578435
research-article2015
FAIXXX10.1177/1071100715578435Foot & Ankle InternationalGörmeli et al
Article
Clinical Effects of Platelet-Rich Plasma and Hyaluronic Acid as an Additional Therapy for Talar Osteochondral Lesions Treated with Microfracture Surgery: A Prospective Randomized Clinical Trial
Foot & Ankle International® 1–10 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1071100715578435 fai.sagepub.com
Gökay Görmeli, MD1, Mustafa Karakaplan, MD1, Cemile Ayşe Görmeli, MD2, Baran Sarıkaya, MD3, Nurzat Elmalı, MD4, and Yüksel Ersoy, MD5
Abstract Background: Osteochondral ankle injuries commonly affect the dome of the talus, and these injuries are a common cause of athletic disability. Various treatment options are available for these injuries including intra-articular hyaluronic acid (HA) and platelet-rich plasma (PRP) injections. The purpose of this study was to compare the effects of HA and PRP as adjunct therapies after arthroscopic microfracture in osteochondral lesions (OCLs) of the talus. Methods: In this prospective, randomized blinded study, 40 patients with talar OCLs in their ankle joints were treated with arthroscopic debridement and a microfracture technique. Thirteen randomly selected patients received PRP, 14 patients received HA, and the remaining 13 patients received saline as a control group. The participants were assessed using the American Orthopaedic Foot & Ankle Society (AOFAS) and visual analog pain scale (VAS) scores after a 15.3-month (range, 11-25 months) follow-up. Results: Postoperatively, all the groups exhibited significantly increased AOFAS scores and decreased VAS scores compared with their preoperative results (P < .005). The AOFAS scores were significantly increased in the PRP group versus the HA and control groups (P < .005), although the increased AOFAS scores in the HA group versus the control group were also significant (P < .005). Similar to the AOFAS scores, the decrease in the VAS scores was significantly lower in the PRP group versus the HA and control groups (P < .005). In addition, the HA group had significantly lower VAS scores than the control group (P < .005). Conclusion: Both PRP and HA injections improved the clinical outcomes of patients who underwent operation for talar OCLs in the midterm period and can be used as adjunct therapies for these patients. Because a single dose of PRP provided better results, we recommend PRP as the primary adjunct treatment option in the talar OCL postoperative period. Level of Evidence: Level I, prospective randomized study. Keywords: osteochondral lesions, talus, platelet-rich plasma, hyaluronic acid, microfracture
Introduction
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Intra-articular (IA) ankle injuries are a common cause of athletic disability, with approximately 27,000,000 occurrences per year.4 Osteochondral lesions (OCLs) have been estimated to occur in approximately 6.5% of these injuries. Osteochondral lesions can involve the articular surface and/ or the subchondral bone, which commonly affects the dome of the talus.2,15 Posteromedial lesions are common and deeper in thickness in these injuries. The young population is typically affected by these injuries as a result of running, jumping, or rotating.25 Ischemia, necrosis, inflammatory diseases, and genetic factors are other common etiological
Corresponding Author: Gökay Görmeli, MD, Department of Orthopedics and Traumatology, Inonu University, Turgut Ozal Medical Center, Malatya, 44000, Turkey. Email: [email protected]
Inonu University, Turgut Ozal Medical Center, Department of Orthopedics and Traumatology, Malatya, Turkey 2 Inonu University, Turgut Ozal Medical Center, Department of Radiology, Malatya, Turkey 3 Baskent University, Department of Orthopedics and Traumatology, Adana, Turkey 4 Vakıf Gureba University, Department of Orthopedics and Traumatology, İstanbul, Turkey 5 Inonu University, Turgut Ozal Medical Center, Department of Physiotherapy and Rehabilitation, Malatya, Turkey
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factors for OCLs.42 After the injury, because of the cartilage’s avascularity and poor tendency for healing, progression of the depth and size of the lesion and severity can occur and may cause osteoarthritis.1,8,26,31,32 Intra-articular injections are used for cartilage injuries and joint degeneration. Synovial fluid, a lubricant for articular surfaces, reduces surface stress and plays an important role in the movement of chondronutritive substances from the synovium.33 Hyaluronic acid (HA) is a lubricant for articular surfaces that reduces pain and inflammation and supplements the endogenous joint fluid.46 Platelet-rich plasma (PRP) is an autologous blood product that contains a high concentration of platelets.47 Platelet α-granules contain and release numerous growth factors (GFs) that have important roles in chondrogenic differentiation, matrix deposition, and decreasing the suppressive effects of interleukin (IL)-1 on proteoglycan synthesis in cartilage.6,35 Platelet-rich plasma is widely used in clinical practice to treat bone, tendon, ligament, and cartilage injuries and osteoarthritis.18,30 Despite the promising preclinical results and wide clinical interest in orthopedic and sports medicine, many unanswered questions regarding the clinical application and efficacy of PRP remain. There is a lack of clarity regarding the number and frequency of injections to ensure treatment efficacy. Despite previous reports on the effects of HA and PRP administration in a number of different conditions, to our knowledge, there have been no comparative studies of HA and PRP treatment for OCLs of the talus following arthroscopic microfracture surgery. We performed this prospective randomized study to evaluate the role of PRP and HA injections in patients with talar OCLs who were treated with arthroscopic microfracture surgery. This study’s hypothesis was that the combination of PRP or HA with arthroscopic microfracture for talar OCLs would result in better clinical outcomes compared to a control group (arthroscopic microfracture surgery combined with saline injections). The purpose of this study was to report the clinical outcomes of IA injection therapies (PRP and HA) after arthroscopic microfracture for talar OCLs.
Methods Study Design This study was designed as a prospective, blinded (observer blinded), placebo-controlled trial with 3 groups and 3 treatment methods (1 group served as the placebo group). All the participants provided written informed consent, and the study was approved by the local ethics committee. The volunteer participants were subjected to a standardized IA injection protocol that was assessed with American Orthopaedic Foot & Ankle Society (AOFAS) objective data from the physical examination of the ankle and hindfoot27 and the visual analog pain scale (VAS),12 which is a simple,
validated, and commonly used patient-administered method that assesses pain intensity.
Patient Selection Between January 2011 and January 2013, 40 patients with talar OCLs in their ankle joints were included in this study. The demographic and pretreatment score data are summarized in Table 1. The inclusion and exclusion criteria are shown in Table 2. We excluded the posterior lesions as they were very frequent and visualizing only with arthroscopy can be difficult, so additional posterior arthroscopy or osteotomy might have been needed. For patients with chronic ankle pain, a detailed medical history was obtained and a physical examination was performed. The diagnosis of OCL of the talus was confirmed via preoperative radiographs and magnetic resonance imaging (MRI). The MRI findings were classified by a blinded radiologist (CAG) using the classification systems described by Hepple et al,24 and location of lesions was addressed according to the 9-zone grid scheme described by Raikin et al.37 A total of 40 participants who met the inclusion criteria were randomly divided by computer-derived random assignments into 3 groups, and all the injections were performed 24 to 48 hours after the operation. The 13 patients receiving therapy with a PRP injection after arthroscopic microfracture constituted the PRP group, the 14 patients receiving therapy with an HA injection constituted the HA group, and the 13 patients receiving saline injections were the controls. The group assignments were accessible only to the study assistant and were concealed from the researchers in the study.
