Abstract
Background:
Platelet-rich plasma (PRP) has been studied with the objective of reducing the retear rate and improving functional outcomes after rotator cuff repair. Only one study to date has reported its midterm effect.
Hypothesis:
PRP promotes better functional and structural results in arthroscopic rotator cuff repair.
Study Design:
Randomized controlled trial; Level of evidence, 2.
Methods:
All patients underwent arthroscopic single-row repair of small to medium supraspinatus tears. At the end of the surgical procedure, liquid PRP prepared by apheresis with autologous thrombin was applied in the tendon-to-bone interface in the PRP group. The outcomes were assessed by the University of California, Los Angeles (UCLA) and Constant scales and the visual analog scale (VAS) for pain at 6, 12, 24, and 60 months after surgery and magnetic resonance imaging at 12 and 60 months.
Results:
Of 54 patients initially randomized, we analyzed the clinical outcomes in 51 (25 control, 26 PRP) and the structural outcomes in 44 (22 each group). At 60-month follow-up, the mean UCLA scores were 32.5 ± 3.8 and 32.1 ± 4.6 in the control and PRP groups, respectively (P = .992). The mean Constant scores were 82.0 ± 9.5 in the control group and 82.1 ± 11.0 in the PRP group (P = .699). The mean VAS scores were 1.4 ± 1.8 and 1.5 ± 2.1 in the control and PRP groups, respectively (P = .910). None of the clinical assessments at 6, 12, and 24 months in either group produced statistically significant differences, and both groups showed significant improvements throughout the follow-up time in the 3 evaluations (P < .001). The control group exhibited 1 full-thickness retear (Sugaya type IV) and 11 partial-thickness retears (Sugaya type III), while the PRP group had 7 partial-thickness retears (Sugaya type III). The overall number of retears did not differ between groups (P = .203).
Conclusion:
PRP obtained by apheresis and applied in liquid form with the addition of thrombin at the end of single-row repair of supraspinatus tears did not promote better clinical or structural results at 60-month follow-up.
Registration:
NCT01029574 (ClinicalTrials.gov identifier)
Keywords
Rotator cuff repair promotes significant clinical improvement. However, a retear occurs in approximately 27% of cases. 28 Deficiency in tendon-to-bone healing is an important cause of the occurrence of retears.5,16 After surgery, the tendon does not return to its original characteristics, and its fixation occurs through scar tissue 33 with lower biomechanical resistance. 17
Platelet-rich plasma (PRP) is a volume of autologous plasma with platelet concentrations above baseline levels and is rich in growth factors, 14 substances that play a key role in the healing process. PRP has been studied with the objective of reducing the retear rate and improving functional outcomes after rotator cuff repair. The basic research is consistent in demonstrating the effectiveness of PRP in rotator cuff repair. 2 However, comparative clinical studies have demonstrated conflicting results. ‡ Even systematic reviews do not point to a consensus, and the results are described as both favorable 6 and unfavorable 40 for the use of PRP in rotator cuff repair; additionally, the cost-effectiveness of the procedure has not yet proven favorable. 38
Most of the comparative studies published so far on the use of PRP in rotator cuff repair have reported structural results after 12 or 24 months. § Only Ebert et al, 12 in a recently published article, performed a midterm evaluation, with magnetic resonance imaging (MRI) performed at 42 months after surgery. The objective of this study was to evaluate the clinical and structural effects of PRP on arthroscopic rotator cuff repair 60 months after surgery.
Methods
We conducted a single-center, prospective, 1:1 randomized, parallel, therapeutic clinical trial in which both the participants and the examiners were blinded. The study was approved by the local research ethics committee. The study was registered and approved by the National Institutes of Health (ClinicalTrials.gov identifier: NCT01029574).
Of 54 patients described in a previous study, 27 51 returned for a clinical evaluation and 44 for imaging 60 months after the surgical procedure. The methods described in this section are the same as those used previously, 27 with the exception of the midterm evaluation, at 60 months. The surgical procedures were performed between September 2008 and April 2012. The patients maintained regular follow-ups at our outpatient clinic.
Participants
The inclusion criteria were as follows: complete supraspinatus tears confirmed by MRI without a history of trauma and retraction of less than 3 cm. Cases with tears in other tendons, fatty degeneration (grade 3 on the Fuchs scale 15 ), glenohumeral arthrosis, previous shoulder surgery, psychiatric or rheumatological diseases, fibromyalgia, spine diseases, or platelet counts lower than 150,000/mm3 were excluded. Participants were also excluded when the following were observed during surgery: subscapularis tears requiring repair, infraspinatus tears, not fully reparable tears, or the need to convert to open surgery.
