Acp-comparison of surgically repaired achilles tendon tears using platelet-rich fibrin matrices

Comparison of Surgically Repaired Achilles Tendon Tears Using Platelet-Rich Fibrin Matrices
Mikel Sánchez, Eduardo Anitua, Juan Azofra, Isabel Andía, Sabino Padilla and Iñigo Mujika 2007; 35; 245 originally published online Nov 12, 2006; The online version of this article can be found at: http://ajs.sagepub.com/cgi/content/abstract/35/2/245 Additional services and information for
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The American Journal of Sports Medicine during the healing process of tendinous tissue.10,14 Furthermore, the healing tendon is also responsive to localapplication of growth factors.1,13,20,24,27,34 An autologous platelet-rich fibrin (prepared from platelet-rich plasma) Twelve athletes with spontaneous complete rupture of secretes a complex mixture of biological mediators essen- the Achilles tendon were treated operatively at the tial to natural repair, including transforming growth Arthroscopic Surgery Unit, USP–La Esperanza Clinic, factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), Vitoria-Gasteiz, Spain, between 1997 and 2004. Approval vascular endothelial growth factor (VEGF), epithelial by the local ethics committee for the prospective use of growth factor (EGF), hepatocyte growth factor (HGF), and PRGF and written informed consent were obtained.
insulin-like growth factor (IGF-I). Because most of these Exclusion criteria were previous tendon injury, history of growth factors have been identified as playing key roles in diabetes mellitus, platelet abnormality, hematologic abnor- tendon healing,15,24 the use of autologous platelet-rich mality, serum hemoglobin concentration <11 g/dL or hema- plasma has been proposed as a strategy for enhancing the tocrit <34%, use of systemic cortisone, and current use of cellular response to injury within the tendon and, ulti- anticoagulants. A 2-step application method of platelet- rich therapy in conjunction with reconstructive surgery An interesting new feature of the physiologic function of was performed in 6 athletes treated from 2002 to 2004 platelets is their role as vehicles for the local delivery of (Figure 1). Six of 11 athletes treated from 1997 to 2001, growth factors in wound healing.4 At sites of vascular selected by the same mechanism of injury, matched by age, injury, platelets adhere and aggregate and also generate gender, and physical activities, and who had the identical thrombin, which triggers the production of a fibrin matrix surgery procedure but without the application of platelet- rich therapy, were identified retrospectively.
To derive benefit from this natural mechanism, we have Two experienced orthopaedic surgeons of our group (M.S.
developed a procedure in which Ca2+ is added to plasma and J.A.) performed all surgeries. All patients were male; enriched in platelets, triggering the formation of a fibrin descriptors of both groups are summarized in Table 1.
matrix containing embedded platelets. The resulting prepa- Clinical evaluation and a positive Thompson sign, followed ration rich in growth factors (PRGF) allows the slow release by complementary ultrasound study (Logic 400 MD, GE of biologically active proteins that initiate and modulate Medical Systems, Milwaukee, Wis) or magnetic resonance wound healing in both soft and hard tissues.4,6 imaging (high-resolution 1.5-T Magnetom Vision unit, Previous studies by our group have shown that tendon Siemens, Erlangen, Germany) were used to diagnose and cells in vitro respond to the secreted pool of growth factors confirm the complete Achilles tendon rupture in all by proliferating, a basic response fundamental for repair.
patients. All cases were operated on no later than 2 weeks Moreover, and also crucial for tissue healing, this treatment elicited an angiogenic response based on the synthesis ofVEGF and HGF by tendon cells.5 This could be especiallyrelevant to the vascular status of tendons, assuming that the low healing capability of tendons is associated with a reducedblood supply when compared with other tissues. From a We studied quantitative aspects of PRGF in a group kinetic point of view, fibrin matrix exerts a control of growth of 21 volunteers affected by ligament, tendon, or muscle factor release mimicking natural expression patterns; this traumatic injuries, including the 6 athletes operated on fact promoted a further examination of tendon cells cultured with PRGF. The mean age of donors was 30.7 ± 7.1 years.