Operative Technique and Intra-articular Administration All of the patients were treated surgically with arthroscopic debridement and the microfracture technique by the senior surgeon. Twenty-four patients underwent surgery with spinal anesthesia, whereas 8 patients underwent surgery with general anesthesia in a supine position with the use of a pneumatic tourniquet with 300 mmHg of pressure. Anteromedial and anterolateral portals were used. A local synovectomy was performed for better visualization of the OCLs. After removal of the necrotic soft tissue and osteochondral fragments, the lesion bed was cleaned, and the microfracture technique was performed by using microfractures of 30-degree, 45-degree, and 90-degree awls until the fat particles were observed. A Hemovac drain was placed, and the portals were closed. The skin was sterilely closed, and elastic bandages were used to wrap the foot and ankle. All of the injections were administered after the drain was removed approximately 24 to 36 hours after the operation. A topical ethyl chloride anesthetic spray was used, and the skin was sterilely dressed. Each injection was
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Görmeli et al Table 1. Clinical and Baseline Characteristics. Parameter Age, mean ± SD, y Sex, No. (%) Male Female Duration of symptoms, mean ± SD, mo Lesion side, No. (%) Right Left Location of lesions, No. (%) Anteromedial Anterocentral Anterolateral Central-medial Central-central Central-lateral BMI, mean ± SD Lesion size, mean (range), cm2 Stage, No. (%)a Stage II Stage III Stage IV AOFAS preop, mean ± SD VAS preop, mean ± SD
PRP (n = 13)
HA (n = 14)
Control (n = 13)
P Value
38.6 ± 9.1
39.7 ± 8.7
40.3 ± 9.4
5 (38.5) 8 (61.5) 25.9 ± 14.3
8 (57.1) 6 (42.9) 26.7 ± 15.4
8 (61.5) 5 (38.5) 26.4 ± 10.8
ns ns ns
8 (61.5) 5 (38.5)
9 (64.3) 5 (35.7)
6 (46.2) 7 (53.8)
3 (23) 1 (7.6) 3 (23) 5 (38.4) — 1 (7.6) 30.5 ± 5.2 1.28 (0.52-1.4) 5 (38.5) 7 (53.8) 1 (7.7) 43.6 ± 7.6 8.0 ± 0.7
3 (21.4) — 3 (21.4) 6 (42.8) — 2 (14.2) 31.2 ± 5.4 1.24 (0.48-1.46) 4 (28.6) 8 (57.1) 2 (14.3) 44.9 ± 9.2 7.8 ± 0.9
2 (15.3) 1 (7.6) 4 (30.7) 4 (30.7) — 1 (7.6) 31.5 ± 4.5 1.18 (0.46-1.38) 4 (30.8) 7 (53.8) 2 (15.4) 42.7 ± 7.1 7.7 ± 0.7
Abbreviations: AOFAS, American Orthopaedic Foot & Ankle Society; BMI, body mass index; HA, hyaluronic acid; ns, nonsignificant; preop, preoperative; PRP, platelet-rich plasma; VAS, visual analog pain scale. a According to Hepple staging based on preoperative magnetic resonance imaging findings.
Table 2. Inclusion and Exclusion Criteria. Inclusion Criteria Age of > 18 years and < 60 years Ankle pain Diagnosed as having osteochondral lesions of the talus in the radiographs Exclusion Criteria Posterior osteochondral lesions Pregnancy Breastfeeding Infection of the ankle or nearby soft tissues Injection of steroid or surgery on the involved joint within 6 mo Treatment with a dosage of glucosamine and/or chondroitin sulfate Treatment with an anticoagulant Systemic inflammatory condition Substantial venous or lymphatic stasis in the legs Pathologies that may confound pain and functional assessments in the ankle (plantar fasciitis, Achilles tendonitis, sprains, and degenerative joint disease of the foot) Diabetic or neuropathic Charcot arthropathy Substantial vascular insufficiency Current treatment with anticoagulants Lower extremity pain syndromes Severe ankle instability or malalignment Known allergy to any of the components of either injection Disabling degenerative joint disease of the ipsilateral hip, knee, or foot
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ns ns ns ns ns ns
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administered using the anteromedial approach with a 22-g needle. In the PRP group, the Smart-PReP®2 system (Harvest Autologous Hemobiologics, Norwell, MA) was used for 13 patients. The mean platelet count increased from 236 000 ± 47 000 platelets/µL to 1 227 000 ± 242 400 platelets/µL. In the HA group, high-molecular-weight, cross-linked hyaluronic acid was administered (2 mL of Hylan G-F 20, Synvisc®; Biomatrix, Inc, Ridgefield, NJ) for 14 patients, whereas the 13 patients in the placebo group received 1 injection of 2.5 mL of normal saline solution.
Postoperative Care and Follow-up No casts or braces were used after the operation to allow range-of-motion exercises to be performed. The patients were mobilized with crutches without weightbearing immediately on the first postoperative day. Cold therapy was performed (ice in a bag 3 times and for 15 minutes at each therapy) 2 days after the operation. Partial weightbearing with crutches was permitted after the third week of the operation, and strengthening exercises began at the same time. After 4 to 6 weeks, full weightbearing was permitted with balance and proprioception exercises. Between months 3 and 6, plain running and jogging without acceleration was permitted. Finally, after 6 months, a return to athletic and more intense physical activities was permitted. The injected materials have different viscosities; thus, the physician who performed the injections could not be blinded. However, the follow-up examinations and data collection for the study instruments were performed by a second physician, who was blinded to the treatment. The AOFAS and VAS scores were used for the assessment of the functional and pain statuses of the patients. All of the volunteers were followed for an average of 15.3 months (range, 11-25 months).
Statistical Analysis GPower software was used for the sample size estimation. A sample size of 36 individuals in total (12 per arm) was proposed. This sample size would provide 80% power to detect an effect size of 0.8 (1-tail) between groups for the continuous outcome variables of the study. The data were expressed as mean ± standard deviation (SD) depending on the overall variable distribution. Normality was assessed using the Shapiro Wilk test. The normally distributed data were analyzed by a 1-way analysis of variance followed by the Bonferroni post hoc test. The qualitative data were analyzed with Pearson’s chi-square test. Spearman’s correlation was used for the relationships between the variables. P values < .05 were considered significant. IBM SPSS Statistics Version 22.0 for Windows was used for the statistical analysis.
Results All the groups had similar demographic data, preoperative scores, durations of symptoms, location of lesions, and lesion classification, as shown in Table 1. No severe adverse events occurred during the postoperative follow-up period. According to the VAS scoring system, significantly lower postoperative scores were achieved compared to the preoperative values in the PRP, HA, and control groups (P < .001) (Figure 1). The decrease in the postoperative period was found to be significantly lower in the PRP group compared to the HA and control groups. There was also a significant decrease in the HA group compared to the control group (P < .001) (Table 3). In stage 2 to 3 lesions, the postoperative VAS scores were significantly lower in the PRP group compared to other groups (PRP group: 2.5 ± 0.9; HA group: 3.3 ± 1.1; control group: 4.7 ± 0.8) (P < .05). Similarly, the postoperative AOFAS scores were significantly higher than the preoperative values for all groups (P < .001) (Figure 2). There was a significantly higher increase in the AOFAS scores for the PRP group compared to the HA and control groups (P < .001) (Table 3). Despite the prominent PRP improvement, significantly higher scores were found in the HA group than in the control group (P < .001). In stage 2 to 3 lesions, the postoperative AOFAS scores were significantly higher in the PRP group compared to other groups (PRP group: 84.3 ± 5.8; HA group: 75.9 ± 9.8; control group: 68.1 ± 11.0) (P < .05). There was no significant correlation between the postoperative AOFAS scores and age (Spearman’s rho: 0.16; P = .33), body mass index (BMI) (Spearman’s rho: 0.31; P = .84), or the duration of symptoms (Spearman’s rho: –0.41; P = .8). Similar to the AOFAS scores, there was no correlation between the postoperative VAS scores and age (Spearman’s rho: 0.27; P = .08), BMI (Spearman’s rho: –0.06; P = .69), or the duration of symptoms (Spearman’s rho: 0.14; P = .38). At the end of 1 year, 61.5% of the patients were satisfied, 23% were partially satisfied, and 15.4% were not satisfied in the PRP group. In the HA group, 35.7% of the patients were satisfied, 50% were partially satisfied, and 14.3% were not satisfied at the end of the procedure. In the control group, 46.2% of the patients were satisfied, 30.8% were partially satisfied, and 23.1% were not satisfied with the postoperative IA injection procedure. However, the difference among the 3 groups was not significant (P > .005).