PRP Preparation
PRP was prepared after anesthesia to ensure appropriate blinding. The MCS1 9000 blood cell separator and 994-CFE apheresis set (Haemonetics) were used to prepare PRP. Approximately 400 mL of blood was directed through peripheral access to the continuous blood cell separation device at 5800 rpm for 15 minutes. Sodium citrate (10%) was used as an anticoagulation agent. The device used in the present study can separate approximately 40 mL of PRP. Platelet-poor plasma (~360 mL) was returned to the participants using the same peripheral access. Autologous thrombin was prepared using 10 mL of PRP and 0.4 mL of 10% calcium chloride. After gel formation, the thrombin-rich supernatant was collected. The material needed for the later application of activated PRP was placed in syringes: two 10-mL aliquots of PRP as well as 2 fractions of thrombin and 10% calcium chloride (1.5 and 0.8 mL, respectively). This method provided a mean platelet concentration of 1,185,166/mm3 ± 404,472/mm3, representing an increase of 7.65 times (range, 3.82-26.03) the baseline level, and a mean white blood cell concentration of 0.91/mm3 ± 0.81/mm3. 10
Surgical Procedure
The same surgeon (E.A.M.) performed all 54 surgical procedures. Surgery was performed with the participants in the beach-chair position under general anesthesia and interscalene block. Acromioplasty was performed in all cases, as was debridement without decortication of the greater tuberosity. Single-row repair was performed with absorbable double-loaded suture anchors (Twinfix; Smith & Nephew) and simple stitches. The number of anchors and the need for additional side-to-side sutures were decided at surgery. Procedures on the biceps tendon were performed in cases with partial tears, subluxations, and complete dislocations. Tenotomy was performed in patients older than 60 years and tenodesis in younger patients. Whenever needed, biceps tenodesis was performed with 1 of the anterior suture anchors above the rotator cuff.
PRP Application
In the PRP group, the arthroscopic portals were sutured after the end of the surgical procedure, with the exception of the posterior portal, which was left open to provide visibility. A 14-gauge intravenous catheter (Jelco) was introduced through an area covered by intact skin, that is, not through any portal. The needle entry site was located between the anterior and lateral portals. The needle was placed at the tendon-to-bone interface. Next, the infusion of normal saline solution was interrupted, and the fluid remaining in the subacromial space was aspirated. Subsequently, the platelet concentrate was applied. Ten milliliters of the collected PRP was mixed with 1.5 mL of the previously prepared autologous thrombin and 0.8 mL of 10% calcium chloride and injected in liquid form through the needle positioned as described above. A total volume of 24.6 mL was applied, comprising 20 mL of PRP, 3 mL of thrombin, and 1.6 mL of calcium chloride. An assistant blocked the sutured portals with his fingers to minimize leakage of the injected material. The technique used in the present study to apply PRP was based on that of Randelli et al. 32 The assistant stopped blocking the portals 5 minutes after the application of PRP. Finally, the posterior portal was closed using the same technique as used previously.
Rehabilitation
The analgesic regimen was standardized for all patients. During the hospital stay, the participants were given intravenous medication comprising 1 analgesic agent (2 g dipyrone every 6 hours), 1 nonsteroidal anti-inflammatory drug (NSAID) (100 mg ketoprofen every 12 hours), and 1 opioid analgesic agent (100 mg tramadol every 8 hours). After discharge, medication was prescribed per the oral route, comprising 1 NSAID (200 mg celecoxib every 12 hours) and 1 analgesic agent (500 mg acetaminophen every 6 hours) on a continuous basis and 1 opioid analgesic agent (30 mg codeine every 6 hours) to be taken in case of very severe pain. The standardized analgesic regimen was indicated for 7 days and subsequently modified on an individual basis. The shoulder was immobilized for 6 weeks. No motion was allowed during the first 3 weeks; passive exercise was permitted thereafter. Active-assisted and active-free exercises were started after week 6, when sling use was discontinued. Muscle strengthening was started at week 12.
Outcomes
A functional assessment, as performed with the University of California, Los Angeles (UCLA) shoulder rating scale, was the primary outcome. The secondary outcomes included a functional assessment according to the Constant shoulder scale, pain as measured by the visual analog scale (VAS), and retear rate assessed by MRI. All the clinical analyses were performed at 60 months, in addition to the previous publication data (before surgery and 3, 6, 12, and 24 months afterward). The number of complications was also assessed.