on autologous fibrin matrices and the effects of their admin- Blood was collected in tubes with 5 mL trisodium citrate, istration in vivo. Results demonstrated that PRGF is a safe and then centrifuged at 460g for 8 minutes (PRGF System strategy to accelerate tendon cell proliferation, stimulate II, BTI, Vitoria-Gasteiz, Spain). The 1-mL fractions imme- the synthesis of type I collagen, and promote neovascular- diately above the erythrocyte pellet were collected from ization both in vivo and in vitro.8 Moreover, other studies each tube and transferred to sterile tubes, and the platelet have reported the potential impact of platelet-rich fibrin on count was determined. Care was taken to avoid collecting impaired wound healing,12 which is considered the major potential complication associated with operative treatment For the in vitro determinations, a platelet-rich fibrin matrix was formed by adding calcium chloride at a final All these arguments provided the fundamentals for test- concentration of 22.8 mM; clots were allowed to retract for ing the defined PRGF in conjunction with the surgical treat- 1 hour at 37°C. The released supernatants were assayed ment of a ruptured Achilles tendon in a preliminary to provide relevant information about the concentration of observational study in athletes, for whom accelerated func- potentially therapeutic growth factors in platelet-rich tional recovery is essential. Before February 2002, Achilles plasma preparations such as PDGF-AB, TGF-β1, VEGF, tendon surgery was performed using a surgical procedure EGF, and plasmatic factors such as IGF-I and HGF. All previously described.31 After February 2002, a method for these factors were assessed utilizing commercially available the application of PRGF during surgery was introduced.
enzyme-linked immunosorbent assay kits (Quantikine col- Thus, we were able to study and compare 2 groups of orimetric ELISA kits, R&D, Minneapolis, Minn), used accord- patients: those who underwent the conventional surgical ing to the manufacturer’s instructions. All measurements procedure and those who underwent the same procedure were performed in triplicate, and no unexpected scattering combined with autologous PRGF therapy.
2007 American Orthopaedic Society for Sports Medicine. All rights reserved. Not for commercial use or unauthorized distribution.
Enhanced Tendon Healing With Autologous Plasma Figure 1. The surgical procedure applying preparation rich in growth factors (PRGF). A, the ruptured ends of the Achilles tendon
are approximated and sutured. B, injection of calcified unclotted plasma within the fascicles; the fibrin matrix develops in situ.
C, the affected area is covered with an autologous platelet-rich fibrin matrix before closure of the overlying skin. D, subcutaneous
infiltration of calcified unclotted PRGF before suturing.
For the surgical procedure, 40 mL of blood was drawn by puncture from an antecubital vein 20 to 30 minutes before surgery and before the administration of anesthesia.
Platelet-rich plasma was separated as explained above.
Four milliliters were supplemented with calcium chlorideat a final concentration of 22.8 mM and left to rest for 30 minutes in a glass container, allowing the fibrin scaffoldto develop before grafting. In addition, 4 mL of injectable PRGF, in which calcium chloride was added just before The same surgical technique was used in both groups.
Briefly, after debridement of the tendon edges, a polydiox- anone (PDS) tape 5 mm large and 60 cm in length (Ethicon Inc, Johnson & Johnson, Brussels, Belgium) is placed with a V-40 half-circle needle using a Kessler technique in the proximal stump. A second suture is placed in the distalstump. The knee is then flexed, and the foot is plantar aPRGF, preparation rich in growth factors. Applicable values are flexed; the ends of the suture can be tied without tension.31 mean (SD); no significant differences were found.
2007 American Orthopaedic Society for Sports Medicine. All rights reserved. Not for commercial use or unauthorized distribution.