Discussion The results of this study showed that both the PRP and HA injections improved the clinical outcomes of the patients who were operated on for talar OCLs; therefore, these treatments can be used as adjunct therapies for these patients. Because a single dose of PRP showed better results
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VAS Scores 10 9 8 7 6 5 4 3 2 1 0 PRP group
HA group
Control
Preopera ve VAS scores
Postopera ve VAS scores
Figure 1. Significantly lower results achieved between preoperative and postoperative visual analog pain scale scores for platelet-rich plasma, hyaluronic acid, and control groups. Table 3. Follow-up Measurements. Parameter AOFAS, mean ± SD VAS, mean ± SD
PRP Group (n = 13) a
85.1 ± 6.1 2.4 ± 0.9a
HA Group (n = 14) b
75.1 ± 9.5 3.3 ± 1.0b
Control Group (n = 13)
P Value
68.3 ± 10.1 4.5 ± 0.9
.001 .001
Abbreviations: AOFAS, American Orthopaedic Foot & Ankle Society; HA, hyaluronic acid; PRP, platelet-rich plasma; VAS, visual analog pain scale. a Significant difference from HA and control groups. b Significant difference from PRP and control groups.
compared to HA, we recommend PRP as the primary adjunct treatment in the postoperative period following surgery for talar OCLs. To our knowledge, this is the first prospective randomized blinded controlled study to compare the effects of PRP and HA after microfracture surgery for talar OCLs. Treatment strategies are dependent on the stage of the OCL, which was determined by computed tomography (CT) as described by Ferkel et al.17 The nonoperative treatment options (immobilization, restriction of weightbearing, and physical therapy) are reserved for grade 1 and 2 lesions, with a lower success rate compared to surgery.10 Operative intervention is recommended if the nonoperative treatment is unsuccessful, in chronic OCLs of the talus, if symptoms persist despite 6 months of the conservative treatment or for the initial treatment of greater than grade 3 lesions.16,28 In this study, we performed surgery on the talar OCLs according to this protocol. Current operative treatment options include reparative and restorative techniques. Reparative techniques include bone marrow stimulation (BMS) of the subchondral bone
(drilling, microfracture) and cell-based techniques (autologous chondrocyte implantation [ACI], matrix-assisted ACI). The restorative techniques are autologous osteochondral transplantation (AOT), osteochondral allograft, and juvenile cartilage allograft.40 Arthroscopic debridement and BMS (microfracture formation) is the current first-line operative treatment for lesions up to 15 mm in diameter.52 Early lesions with continuity in the cartilaginous surface and the stability of the OCL fragment are the specific indications for BMS. After microfracture, there is a biological shift to fibrocartilaginous repair tissue exhibiting primarily type I collagen at 1 year. Compared to hyaline cartilage, type I collagen may degenerate over time because it has different biological and mechanical properties.43 In addition, for large defects (> 15 mm), type I collagen may not be the optimal treatment, whereas ACI and AOT techniques would be preferred to reproduce the original hyaline cartilage at the defect site.36 We believe that although microfracture with drilling is a good treatment option with acceptable success rates, the fibrocartilage that is formed after drilling has a different
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AOFAS Scores 90 80 70 60 50 40 30 20 10 0 PRP Group
HA Group
Control Group
Preopera ve Scores
Postopera ve Scores
Figure 2. Significantly better results achieved between preoperative and postoperative American Orthopaedic Foot & Ankle Society scores for platelet-rich plasma, hyaluronic acid, and control groups.
structure from that of the hyaline cartilage, which may negatively affect the long-term outcomes. Several authors have reported good results following arthroscopic BMS,29,48 but there are many reports of poorer outcomes as well.11,25,38 Therefore, we believe that an additional IA administration would improve the clinical outcomes. The preference for the microfracture technique over ACI and AOT in this study can be debated because the success rates of these techniques have been reported to be in the ranges of 74% to 100% and 70% to 92%, respectively.52 In our study, greater than 15 mm lesions were excluded. In addition, we considered the disadvantages of these techniques: AOT has donor site morbidity and the risk of joint incongruency, whereas ACI has a high cost, is technically demanding, and requires a second surgery. In contrast to the disadvantages of the AOT and ACI techniques, the main advantages of the microfracture technique include arthroscopic application with no donor site morbidity, fewer wound healing problems, a quick recovery, and a decreased cost.14,21 The healing capacity of cartilage is limited by its limited vascularity and its contribution to the progressive degeneration of damage.9 The α-granules of platelets contain a variety of factors (transforming growth factor β, fibroblast growth factor, and platelet-derived growth factor) that promote cartilage matrix synthesis and inhibit the catabolic effects of IL-1β and TNF-α on articular cartilage.7,34,45 In an in vitro study on human knee chondrocytes, Woodell-May et al51 showed that PRP significantly inhibited the production of matrix metalloproteinase (MMP)-13 induced by IL-1β and TNF-α. In addition, Fortier et al19 showed that PRP increases cell growth and the chondrocyte transcription of
proteins with a decrease in the NF-kB-mediated production of catabolic cytokines. Synovial fluid acts as a lubricant and shock absorber for joint function, and the viscoelasticity of synovial fluid results from HA.3 With a decrease in synovial fluid, increased stress occurs in the joint, which leads to cartilage degeneration. Hyaluronic acid decreases the development of osteoarthritis by decreasing the degradation of cartilage proteoglycans and inhibiting arachidonic acid release, prostaglandin E2 synthesis, and IL-1 and MMP-3 expression.22,44 Hyaluronic acid has analgesic activities based on its anti-inflammatory effects, which have been demonstrated by in vitro and animal studies.20 This property may explain the significant decrease in the VAS scores of the patients treated with HA in our study. These studies suggest an important role for PRP and HA as potent biological regulators of chondrocytes in cartilage repair. To our knowledge, only a few prospective studies have been designed to evaluate the effectiveness of PRP and HA injection therapies for osteoarthritis of the ankle in clinical practice. Salk et al39 randomized 20 patients to receive 5 weekly IA injections of either 1 mL of sodium hyaluronate (10 mg/ mL) or 1 mL of phosphate-buffered saline solution into the ankle joint. The authors concluded that IA injections of sodium hyaluronate can provide sustained relief from pain and can improve function in patients with osteoarthritis of the ankle. However, contrasting results were obtained in a study involving 64 patients with ankle osteoarthritis who were randomly assigned to a single IA injection of 2.5 mL of low-molecular-weight, non-cross-linked HA or a single
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Görmeli et al IA injection of 2.5 mL of normal saline solution. The AOFAS clinical rating scores at 6 and 12 weeks were evaluated. The authors found that a single IA injection of lowmolecular-weight, non-cross-linked HA was not superior to a single IA injection of saline solution for the treatment of osteoarthritis of the ankle.13 This result may be related to the content of the HA (low molecular-weight, non-cross-linked HA) they used during their treatment. In our study, we used a single injection of a high-molecular-weight, cross-linked hyaluronic acid product (Synvisc), which has been shown to be effective in the ankle.49 The administration of a high-molecular-weight, cross-linked HA product instead of a low-molecular-weight, non-cross-linked HA product may explain our significantly better scores for the HA group. Similar to Salk et al, there was a significant improvement in the clinical and pain scores for the HA group in our study. The significantly better results achieved in the postoperative period may not have been merely a placebo effect. These results may be related to the role of saline solution in providing a lubricating effect, thus diluting the lytic enzymes and proinflammatory cytokines associated with cartilage degeneration. In a randomized controlled trial, Mei-Dan et al32 treated 32 patients with IA injections of either HA or PRP (for OCLs of the talus). These patients received 3 consecutive IA therapeutic injections and were followed for 28 weeks by assessing their AOFAS, Ankle-Hindfoot Scale, and VAS scores. Similar to our results, the authors concluded that the use of both HA and PRP offers a viable treatment option for patients with ankle OCLs, with a significantly better outcome for the PRP treatment. They also suggested the IA injection of either PRP or HA as the first-line treatment of symptomatic talar OCLs or as a second-line treatment for patients who are symptomatic after surgery. Despite the well-designed studies investigating IA injection for talar OCLs in a nonoperative treatment, to our knowledge, only a few studies have evaluated adjunct therapies for microfracture surgery for OCLs of the talus. In a welldesigned randomized prospective study performed by Guney et al,23 patients who received microfracture surgery were divided into 2 groups. Sixteen patients received treatment with microfracture surgery alone, whereas the remaining patients (PRP group, n = 19) were also given 1 dose of PRP the day after surgery. Similar to our results, the authors found that the combined treatment with PRP resulted in better outcomes compared to arthroscopic microfracture surgery alone. A limitation of this study, which the authors discussed in the article, was that the control group did not receive IA injections. However, the necessity of adding an IA saline injection to the control is debatable because of the potential positive effects of the saline solution for the ankle joint, as described above. To determine the effect of a saline injection in the ankle joint, a group of patients undergoing the microfracture surgery alone, without saline injection, should perhaps have
been added as another group in our study. The unblinded design was another limitation of this study. In our study, the blinded observer performed and recorded the results; the individual who performed all the injections was not blinded because of the distinct difference in the viscosity of the injected materials in the different groups. In another randomized prospective study performed by Doral et al,14 41 patients were injected intra-articularly with HA, whereas the remaining 16 patients did not receive a postoperative injection after arthroscopic debridement and microfracture for talar OCLs. After 2 years of follow-up, the authors found significantly higher scores in the injection group compared to the noninjection group in both the Freiburg and AOFAS scoring systems. They concluded that additional treatment with an IA hyaluronan injection as an adjunct to the microfracture technique may offer better clinical outcomes compared to the microfracture technique alone. To our knowledge, there have been no prospective, randomized, blinded studies that evaluated both HA and PRP IA injection therapies as adjuncts to arthroscopic microfracture for talar OCLs. Similar to the studies summarized above, we believe that either PRP or HA IA injection after BMS may be used as an adjunct therapy. We also believe that because it was associated with better functional and pain-related scores, 1 dose of PRP the day after surgery may be the primary adjunct therapy versus HA injection. We administered a single injection of HA and PRP the day after surgery rather than 3 or 5 weekly injections. As discussed by Guney et al,23 the advantages of an injection after the first postoperative day are that it does not necessitate any additional admissions and that anesthesia is not required because the patient does not experience any pain. In addition, no differences were found between the singleand double-dose injections in a study performed by Witteveen et al.50 The infection risk as a result of potential aseptic conditions with multiple conditions must be considered as well. In addition, multiple injections might have led to a loss of patients from the study because returning to the clinic regularly may be challenging. Previous outcome scores were negatively affected by degenerative arthritis, increased age, and a higher BMI.41 Conversely, in our study, we found no relationship between the postoperative results and the patient’s sex, age, BMI, or OCL grade. This finding is related to the IA adjunct therapies after the surgery, which may improve the outcome scores of all the patients. The strengths of this study are the randomized, prospective, blinded design; the adequate number of patients who clearly presented with ankle-related pain, which was correlated with radiographic findings that were calculated with a power analysis; the lack of significant differences in the baseline characteristics for all the randomly assigned groups; and the absence of any financial support from the manufacturer of the device.