MRI was performed using a 1.5-T magnet (Signa HDxT; GE Healthcare) with a dedicated shoulder coil. The shoulder imaging protocol included oblique coronal proton density–weighted images (repetition time/echo time [TR/TE], 2800/38 milliseconds; field of view [FOV], 14 cm; slice thickness, 3.5 mm; intersection gap, 0.4 mm; matrix, 320 × 256); axial, oblique coronal, and oblique sagittal fat-suppressed T2-weighted images (TR/TE, 3400/50 milliseconds; FOV, 14 cm; slice thickness, 3.5 mm; intersection gap, 0.4 mm; matrix, 256 × 256); and oblique sagittal T1-weighted images (TR/TE, 780/15 milliseconds; FOV, 14 cm; slice thickness, 3.5 mm; intersection gap, 0.4 mm; matrix, 320 × 256). Neither intra-articular nor intravenous gadolinium was used for any of the examinations. The images were analyzed by a musculoskeletal radiologist with 17 years of experience (M.B.-R.). The MRI scans were assessed for the tendon state according to the Sugaya classification. 36 Furthermore, the incidence of complete retears and the overall retear rate (partial and complete retears) were compared. MRI was performed at 60 months, in addition to the previous publication data (before surgery and 3, 6, and 12 months afterward).
Randomization
The participants’ allocation was formulated by a simple randomization strategy using a tool available at http://www.random.org/coins/. Study participants were randomized by a physician who was not involved in the study.
Blinding
The physical therapist who performed the functional assessment, the physical therapists involved during the stage of rehabilitation, the radiologist who performed the MRI analysis, the participants, and the statistician were all blinded as to which of the groups the participants were allocated.
Statistical Analysis
Clinical parameters at 60 months were analyzed by the Mann-Whitney test. The Friedman test was used to compare the groups according to the UCLA, Constant, and VAS scores at other time points. The Wilcoxon signed-rank test was used to perform the post hoc analysis.
The postoperative MRI results were analyzed by the chi-square or Fisher exact test. The significance level was established as P < .05. No imputation method was used for missing data, and the results were shown considering 51 patients for the clinical analysis (25 control, 26 PRP) and 44 for the structural analysis (22 control, 22 PRP). The post hoc power of the structural analysis was 32.6% (22 cases in each group: 12 retears in the control group and 7 in the PRP group; alpha = .05). Statistical analysis was performed using SPSS version 21.0 software (IBM).
Results
Participant Flow
A previously published article 27 reported the results of the sample up to 24-month follow-up, without any losses to follow-up. At midterm follow-up, a clinical evaluation was performed in 25 patients in the control group and 26 in the PRP group. The evaluation by MRI was performed on 22 patients in each group. The flowchart representing the participants included in the study is shown in Figure 1.

Flowchart of participants.
Baseline Data
The baseline characteristics of the participants in the groups were compared, and the results are described in Table 1. No investigated variable exhibited significant differences. The number of anchors ranged from 1 to 3, with a mean of 1.6 ± 0.6 in the control group and 1.4 ± 0.5 in the PRP group, with no statistical difference (P = .414). Tendon-tendon sutures were used in 4 patients: 1 in the control group and 3 in the PRP group.
Patient Characteristics, Operative Variables, and Time Between Surgery and MRI a
Data are presented as mean ± SD unless otherwise indicated. MRI, magnetic resonance imaging; PRP, platelet-rich plasma.
Clinical Assessment
The mean preoperative UCLA scores were 13.6 ± 3.8 in the control group and 14.2 ± 4.6 in the PRP group (P = .670). At 60 months, the mean scores were 32.5 ± 3.8 and 32.1 ± 4.6, respectively (P = .992). The mean preoperative Constant scores were 48.1 ± 11.2 in the control group and 47.2 ± 12.1 in the PRP group (P = .748). At 60 months, the mean scores were 82.0 ± 9.5 and 82.1 ± 11.0, respectively (P = .699). The mean preoperative VAS scores were 6.9 ± 1.9 in the control group and 6.6 ± 1.6 in the PRP group (P = .426). At 60 months, the mean scores were 1.4 ± 1.8 and 1.5 ± 2.1, respectively (P = .910). None of the assessments at 3, 6, 12, and 24 months in either group produced statistically significant differences. The Friedman test revealed that both groups showed significant improvements throughout the follow-up time in the 3 evaluations (P < .001). The results are shown in Figures 2, 3, and 4 and Table 2.

Functional assessment: University of California, Los Angeles (UCLA) score. PRP, platelet-rich plasma.

Functional assessment: Constant score. PRP, platelet-rich plasma.

Pain level assessment: visual analog scale score. PRP, platelet-rich plasma.
