40 [95% CI, 0.02 – 0.79; I2 = 65.11%; p = 0.04)], while solid formulations did not [(MD −1.42 [95% CI, −3.11 – 0.27; I2 = 0%; p = 0.0991), (SMD −0.25 [95% CI, −0.61 – 0.10; I2 = 0%; p = 0.1647)]. When stratified based on PRP type, neither P-PRP nor P-PRF resulted in significantly improved UCLA scores when compared to controls [(MD 1.35 [95% CI, −0.04 – 2.73; I2 = 51.37%; p = 0.057), (SMD 0.36 [95% CI, −0.11 – 0.83; I2 = 72.98%; p = 0.1381)] and [(MD −1.42 [95% CI, −3.11 – 0.27; I2 = 0%; p = 0.0991), (SMD −0.25 [95% CI, −0.61 – 0.10; I2 = 0%; p = 0.1647)], respectively. See Figure VIII for analysis of UCLA scores.

Figure VIII:

Figure VIII:

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Analysis of UCLA scores

Discussion

This study demonstrates that augmenting rotator cuff repair with PRP at the time of surgery may result in significantly fewer retears, while also providing benefits in clinical outcome scores. This study stratified pooled data based on leukocyte concentration, liquid and solid formulation, and all four types of PRP (P-PRP, P-PRF, L-PRP, L-PRF). In doing so, our results demonstrate that P-PRP appears to be the optimal formulation for use in rotator cuff repair. While it is possible that there may be a potential benefit to utilizing various types of platelet-rich products, P-PRP was found to yield the most consistently positive outcomes of the metrics analyzed.

It should be noted that only four trials included in the analysis utilized leukocyte-rich products, and the sample size of patients receiving L-PRP or L-PRF (n=112) may have been too small to accurately reflect potential differences in outcomes between treatment and control groups, particularly in retear rates. For a number of the clinical outcome measures, no sub-analyses could successfully be completed for leukocyte-rich products, as a limited number of studies had complete information. However, it was found that leukocyte-rich products yielded significant differences in Constant and STT scores, while leukocyte-poor products did not. This can likely be attributed to the poorer outcomes of P-PRF diminishing the positive impact of P-PRP when only examining leukocyte concentration.

When stratified by liquid or solid formulations of PRP, it was found that liquid formulations (P-PRP and L-PRP) yielded significant improvements in retear rate, as well as VAS, ASES, UCLA scores, and Constant scores, while solid formulations (P-PRF and L-PRF) did not. However, it should be noted that the effects of the liquid formulations appear to be attributable to P-PRP rather than L-PRP. A previous meta-analysis of PRP in arthroscopic rotator cuff repair by Hurley et al. also found no evidence to support the use of PRF in arthroscopic rotator cuff repair.37

Despite the theoretical advantage of containing growth factors for longer periods of time in the fibrin meshwork, it has been hypothesized that because the solid fibrin product must be sutured in, a space-occupying effect may result in a gap between the tendon and bone after the fibrin dissolves.51

Heterogeneity between studies was quantified using the I2 statistic.56 We chose an I2 value of <25% to represent low heterogeneity and an I2 value of >75% to indicate high heterogeneity, with values in between indicating moderate heterogeneity. When pooling data from all studies, there was found to be moderate heterogeneity among Constant scores, however when stratified by leukocyte-rich formulations, the heterogeneity was found to be low. VAS, ASES, and SST scores all exhibited low heterogeneity, suggesting consistent effects throughout the included studies. Notably, UCLA scores exhibited the highest level of heterogeneity of the metrics analyzed. When pooling the data from all studies, the I2 value was found to be 64.18%, and when stratified by leukocyte-poor formulations, it was 66.16%. While the I2 values for UCLA scores did not meet criteria to be considered high heterogeneity, they were notably greater than those of the other clinical outcome measures. Given the considerable heterogeneity among the studies included in this analysis, and it is recommended that additional high-quality studies continue to be done.