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This study has several limitations. One limitation is the relatively short-term follow-up period. We evaluated our patients at a maximum follow-up of 12 months because the viscosupplementation therapy could be repeated after a certain time interval, and a different treatment option may have been required for the patients. In addition, longer followups without additional treatment might have led to a loss of patients from the study. However, the literature has shown that a treatment effect is observed as soon as 1 week after the injection, and the maximal effect appears to occur between 5 and 13 weeks after the injection.5 Another weakness of our study is that we did not use image guidance to ensure the location of the needle in the ankle joint. The lack of accurate documentation of analgesic use is another limitation of this study. The patients were permitted to use paracetamol as required in the postoperative period. This factor may have affected the results, but we believe that such an effect would be similar for both groups because most of the patients stated that they did not use analgesics upon follow-up. Radiographic follow-up methods to evaluate cartilage degeneration and microscopic information on the effects of PRP and HA on the quality of repair tissue could have been reported in this study. However, we could not conduct these evaluations because of cost and ethical limitations. Despite the adequate group size calculated by the power analysis, it would be preferable to perform this study with larger groups. However, OCLs of the talus are not common, and it is relatively difficult to recruit patients suffering from this problem. Ideally, the present investigation would have been conducted through a multicenter study; however, we hypothesized that it would be difficult to optimize the treatment protocols for all the centers. Not optimizing the treatment protocols would affect the reliability of the study; thus, we performed a single-center study.
Conclusion This study suggests that an early single-dose IA PRP and HA administration to the ankle joint can be used as an adjunct therapy after arthroscopic debridement and microfracture for talar OCLs. In particular, PRP injections were more effective than HA injection in patients with OCLs of the talus and PRP is thus recommended by us as the primary adjunct treatment option in the talar OCL postoperative period. However, longer term results and multicenter studies with larger sample groups are required to design optimal guidelines for the adjunct therapies of talar OCLs that are treated with debridement and the microfracture technique. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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Görmeli et al 16. Easley ME. Osteochondral lesions of the talus: diagno sis and treatment. Curr Opin Orthop. 2003;14(2):69-73. doi:10.1097/00001433-200304000-00001. 17. Ferkel RD, Zanotti RM, Komenda GA, et al. Arthroscopic treatment of chronic osteochondral lesions of the talus: long-term results. Am J Sports Med. 2008;36(9):1750-1762. doi:10.1177/0363546508316773. 18. Filardo G, Kon E, Di Martino A, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012;13:229. 19. Fortier LA, Hackett CH, Cole BJ. The effects of platelet-rich plasma on cartilage: basic science and clinical application. Op Tech Sports Med. 2011;19:154-159. 20. Ghosh P. The role of hyaluronic acid (hyaluronan) in health and disease: interactions with cells, cartilage and components of synovial fluid. Clin Exp Rheumatol. 1994;12(1):75-82. 21. Gobbi A, Francisco RA, Lubowitz JH, Allegra F, Canata G. Osteochondral lesions of the talus: randomized controlled trial comparing chondroplasty, microfracture, and osteochondral autograft transplantation. Arthroscopy. 2006;22(10):10851092. doi:10.1016/j.arthro.2006.05.016. 22. Goldberg VM, Buckwalter JA. Hyaluronans in the treat ment of osteoarthritis of the knee: evidence for diseasemodifying activity. Osteoarthr Cartil. 2005;13(3):216-224. doi:10.1016/j.joca.2004.11.010. 23. Guney A, Akar M, Karaman I, Oner M, Guney B. Clinical outcomes of platelet rich plasma (PRP) as an adjunct to microfracture surgery in osteochondral lesions of the talus [published online November 30, 2013]. Knee Surg Sports Traumatol Arthrosc. doi:10.1007/s00167-013-2784-5. 24. Hepple S, Winson IG, Glew D. Osteochondral lesions of the talus: a revised classification. Foot Ankle Int. 1999;20(12):789793. doi:10.1177/107110079902001206. 25. Hunt SA, Sherman O. Arthroscopic treatment of osteochondral lesions of the talus with correlation of outcome scoring systems. Arthroscopy. 2003;19(4):360-367. doi:10.1053/ jars.2003.50047. 26. Jackson DW, Lalor PA, Aberman HM, Simon TM. Spontaneous repair of full-thickness defects of articular cartilage in a goat model. A preliminary study. J Bone Joint Surg Am. 2001;83-A(1):53-64. 27. Kitaoka HB, Alexander IJ, Adelaar RS, et al. Clinical rating systems for the ankle-hindfoot, midfoot, hallux, and lesser toes. Foot Ankle Int. 1994;15(7):349-353. doi:10.1177/107110079401500701. 28. Kreuz PC, Steinwachs M, Erggelet C, et al. Mosaicplasty with autogenous talar autograft for osteochondral lesions of the talus after failed primary arthroscopic management: a prospective study with a 4-year follow-up. Am J Sports Med. 2006;34(1):55-63. doi:10.1177/0363546505278299. 29. Lee KB, Bai LB, Chung JY, Seon JK. Arthroscopic microfracture for osteochondral lesions of the talus. Knee Surg Sports Traumatol Arthrosc. 2010;18(2):247-253. doi:10.1007/ s00167-009-0914-x. 30. Lopez-Vidriero E, Goulding KA, Simon DA, Sanchez M, Johnson DH. The use of platelet-rich plasma in arthroscopy and sports medicine: optimizing the healing environment. Arthroscopy. 2010;26(2):269-278. doi:10.1016/j.arthro.2009.11.015.