Clinical Results at 60-Month Follow-up a
IQR, interquartile range; PRP, platelet-rich plasma; UCLA, University of California, Los Angeles; VAS, visual analog scale.
No difference was found for the clinical outcomes between patients who did and did not undergo a biceps procedure (Table 3).
Subgroup Analysis Comparing Patients Who Did and Did Not Undergo a Biceps Procedure a
Data are presented as median (interquartile range). PRP, platelet-rich plasma; UCLA, University of California, Los Angeles; VAS, visual analog scale.
Complications
We did not have any case of infection, reoperation, or neurological lesion. One patient from each group presented with a stiff shoulder, without significant differences between groups (P > .999).
MRI Assessment
Tendon Classification
At 60 months, 4.5% of the participants in the control group and 22.7% of the participants in the PRP group exhibited normal signals and sufficient thickness (Sugaya type I). The incidence of partial retears (Sugaya type III) was higher in the control group compared with the PRP group (50.0% vs 31.8%, respectively). This variable did not exhibit statistically significant differences between groups (Table 4).
Repaired Tendon Types According to the Sugaya Classification a
Data are presented as n (%). PRP, platelet-rich plasma.
Retears
Only 1 case of a complete retear occurred in the control group; this difference was not statistically significant (P > .999). We performed further analyses and added the cases with complete and partial tears together to determine the overall incidence of retears. Thus, 12 and 7 cases were identified in the control and PRP groups, respectively (P = .203) (Table 5).
Anatomic Integrity of Repaired Tendons a
Data are presented as n (%). PRP, platelet-rich plasma.
Temporal Evaluation
The number of complete retears (Sugaya type IV or V) did not change between 12 and 60 months. However, the number of partial tears (Sugaya type III) increased from 14.8% in the control group and 7.4% in the PRP to 50.0% and 31.8%, respectively. The presence of high signal intensity without tears (Sugaya type II), in turn, decreased from 70.4% in the control group and 63.0% in the PRP group to 40.9% and 45.5%, respectively.
Discussion
The aim of using PRP for rotator cuff repair is to improve tendon healing, decreasing the incidence of retears. The platelet concentration, higher than baseline levels, promotes the arrival of growth factors at the repair site. 14 In a systematic review focused on basic research, Baksh et al 2 demonstrated better results with the use of PRP in 30 of 31 studies evaluated. Despite this, clinical studies have presented controversial results. Functional improvement was reported in 1 article 32 and a lower number of retears in 4 articles.3,18,19,23 On the other hand, poorer clinical22,41 and structural 4 results have been reported. A level 1 meta-analysis showed that the use of PRP leads to a lower incidence of retears, both overall (15% vs 30%, respectively; P = .007) and in a subgroup analysis with mild-to-moderate tears (6% vs 19%, respectively; P = .03), but without a clinical difference. 6 However, this meta-analysis included only 5 randomized studies.
Our study did not demonstrate any difference between groups at any of the evaluation times, in relation to the clinical scales, similar to the findings described by Ebert et al. 12 The Constant scores in our study (82.0 control, 82.1 PRP) were very similar to those described by these authors (85.2 control, 86.2 PRP). The absence of a clinical difference is in accordance with previously reported data. 6
In relation to the tendon appearance according to the classification of Sugaya et al, 36 some observations can be made. Our study did not demonstrate any new case of a complete retear (Sugaya type IV or V) between 12 and 60 months. The only complete retear occurred before 12 months, in the control group, but the patient did not undergo a reoperation. Ebert et al, 12 meanwhile, observed 2 complete retears in the control group, both before 4 months. They performed reoperations in 4 patients, 2 in each group. The incidence of partial retears (Sugaya type III) in our case series (50.0% control, 31.8% PRP) is higher than that described by Ebert et al 12 (14.3% control, 11.1% PRP). On the contrary, the rate of cases with normal signal intensity and thickness (Sugaya type I) was significantly lower in our case series (4.5% control, 22.7% PRP) in relation to that of the other authors 12 (64.3% control, 66.7% PRP). One possible explanation for the higher incidence of Sugaya type III in our case series is the fact that we performed single-row repair, unlike Ebert et al. 12 Although both studies did not demonstrate any statistical difference between groups, a better panorama was observed in the PRP group (higher frequency of Sugaya types I and II and lower frequency of Sugaya types III, IV, and V), which may mean a positive effect of PRP in tendon healing. It should be emphasized that in the meta-analysis published by Cai et al, 6 of the 4 randomized studies used in the structural analysis, only 1 reported a statistical difference. 23 The others, meanwhile, presented a lower number of retears, but this difference was not significant.7,27,32 It is possible that the majority of studies published to date, including ours, have insufficient samples for the outcomes analyzed, resulting in a type II error. Our study also demonstrated the change observed between 12 and 60 months, with a decrease in normal signal intensity and an increase in partial retears over time, demonstrating possible degenerative changes inherent to aging.