Hurley et al. was the first large meta-analysis to report that PRP was associated with an improvement in tendon healing rates in medium-large (>3 cm) rotator cuff tears, while previous studies have only reported a significant difference in tears <3 cm.30,35,37,57 Notably, the authors found that the use of PRP improved tendon healing rates in tears of all sizes, pain levels, and functional outcomes in rotator cuff repair.37 Additionally, two studies by Jo et al. utilized interstudy protocols to compare the effect of P-PRP on medium to large tears and again on large to massive tears.46,47 They found significant reductions in retears in both RCTs, indicating that P-PRP may be beneficial regardless of tear size. Contrarily, a meta-analysis by Warth et al. looked at PRP supplementation in arthroscopic repair of full-thickness rotator cuff tears, and found no statistically significant differences between the PRP and control groups for overall outcome scores or retear rates. However, a notable finding was that Constant scores increased significantly when PRP was applied at the tendon-bone interface, compared to application over the top of the repaired tendon.34 This finding may offer potential insight regarding the optimal placement of PRP in rotator cuff repairs.

Subgroup analysis in the included RCT by Flury et al. examining P-PRP in arthroscopic rotator cuff repair, found smoking status to be a significant effect modifier associated with a reduction in the effect of PRP based on the Oxford Shoulder Scores at 6 months postoperatively.50 This negative effect of smoking, and nicotine specifically, on the biology of tendinous cells and tendon healing is a topic which should be explored further in patients receiving PRP for rotator cuff repairs.

A 2015 meta-analysis by Yang et al. also explored the use of PRP in rotator cuff repairs. This study included eight randomized controlled trials, all of which were encompassed in the present meta-analysis. In contrast to the present findings, the meta-analysis by Yang et al. found there to be no significant difference in retear rate between the PRP and non-PRP groups. With the exception of this notable difference between the two studies, the analyses of clinical outcome measures yielded similar results. Yang et al. reported that there were improvements in Constant, SST, and VAS scores between the PRP and non-PRP groups, while there were no significant differences in ASES or UCLA scores. These conclusions mirror those of the current study. However, it appears that the additional nine studies included in the present meta-analysis resulted in the key difference of a statistically significant reduction in retear rate.

The platelet-rich products utilized in the studies included in this analysis were stratified according to their leukocyte content and fibrin architecture. Leukocytes in platelet-rich products are involved in the regulation of the healing process, as they are able to increase the production of growth factors, release anti-pain mediators, and promote natural anti-infectious activity.59,60 Others hypothesize that leukocytes may have a negative effect on healing, due to the potential risk of stimulation of the inflammatory process after the injection in a wounded site.61 Currently, it has not been definitively established whether there is a difference in efficacy between leukocyte-rich or leukocyte-poor platelet-rich products in augmenting the healing process of rotator cuff tendon. This analysis suggests a concentrate with lower leukocyte concentration is optimal for rotator cuff healing.

Limitations

This meta-analysis has multiple limitations. Notably, any meta-analysis possesses the potential for selection bias, performance bias, detection bias, attrition bias, and reporting bias. A thorough risk-of-bias assessment was performed to aid in data interpretation, detailed above in Figure II.

While all included studies followed patients for at least 12 months, some included studies performed final imaging prior to this timepoint, ranging from 3–9 months. Longer term follow up would be beneficial. Additionally, there are theoretical limitations to using the Constant score as one of the outcomes analyzed in this study. While this score has been widely reported in the literature for use in rotator cuff disease, it has not been specifically validated for this purpose.34 Additionally, statistically significant improvements in outcome scores do not always confer clinical significance.

An important confounding factor that may have affected the results is the lack of standardization in the operative technique amongst studies. There were various surgical techniques implemented across the studies, which in itself is likely to create variability in outcomes. Additionally, there was an inability to stratify tear sizes, as most studies used a combination of multiple tear sizes. Due to the underreporting of all variables across the studies, it was not possible to account for a multitude of factors, which may have potentially affected outcomes. There were also variations in the platelet count, leukocyte count, and growth factor concentration of the PRP, which was dependent on the preparation technique. Also, as stated previously, the outcome measures may be insufficiently powered in the leukocyte-rich (L-PRP and L-PRF) groups, as there were only 112 patients analyzed in the treatment group. The limited number of studies and lack of complete information resulted in the inability to complete sub-analyses for these groups. While it is important to consider these study limitations, we believe that they were not significant enough to nullify the conclusions drawn from this analysis.

Conclusion

This analysis demonstrates significant reductions in retear rates when rotator cuff repair is augmented with PRP. P-PRP appears to be the most effective formulation, resulting in significantly improved retear rates and clinical outcome scores when compared with controls.

Supplementary Material

1

Footnotes

Social media handle for Rutgers Robert Wood Johnson Medical School: Instagram: RutgersRWJOrtho

Level of Evidence: Level II, meta-analysis of Level I and Level II studies

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