31. Mankin HJ. The response of articular cartilage to mechanical injury. J Bone Joint Surg Am. 1982;64(3):460-466. 32. Mei-Dan O, Carmont MR, Laver L, et al. Platelet-rich plasma or hyaluronate in the management of osteochondral lesions of the talus. Am J Sports Med. 2012;40(3):534-541. doi:10.1177/0363546511431238. 33. Mongkhon JM, Thach M, Shi Q, et al. Sorbitol-modified hyaluronic acid reduces oxidative stress, apoptosis and mediators of inflammation and catabolism in human osteoarthritic chondrocytes. Inflamm Res. 2014;63(8):691-701. doi:10.1007/ s00011-014-0742-4. 34. Park KH, Na K. Effect of growth factors on chondrogenic differentiation of rabbit mesenchymal cells embedded in injectable hydrogels. J Biosci Bioeng. 2008;106(1):74-79. doi:10.1263/jbb.106.74. 35. Pujol JP, Chadjichristos C, Legendre F, et al. Interleukin-1 and transforming growth factor-beta 1 as crucial factors in osteoarthritic cartilage metabolism. Connect Tissue Res. 2008;49(3):293-297. doi:10.1080/03008200802148355. 36. Raikin SM. Stage VI: massive osteochondral defects of the talus. Foot Ankle Clin. 2004;9(4):737-744. doi:10.1016/j. fcl.2004.06.003. 37. Raikin SM, Elias I, Zoga A, et al. Osteochondral lesions of the talus: localization and morphologic data from 424 patients using a novel anatomical grid scheme. Foot Ankle Int. 2007;28(2):154-161. doi:10.3113/FAI.2007.0154. 38. Robinson DE, Winson IG, Harries WJ, Kelly AJ. Arthroscopic treatment of osteochondral lesions of the talus. J Bone Joint Surg Br. 2003;85(7):989-993. doi:10.1302/0301620X.85B7.13959. 39. Salk RS, Chang TJ, D’Costa WF, Soomekh DJ, Grogan KA. Sodium hyaluronate in the treatment of osteoarthritis of the ankle: a controlled, randomized, double-blind pilot study. J Bone Joint Surg Am. 2006;88(2):295-302. doi:10.2106/ JBJS.E.00193. 40. Savage-Elliott I, Ross KA, Smyth NA, Murawski CD, Kennedy JG. Osteochondral lesions of the talus: a current concepts review and evidence-based treatment paradigm. Foot Ankle Spec. 2014;7(5):414-422. doi:10.1177/ 1938640014543362. 41. Saxena A, Eakin C. Articular talar injuries in athletes: results of microfracture and autogenous bone graft. Am J Sports Med. 2007;35(10):1680-1687. doi:10.1177/0363546507303561. 42. Schachter AK, Chen AL, Reddy PD, Tejwani NC. Osteochondral lesions of the talus. J Am Acad Orthop Surg. 2005;13(3):152-158. 43. Shapiro F, Koide S, Glimcher MJ. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J Bone Joint Surg Am. 1993;75(4):532-553. 44. Simon LS. Viscosupplementation therapy with intra articular hyaluronic acid. Fact or fantasy? Rheum Dis Clin North Am. 1999;25(2):345-357. doi:10.1016/S0889857X(05)70072-7. 45. Solorio LD, Dhami CD, Dang PN, Vieregge EL, Alsberg E. Spatiotemporal regulation of chondrogenic differentiation with controlled delivery of transforming growth factor-β1 from gelatin microspheres in mesenchymal stem cell aggregates. Stem Cells Transl Med. 2012;1(8):632-639. doi:10.5966/sctm.2012-0039.
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46. Sun SF, Chou YJ, Hsu CW, et al. Efficacy of intra-articular hyaluronic acid in patients with osteoarthritis of the ankle: a prospective study. Osteoarthr Cartil. 2006;14(9):867-874. doi:10.1016/j.joca.2006.03.003. 47. Sundman EA, Cole BJ, Fortier LA. Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma. Am J Sports Med. 2011;39(10):2135-2140. doi:10.1177/0363546511417792. 48. Van Buecken K, Barrack RL, Alexander AH, Ertl JP. Arthroscopic treatment of transchondral talar dome fractures. Am J Sports Med. 1989;17(3):350-355. doi:10.1177/ 036354658901700307. 49. Witteveen AG, Giannini S, Guido G, et al. A prospec tive multi-centre, open study of the safety and efficacy of hylan G-F 20 (Synvisc) in patients with symptomatic ankle
(talo-crural) osteoarthritis. Foot Ankle Surg. 2008;14(3):145152. doi:10.1016/j.fas.2008.01.001. 50. Witteveen AG, Sierevelt IN, Blankevoort L, Kerkhoffs GM, van Dijk CN. Intra-articular sodium hyaluronate injections in the osteoarthritic ankle joint: effects, safety and dose dependency. Foot Ankle Surg. 2010;16(4):159-163. doi:10.1016/j. fas.2009.10.003. 51. Woodell-May J, Matuska A, Oyster M, et al. Autologous protein solution inhibits MMP-13 production by IL-1beta and TNFalpha-stimulated human articular chondrocytes. J Orthop Res. 2011;29(9):1320-1326. doi:10.1002/jor.21384. 52. Zengerink M, Struijs PA, Tol JL, van Dijk CN. Treatment of osteochondral lesions of the talus: a systematic review. Knee Surg Sports Traumatol Arthrosc. 2010;18(2):238-246. doi:10.1007/s00167-009-0942-6.No
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research-article2015
FAIXXX10.1177/1071100715578435Foot & Ankle InternationalGörmeli et al
Article
Clinical Effects of Platelet-Rich Plasma and Hyaluronic Acid as an Additional Therapy for Talar Osteochondral Lesions Treated with Microfracture Surgery: A Prospective Randomized Clinical Trial
Foot & Ankle International® 1–10 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1071100715578435 fai.sagepub.com
Gökay Görmeli, MD1, Mustafa Karakaplan, MD1, Cemile Ayşe Görmeli, MD2, Baran Sarıkaya, MD3, Nurzat Elmalı, MD4, and Yüksel Ersoy, MD5
Abstract Background: Osteochondral ankle injuries commonly affect the dome of the talus, and these injuries are a common cause of athletic disability. Various treatment options are available for these injuries including intra-articular hyaluronic acid (HA) and platelet-rich plasma (PRP) injections. The purpose of this study was to compare the effects of HA and PRP as adjunct therapies after arthroscopic microfracture in osteochondral lesions (OCLs) of the talus. Methods: In this prospective, randomized blinded study, 40 patients with talar OCLs in their ankle joints were treated with arthroscopic debridement and a microfracture technique. Thirteen randomly selected patients received PRP, 14 patients received HA, and the remaining 13 patients received saline as a control group. The participants were assessed using the American Orthopaedic Foot & Ankle Society (AOFAS) and visual analog pain scale (VAS) scores after a 15.3-month (range, 11-25 months) follow-up. Results: Postoperatively, all the groups exhibited significantly increased AOFAS scores and decreased VAS scores compared with their preoperative results (P < .005). The AOFAS scores were significantly increased in the PRP group versus the HA and control groups (P < .005), although the increased AOFAS scores in the HA group versus the control group were also significant (P < .005). Similar to the AOFAS scores, the decrease in the VAS scores was significantly lower in the PRP group versus the HA and control groups (P < .005). In addition, the HA group had significantly lower VAS scores than the control group (P < .005). Conclusion: Both PRP and HA injections improved the clinical outcomes of patients who underwent operation for talar OCLs in the midterm period and can be used as adjunct therapies for these patients. Because a single dose of PRP provided better results, we recommend PRP as the primary adjunct treatment option in the talar OCL postoperative period. Level of Evidence: Level I, prospective randomized study. Keywords: osteochondral lesions, talus, platelet-rich plasma, hyaluronic acid, microfracture
Introduction
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Intra-articular (IA) ankle injuries are a common cause of athletic disability, with approximately 27,000,000 occurrences per year.4 Osteochondral lesions (OCLs) have been estimated to occur in approximately 6.5% of these injuries. Osteochondral lesions can involve the articular surface and/ or the subchondral bone, which commonly affects the dome of the talus.2,15 Posteromedial lesions are common and deeper in thickness in these injuries. The young population is typically affected by these injuries as a result of running, jumping, or rotating.25 Ischemia, necrosis, inflammatory diseases, and genetic factors are other common etiological
Corresponding Author: Gökay Görmeli, MD, Department of Orthopedics and Traumatology, Inonu University, Turgut Ozal Medical Center, Malatya, 44000, Turkey. Email: [email protected]
Inonu University, Turgut Ozal Medical Center, Department of Orthopedics and Traumatology, Malatya, Turkey 2 Inonu University, Turgut Ozal Medical Center, Department of Radiology, Malatya, Turkey 3 Baskent University, Department of Orthopedics and Traumatology, Adana, Turkey 4 Vakıf Gureba University, Department of Orthopedics and Traumatology, İstanbul, Turkey 5 Inonu University, Turgut Ozal Medical Center, Department of Physiotherapy and Rehabilitation, Malatya, Turkey
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factors for OCLs.42 After the injury, because of the cartilage’s avascularity and poor tendency for healing, progression of the depth and size of the lesion and severity can occur and may cause osteoarthritis.1,8,26,31,32 Intra-articular injections are used for cartilage injuries and joint degeneration. Synovial fluid, a lubricant for articular surfaces, reduces surface stress and plays an important role in the movement of chondronutritive substances from the synovium.33 Hyaluronic acid (HA) is a lubricant for articular surfaces that reduces pain and inflammation and supplements the endogenous joint fluid.46 Platelet-rich plasma (PRP) is an autologous blood product that contains a high concentration of platelets.47 Platelet α-granules contain and release numerous growth factors (GFs) that have important roles in chondrogenic differentiation, matrix deposition, and decreasing the suppressive effects of interleukin (IL)-1 on proteoglycan synthesis in cartilage.6,35 Platelet-rich plasma is widely used in clinical practice to treat bone, tendon, ligament, and cartilage injuries and osteoarthritis.18,30 Despite the promising preclinical results and wide clinical interest in orthopedic and sports medicine, many unanswered questions regarding the clinical application and efficacy of PRP remain. There is a lack of clarity regarding the number and frequency of injections to ensure treatment efficacy. Despite previous reports on the effects of HA and PRP administration in a number of different conditions, to our knowledge, there have been no comparative studies of HA and PRP treatment for OCLs of the talus following arthroscopic microfracture surgery. We performed this prospective randomized study to evaluate the role of PRP and HA injections in patients with talar OCLs who were treated with arthroscopic microfracture surgery. This study’s hypothesis was that the combination of PRP or HA with arthroscopic microfracture for talar OCLs would result in better clinical outcomes compared to a control group (arthroscopic microfracture surgery combined with saline injections). The purpose of this study was to report the clinical outcomes of IA injection therapies (PRP and HA) after arthroscopic microfracture for talar OCLs.