The majority of published studies on this theme have evaluated clinical and structural results at the end of 12 or 24 months. ∥ To date, only Ebert et al 12 have reported results of a midterm evaluation, at around 42 months after the surgical procedure. Our study is the second to present midterm results for the use of PRP in rotator cuff repair, with the longest follow-up until now.
Midterm and long-term evaluations after rotator cuff repair are infrequent. Some articles have described a structural evaluation with follow-ups of between 5 and 10 years25,29,43 or longer than 10 years,13,30,37 but they have analyzed open repair. The number of retears reported varies between 12% and 60% in articles with follow-ups of between 5 and 10 years25,29,43 and from 33% to 94% in those with follow-ups of more than 10 years.13,30,37 The clinical scores observed in studies with a longer follow-up13,30,37 were lower than those reported by us. The presence of larger rotator cuff tears and older patients in those studies may explain the differences.
Although the majority of retears occur in the first 6 months after repair, failure may occur in later periods. Iannotti et al 21 demonstrated that 5% of retears occurred 6 months after surgery. Ebert et al 12 reported that 6.7% of patients had retears at between 4 and 42 months. Hernigou et al, 20 in a study on the use of mesenchymal stem cells in rotator cuff repair, observed an increase in the number of retears, from 0% at 6 months to 13% at 10 years, in the group with mesenchymal stem cells, while in the control group, the progression was from 33% to 56% in the same period. Kluger et al 26 reported that 14% of retears were diagnosed at between 2 and 5 years. Thus, the midterm findings of patients undergoing rotator cuff repair are interesting, especially for those treated with biological adjuvants.
PRP presents a wide variation in the different preparation protocols: preparation by apheresis or centrifugation, variable concentrations of platelets and leukocytes, liquid or solid form, volume applied, and use or nonuse of coagulation cascade activators. 11 Furthermore, the number of applications (single or sequential) and the moment of application (during or after surgery) may vary as well as the surgical technique used. All these factors make comparisons between the various studies difficult. Our methodology involved the use of PRP obtained by apheresis, applied in liquid form, with the addition of thrombin, after rotator cuff repair by the single-row technique in a study with blinding of the patient and the evaluator and with a structural evaluation at 60 months. The methodology described by Ebert et al 12 differed from ours, mainly in the use of PRP obtained by centrifugation, applied sequentially (at the time of surgery and at 7 and 14 days), using a double-row repair technique without blinding the patients. In both groups, only the supraspinatus tendon needed repair. Standardized MRI was performed for the tendon evaluation, and the classification of Sugaya et al 36 was used for describing the supraspinatus tendon. To date, there are no clinical studies comparing the effect of single or serial applications of PRP in rotator cuff repair, and the single application has already proven effective in increasing the local level of growth factors for up to 28 days. 42
Our study has some limitations. The sample size was small, which is likely to underestimate the difference regarding the retear rate, and the post hoc power of the structural analysis was 32.6%. We had a rate of loss to follow-up of 5.5% for the clinical evaluation and 18.5% for the structural evaluation. We did not count platelets and leukocytes in the PRP obtained, which may be a reason for criticism. However, the method used by us has already proved to generate more than 1,000,000 platelets/mm3 and lower leukocyte levels compared with baseline.10,31 Some patients underwent concomitant procedures, such as biceps tenodesis or tenotomy. Although these other procedures would not be expected to directly affect the structural outcomes and did not differ statistically between groups, they could affect the clinical outcomes. However, a subgroup analysis for the biceps procedure did not demonstrate differences between the groups for all clinical outcomes. The imaging evaluation, despite the use of high-field MRI and analysis by an experienced radiologist, did not include intraobserver and interobserver analyses. Another limitation is the fact that the surgeon was not blinded. This fact was overcome by blinding the independent evaluator. Moreover, we did not perform adjustments by age or comparisons with the contralateral side in the functional analysis.
To conclude, PRP obtained by apheresis and applied in liquid form, with the addition of thrombin, at the end of single-row supraspinatus repair of small and medium tears, did not demonstrate any statistically significant difference in clinical outcomes or imaging results at the end of 60 months of follow-up.
Footnotes
Acknowledgements
The authors acknowledge Thais Cristina Pereira Vasques, a research assistant, for support in obtaining the study data.
The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.