Methods Study Design This study was designed as a prospective, blinded (observer blinded), placebo-controlled trial with 3 groups and 3 treatment methods (1 group served as the placebo group). All the participants provided written informed consent, and the study was approved by the local ethics committee. The volunteer participants were subjected to a standardized IA injection protocol that was assessed with American Orthopaedic Foot & Ankle Society (AOFAS) objective data from the physical examination of the ankle and hindfoot27 and the visual analog pain scale (VAS),12 which is a simple,
validated, and commonly used patient-administered method that assesses pain intensity.
Patient Selection Between January 2011 and January 2013, 40 patients with talar OCLs in their ankle joints were included in this study. The demographic and pretreatment score data are summarized in Table 1. The inclusion and exclusion criteria are shown in Table 2. We excluded the posterior lesions as they were very frequent and visualizing only with arthroscopy can be difficult, so additional posterior arthroscopy or osteotomy might have been needed. For patients with chronic ankle pain, a detailed medical history was obtained and a physical examination was performed. The diagnosis of OCL of the talus was confirmed via preoperative radiographs and magnetic resonance imaging (MRI). The MRI findings were classified by a blinded radiologist (CAG) using the classification systems described by Hepple et al,24 and location of lesions was addressed according to the 9-zone grid scheme described by Raikin et al.37 A total of 40 participants who met the inclusion criteria were randomly divided by computer-derived random assignments into 3 groups, and all the injections were performed 24 to 48 hours after the operation. The 13 patients receiving therapy with a PRP injection after arthroscopic microfracture constituted the PRP group, the 14 patients receiving therapy with an HA injection constituted the HA group, and the 13 patients receiving saline injections were the controls. The group assignments were accessible only to the study assistant and were concealed from the researchers in the study.
Operative Technique and Intra-articular Administration All of the patients were treated surgically with arthroscopic debridement and the microfracture technique by the senior surgeon. Twenty-four patients underwent surgery with spinal anesthesia, whereas 8 patients underwent surgery with general anesthesia in a supine position with the use of a pneumatic tourniquet with 300 mmHg of pressure. Anteromedial and anterolateral portals were used. A local synovectomy was performed for better visualization of the OCLs. After removal of the necrotic soft tissue and osteochondral fragments, the lesion bed was cleaned, and the microfracture technique was performed by using microfractures of 30-degree, 45-degree, and 90-degree awls until the fat particles were observed. A Hemovac drain was placed, and the portals were closed. The skin was sterilely closed, and elastic bandages were used to wrap the foot and ankle. All of the injections were administered after the drain was removed approximately 24 to 36 hours after the operation. A topical ethyl chloride anesthetic spray was used, and the skin was sterilely dressed. Each injection was
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Görmeli et al Table 1. Clinical and Baseline Characteristics. Parameter Age, mean ± SD, y Sex, No. (%) Male Female Duration of symptoms, mean ± SD, mo Lesion side, No. (%) Right Left Location of lesions, No. (%) Anteromedial Anterocentral Anterolateral Central-medial Central-central Central-lateral BMI, mean ± SD Lesion size, mean (range), cm2 Stage, No. (%)a Stage II Stage III Stage IV AOFAS preop, mean ± SD VAS preop, mean ± SD
PRP (n = 13)
HA (n = 14)
Control (n = 13)
P Value
38.6 ± 9.1
39.7 ± 8.7
40.3 ± 9.4
5 (38.5) 8 (61.5) 25.9 ± 14.3
8 (57.1) 6 (42.9) 26.7 ± 15.4
8 (61.5) 5 (38.5) 26.4 ± 10.8
ns ns ns
8 (61.5) 5 (38.5)
9 (64.3) 5 (35.7)
6 (46.2) 7 (53.8)
3 (23) 1 (7.6) 3 (23) 5 (38.4) — 1 (7.6) 30.5 ± 5.2 1.28 (0.52-1.4) 5 (38.5) 7 (53.8) 1 (7.7) 43.6 ± 7.6 8.0 ± 0.7
3 (21.4) — 3 (21.4) 6 (42.8) — 2 (14.2) 31.2 ± 5.4 1.24 (0.48-1.46) 4 (28.6) 8 (57.1) 2 (14.3) 44.9 ± 9.2 7.8 ± 0.9
2 (15.3) 1 (7.6) 4 (30.7) 4 (30.7) — 1 (7.6) 31.5 ± 4.5 1.18 (0.46-1.38) 4 (30.8) 7 (53.8) 2 (15.4) 42.7 ± 7.1 7.7 ± 0.7
Abbreviations: AOFAS, American Orthopaedic Foot & Ankle Society; BMI, body mass index; HA, hyaluronic acid; ns, nonsignificant; preop, preoperative; PRP, platelet-rich plasma; VAS, visual analog pain scale. a According to Hepple staging based on preoperative magnetic resonance imaging findings.
Table 2. Inclusion and Exclusion Criteria. Inclusion Criteria Age of > 18 years and < 60 years Ankle pain Diagnosed as having osteochondral lesions of the talus in the radiographs Exclusion Criteria Posterior osteochondral lesions Pregnancy Breastfeeding Infection of the ankle or nearby soft tissues Injection of steroid or surgery on the involved joint within 6 mo Treatment with a dosage of glucosamine and/or chondroitin sulfate Treatment with an anticoagulant Systemic inflammatory condition Substantial venous or lymphatic stasis in the legs Pathologies that may confound pain and functional assessments in the ankle (plantar fasciitis, Achilles tendonitis, sprains, and degenerative joint disease of the foot) Diabetic or neuropathic Charcot arthropathy Substantial vascular insufficiency Current treatment with anticoagulants Lower extremity pain syndromes Severe ankle instability or malalignment Known allergy to any of the components of either injection Disabling degenerative joint disease of the ipsilateral hip, knee, or foot
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ns ns ns ns ns ns
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administered using the anteromedial approach with a 22-g needle. In the PRP group, the Smart-PReP®2 system (Harvest Autologous Hemobiologics, Norwell, MA) was used for 13 patients. The mean platelet count increased from 236 000 ± 47 000 platelets/µL to 1 227 000 ± 242 400 platelets/µL. In the HA group, high-molecular-weight, cross-linked hyaluronic acid was administered (2 mL of Hylan G-F 20, Synvisc®; Biomatrix, Inc, Ridgefield, NJ) for 14 patients, whereas the 13 patients in the placebo group received 1 injection of 2.5 mL of normal saline solution.
Postoperative Care and Follow-up No casts or braces were used after the operation to allow range-of-motion exercises to be performed. The patients were mobilized with crutches without weightbearing immediately on the first postoperative day. Cold therapy was performed (ice in a bag 3 times and for 15 minutes at each therapy) 2 days after the operation. Partial weightbearing with crutches was permitted after the third week of the operation, and strengthening exercises began at the same time. After 4 to 6 weeks, full weightbearing was permitted with balance and proprioception exercises. Between months 3 and 6, plain running and jogging without acceleration was permitted. Finally, after 6 months, a return to athletic and more intense physical activities was permitted. The injected materials have different viscosities; thus, the physician who performed the injections could not be blinded. However, the follow-up examinations and data collection for the study instruments were performed by a second physician, who was blinded to the treatment. The AOFAS and VAS scores were used for the assessment of the functional and pain statuses of the patients. All of the volunteers were followed for an average of 15.3 months (range, 11-25 months).
Statistical Analysis GPower software was used for the sample size estimation. A sample size of 36 individuals in total (12 per arm) was proposed. This sample size would provide 80% power to detect an effect size of 0.8 (1-tail) between groups for the continuous outcome variables of the study. The data were expressed as mean ± standard deviation (SD) depending on the overall variable distribution. Normality was assessed using the Shapiro Wilk test. The normally distributed data were analyzed by a 1-way analysis of variance followed by the Bonferroni post hoc test. The qualitative data were analyzed with Pearson’s chi-square test. Spearman’s correlation was used for the relationships between the variables. P values < .05 were considered significant. IBM SPSS Statistics Version 22.0 for Windows was used for the statistical analysis.
Results All the groups had similar demographic data, preoperative scores, durations of symptoms, location of lesions, and lesion classification, as shown in Table 1. No severe adverse events occurred during the postoperative follow-up period. According to the VAS scoring system, significantly lower postoperative scores were achieved compared to the preoperative values in the PRP, HA, and control groups (P < .001) (Figure 1). The decrease in the postoperative period was found to be significantly lower in the PRP group compared to the HA and control groups. There was also a significant decrease in the HA group compared to the control group (P < .001) (Table 3). In stage 2 to 3 lesions, the postoperative VAS scores were significantly lower in the PRP group compared to other groups (PRP group: 2.5 ± 0.9; HA group: 3.3 ± 1.1; control group: 4.7 ± 0.8) (P < .05). Similarly, the postoperative AOFAS scores were significantly higher than the preoperative values for all groups (P < .001) (Figure 2). There was a significantly higher increase in the AOFAS scores for the PRP group compared to the HA and control groups (P < .001) (Table 3). Despite the prominent PRP improvement, significantly higher scores were found in the HA group than in the control group (P < .001). In stage 2 to 3 lesions, the postoperative AOFAS scores were significantly higher in the PRP group compared to other groups (PRP group: 84.3 ± 5.8; HA group: 75.9 ± 9.8; control group: 68.1 ± 11.0) (P < .05). There was no significant correlation between the postoperative AOFAS scores and age (Spearman’s rho: 0.16; P = .33), body mass index (BMI) (Spearman’s rho: 0.31; P = .84), or the duration of symptoms (Spearman’s rho: –0.41; P = .8). Similar to the AOFAS scores, there was no correlation between the postoperative VAS scores and age (Spearman’s rho: 0.27; P = .08), BMI (Spearman’s rho: –0.06; P = .69), or the duration of symptoms (Spearman’s rho: 0.14; P = .38). At the end of 1 year, 61.5% of the patients were satisfied, 23% were partially satisfied, and 15.4% were not satisfied in the PRP group. In the HA group, 35.7% of the patients were satisfied, 50% were partially satisfied, and 14.3% were not satisfied at the end of the procedure. In the control group, 46.2% of the patients were satisfied, 30.8% were partially satisfied, and 23.1% were not satisfied with the postoperative IA injection procedure. However, the difference among the 3 groups was not significant (P > .005).
Discussion The results of this study showed that both the PRP and HA injections improved the clinical outcomes of the patients who were operated on for talar OCLs; therefore, these treatments can be used as adjunct therapies for these patients. Because a single dose of PRP showed better results
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VAS Scores 10 9 8 7 6 5 4 3 2 1 0 PRP group
HA group
Control
Preopera ve VAS scores
Postopera ve VAS scores
Figure 1. Significantly lower results achieved between preoperative and postoperative visual analog pain scale scores for platelet-rich plasma, hyaluronic acid, and control groups. Table 3. Follow-up Measurements. Parameter AOFAS, mean ± SD VAS, mean ± SD
PRP Group (n = 13) a
85.1 ± 6.1 2.4 ± 0.9a
HA Group (n = 14) b
75.1 ± 9.5 3.3 ± 1.0b
Control Group (n = 13)
P Value
68.3 ± 10.1 4.5 ± 0.9
.001 .001
Abbreviations: AOFAS, American Orthopaedic Foot & Ankle Society; HA, hyaluronic acid; PRP, platelet-rich plasma; VAS, visual analog pain scale. a Significant difference from HA and control groups. b Significant difference from PRP and control groups.
compared to HA, we recommend PRP as the primary adjunct treatment in the postoperative period following surgery for talar OCLs. To our knowledge, this is the first prospective randomized blinded controlled study to compare the effects of PRP and HA after microfracture surgery for talar OCLs. Treatment strategies are dependent on the stage of the OCL, which was determined by computed tomography (CT) as described by Ferkel et al.17 The nonoperative treatment options (immobilization, restriction of weightbearing, and physical therapy) are reserved for grade 1 and 2 lesions, with a lower success rate compared to surgery.10 Operative intervention is recommended if the nonoperative treatment is unsuccessful, in chronic OCLs of the talus, if symptoms persist despite 6 months of the conservative treatment or for the initial treatment of greater than grade 3 lesions.16,28 In this study, we performed surgery on the talar OCLs according to this protocol. Current operative treatment options include reparative and restorative techniques. Reparative techniques include bone marrow stimulation (BMS) of the subchondral bone
(drilling, microfracture) and cell-based techniques (autologous chondrocyte implantation [ACI], matrix-assisted ACI). The restorative techniques are autologous osteochondral transplantation (AOT), osteochondral allograft, and juvenile cartilage allograft.40 Arthroscopic debridement and BMS (microfracture formation) is the current first-line operative treatment for lesions up to 15 mm in diameter.52 Early lesions with continuity in the cartilaginous surface and the stability of the OCL fragment are the specific indications for BMS. After microfracture, there is a biological shift to fibrocartilaginous repair tissue exhibiting primarily type I collagen at 1 year. Compared to hyaline cartilage, type I collagen may degenerate over time because it has different biological and mechanical properties.43 In addition, for large defects (> 15 mm), type I collagen may not be the optimal treatment, whereas ACI and AOT techniques would be preferred to reproduce the original hyaline cartilage at the defect site.36 We believe that although microfracture with drilling is a good treatment option with acceptable success rates, the fibrocartilage that is formed after drilling has a different
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AOFAS Scores 90 80 70 60 50 40 30 20 10 0 PRP Group
HA Group
Control Group
Preopera ve Scores
Postopera ve Scores
Figure 2. Significantly better results achieved between preoperative and postoperative American Orthopaedic Foot & Ankle Society scores for platelet-rich plasma, hyaluronic acid, and control groups.
structure from that of the hyaline cartilage, which may negatively affect the long-term outcomes. Several authors have reported good results following arthroscopic BMS,29,48 but there are many reports of poorer outcomes as well.11,25,38 Therefore, we believe that an additional IA administration would improve the clinical outcomes. The preference for the microfracture technique over ACI and AOT in this study can be debated because the success rates of these techniques have been reported to be in the ranges of 74% to 100% and 70% to 92%, respectively.52 In our study, greater than 15 mm lesions were excluded. In addition, we considered the disadvantages of these techniques: AOT has donor site morbidity and the risk of joint incongruency, whereas ACI has a high cost, is technically demanding, and requires a second surgery. In contrast to the disadvantages of the AOT and ACI techniques, the main advantages of the microfracture technique include arthroscopic application with no donor site morbidity, fewer wound healing problems, a quick recovery, and a decreased cost.14,21 The healing capacity of cartilage is limited by its limited vascularity and its contribution to the progressive degeneration of damage.9 The α-granules of platelets contain a variety of factors (transforming growth factor β, fibroblast growth factor, and platelet-derived growth factor) that promote cartilage matrix synthesis and inhibit the catabolic effects of IL-1β and TNF-α on articular cartilage.7,34,45 In an in vitro study on human knee chondrocytes, Woodell-May et al51 showed that PRP significantly inhibited the production of matrix metalloproteinase (MMP)-13 induced by IL-1β and TNF-α. In addition, Fortier et al19 showed that PRP increases cell growth and the chondrocyte transcription of
proteins with a decrease in the NF-kB-mediated production of catabolic cytokines. Synovial fluid acts as a lubricant and shock absorber for joint function, and the viscoelasticity of synovial fluid results from HA.3 With a decrease in synovial fluid, increased stress occurs in the joint, which leads to cartilage degeneration. Hyaluronic acid decreases the development of osteoarthritis by decreasing the degradation of cartilage proteoglycans and inhibiting arachidonic acid release, prostaglandin E2 synthesis, and IL-1 and MMP-3 expression.22,44 Hyaluronic acid has analgesic activities based on its anti-inflammatory effects, which have been demonstrated by in vitro and animal studies.20 This property may explain the significant decrease in the VAS scores of the patients treated with HA in our study. These studies suggest an important role for PRP and HA as potent biological regulators of chondrocytes in cartilage repair. To our knowledge, only a few prospective studies have been designed to evaluate the effectiveness of PRP and HA injection therapies for osteoarthritis of the ankle in clinical practice. Salk et al39 randomized 20 patients to receive 5 weekly IA injections of either 1 mL of sodium hyaluronate (10 mg/ mL) or 1 mL of phosphate-buffered saline solution into the ankle joint. The authors concluded that IA injections of sodium hyaluronate can provide sustained relief from pain and can improve function in patients with osteoarthritis of the ankle. However, contrasting results were obtained in a study involving 64 patients with ankle osteoarthritis who were randomly assigned to a single IA injection of 2.5 mL of low-molecular-weight, non-cross-linked HA or a single
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Görmeli et al IA injection of 2.5 mL of normal saline solution. The AOFAS clinical rating scores at 6 and 12 weeks were evaluated. The authors found that a single IA injection of lowmolecular-weight, non-cross-linked HA was not superior to a single IA injection of saline solution for the treatment of osteoarthritis of the ankle.13 This result may be related to the content of the HA (low molecular-weight, non-cross-linked HA) they used during their treatment. In our study, we used a single injection of a high-molecular-weight, cross-linked hyaluronic acid product (Synvisc), which has been shown to be effective in the ankle.49 The administration of a high-molecular-weight, cross-linked HA product instead of a low-molecular-weight, non-cross-linked HA product may explain our significantly better scores for the HA group. Similar to Salk et al, there was a significant improvement in the clinical and pain scores for the HA group in our study. The significantly better results achieved in the postoperative period may not have been merely a placebo effect. These results may be related to the role of saline solution in providing a lubricating effect, thus diluting the lytic enzymes and proinflammatory cytokines associated with cartilage degeneration. In a randomized controlled trial, Mei-Dan et al32 treated 32 patients with IA injections of either HA or PRP (for OCLs of the talus). These patients received 3 consecutive IA therapeutic injections and were followed for 28 weeks by assessing their AOFAS, Ankle-Hindfoot Scale, and VAS scores. Similar to our results, the authors concluded that the use of both HA and PRP offers a viable treatment option for patients with ankle OCLs, with a significantly better outcome for the PRP treatment. They also suggested the IA injection of either PRP or HA as the first-line treatment of symptomatic talar OCLs or as a second-line treatment for patients who are symptomatic after surgery. Despite the well-designed studies investigating IA injection for talar OCLs in a nonoperative treatment, to our knowledge, only a few studies have evaluated adjunct therapies for microfracture surgery for OCLs of the talus. In a welldesigned randomized prospective study performed by Guney et al,23 patients who received microfracture surgery were divided into 2 groups. Sixteen patients received treatment with microfracture surgery alone, whereas the remaining patients (PRP group, n = 19) were also given 1 dose of PRP the day after surgery. Similar to our results, the authors found that the combined treatment with PRP resulted in better outcomes compared to arthroscopic microfracture surgery alone. A limitation of this study, which the authors discussed in the article, was that the control group did not receive IA injections. However, the necessity of adding an IA saline injection to the control is debatable because of the potential positive effects of the saline solution for the ankle joint, as described above. To determine the effect of a saline injection in the ankle joint, a group of patients undergoing the microfracture surgery alone, without saline injection, should perhaps have
been added as another group in our study. The unblinded design was another limitation of this study. In our study, the blinded observer performed and recorded the results; the individual who performed all the injections was not blinded because of the distinct difference in the viscosity of the injected materials in the different groups. In another randomized prospective study performed by Doral et al,14 41 patients were injected intra-articularly with HA, whereas the remaining 16 patients did not receive a postoperative injection after arthroscopic debridement and microfracture for talar OCLs. After 2 years of follow-up, the authors found significantly higher scores in the injection group compared to the noninjection group in both the Freiburg and AOFAS scoring systems. They concluded that additional treatment with an IA hyaluronan injection as an adjunct to the microfracture technique may offer better clinical outcomes compared to the microfracture technique alone. To our knowledge, there have been no prospective, randomized, blinded studies that evaluated both HA and PRP IA injection therapies as adjuncts to arthroscopic microfracture for talar OCLs. Similar to the studies summarized above, we believe that either PRP or HA IA injection after BMS may be used as an adjunct therapy. We also believe that because it was associated with better functional and pain-related scores, 1 dose of PRP the day after surgery may be the primary adjunct therapy versus HA injection. We administered a single injection of HA and PRP the day after surgery rather than 3 or 5 weekly injections. As discussed by Guney et al,23 the advantages of an injection after the first postoperative day are that it does not necessitate any additional admissions and that anesthesia is not required because the patient does not experience any pain. In addition, no differences were found between the singleand double-dose injections in a study performed by Witteveen et al.50 The infection risk as a result of potential aseptic conditions with multiple conditions must be considered as well. In addition, multiple injections might have led to a loss of patients from the study because returning to the clinic regularly may be challenging. Previous outcome scores were negatively affected by degenerative arthritis, increased age, and a higher BMI.41 Conversely, in our study, we found no relationship between the postoperative results and the patient’s sex, age, BMI, or OCL grade. This finding is related to the IA adjunct therapies after the surgery, which may improve the outcome scores of all the patients. The strengths of this study are the randomized, prospective, blinded design; the adequate number of patients who clearly presented with ankle-related pain, which was correlated with radiographic findings that were calculated with a power analysis; the lack of significant differences in the baseline characteristics for all the randomly assigned groups; and the absence of any financial support from the manufacturer of the device.
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This study has several limitations. One limitation is the relatively short-term follow-up period. We evaluated our patients at a maximum follow-up of 12 months because the viscosupplementation therapy could be repeated after a certain time interval, and a different treatment option may have been required for the patients. In addition, longer followups without additional treatment might have led to a loss of patients from the study. However, the literature has shown that a treatment effect is observed as soon as 1 week after the injection, and the maximal effect appears to occur between 5 and 13 weeks after the injection.5 Another weakness of our study is that we did not use image guidance to ensure the location of the needle in the ankle joint. The lack of accurate documentation of analgesic use is another limitation of this study. The patients were permitted to use paracetamol as required in the postoperative period. This factor may have affected the results, but we believe that such an effect would be similar for both groups because most of the patients stated that they did not use analgesics upon follow-up. Radiographic follow-up methods to evaluate cartilage degeneration and microscopic information on the effects of PRP and HA on the quality of repair tissue could have been reported in this study. However, we could not conduct these evaluations because of cost and ethical limitations. Despite the adequate group size calculated by the power analysis, it would be preferable to perform this study with larger groups. However, OCLs of the talus are not common, and it is relatively difficult to recruit patients suffering from this problem. Ideally, the present investigation would have been conducted through a multicenter study; however, we hypothesized that it would be difficult to optimize the treatment protocols for all the centers. Not optimizing the treatment protocols would affect the reliability of the study; thus, we performed a single-center study.
Conclusion This study suggests that an early single-dose IA PRP and HA administration to the ankle joint can be used as an adjunct therapy after arthroscopic debridement and microfracture for talar OCLs. In particular, PRP injections were more effective than HA injection in patients with OCLs of the talus and PRP is thus recommended by us as the primary adjunct treatment option in the talar OCL postoperative period. However, longer term results and multicenter studies with larger sample groups are required to design optimal guidelines for the adjunct therapies of talar OCLs that are treated with debridement and the microfracture technique. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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