The American Journal of Sports Medicine The repair is then augmented using a 0-coated Vicril (CP Medical, Johnson & Johnson, Belgium) vertical locking circumferential suture. In the platelet-rich treated group, All patients underwent standardized ultrasound evalua- approximately 4 mL of the activated plasma was injected tion by 2 experienced musculoskeletal radiologists blinded among the tendon fibers after the tendon was sutured.
to the surgical treatment (Logic 400 MD, GE Medical After closing the paratenon and before closing the overly- Systems, with 7.5-12.0 MHz linear array transducer). The ing skin, the affected area was covered with the fibrin scaf- interval between surgery and this examination was differ- fold prepared as described above (Figure 1). Patients ent between groups (control, 50 ± 11 months; PRGF, 32 ± received a single preoperative dose of 2 g intravenous 10 months); however, both time intervals are long enough cefonicid (Rottapharm, Valencia, Spain); a subcutaneous to ensure complete remodeling of the scar. Patients were dose of 2500 UI bemiparine (Hibor, Laboratorios Rovi, examined in the prone position with the affected foot hang- Madrid, Spain) was administered daily for 3 weeks postop- ing over the end of the examination table. For each subject, eratively, and 500 mg diclofenac was administered twice ultrasound scans were performed at both Achilles tendons, daily for a period up to 10 days or longer postoperatively as 4 to 5 cm proximal to the insertion with the ankle in neu- tral position (90° of flexion). The Achilles tendon wasscanned transversely with the transducer perpendicular to the Achilles tendon. The transducer was angled craniallyand caudally until the scan plane showed an Achilles ten- A below-knee plaster cast with neutral position of the don with maximum echogenicity. The cross-sectional area ankle was used for 2 to 3 weeks; patients were allowed to of the Achilles tendon was measured by trace ellipse walk with elbow crutches for this period. At 2 to 3 weeks, method so that the ellipse just surrounded the echogenic the cast was removed, and the patients commenced an boundary of the Achilles tendon.33 The intraclass correla- active rehabilitation protocol instructed and supervised by tion coefficient (ICC) of the cross-sectional area was 0.891; a physical therapist blinded to the surgical treatment.
the upper 95% confidence interval (CI) was 0.915; the A reduction in heel size (1.5 cm), followed by a gradual lower 95% CI was 0.841, indicating a reproducibility of increase in active and passive dorsiflexion, was begun.
89%. The cross-sectional area of the contralateral asymp- Unloaded stationary bicycling and swimming were tomatic tendon was used as a reference to calculate the included later in this phase. Patients were authorized to begin running daily for about 10 minutes based on tactileexploration, recovery of movement and calf strength (based on the 1-footed tiptoe test, in which subjects arerequired to stand on tiptoes of the injured side for 5 sec- All results are expressed as mean ± SD. Significant dif- onds, 10 times), and examination of ultrasonographic ferences among groups were evaluated using the Mann- scans; intensity and duration were increased gradually as Whitney U test. The mean cross-sectional area was compared using the Student t test. Scatter plots andPearson correlations were used to examine the relation-ship between platelet counts and growth factor concentra- tions. A difference of P < .05 was considered to be Patients were examined by the operating surgeons; in statistically significant (Statgraphics Plus, Manugistic, general, time frames of follow-up were scheduled every other week during the first month, every 4 to 6 weeks upto 6 months, and then after 9 and 12 months. Functional outcome evaluation was based on the following 3 indica-tors: time necessary to reach full range of motion, time needed to take up gentle running, and time to resumetraining activities. The range of motion of the ankle was All ruptures were localized in the main body of the tendon, measured using a goniometer (Biomet Inc, Warsaw, Ind) at 4 to 5 cm proximal to the calcaneus insertion. Hospital and compared with the contralateral ankle. The date on stay was 48 hours for all patients. No patient had major which surgeons authorized gentle running according to complications such as rerupture or deep infection. All the criteria above was used as an outcome indicator.
wound complications appeared in the control group. Two Complications such as infections, wound healing defects, patients presented keloid scars, but they did not require subcutaneous tendon adhesions, symptoms of sural nerve further treatment. Another patient suffered a superficial injury, and calcifications were evaluated in both groups.
skin and subcutaneous infection 6 weeks after surgery and Final decisions regarding suitability to return to practice required surgical debridement that was followed by pri- and competition remained solely with the sports medicine mary closure. We did not find any calcification or altered staff of each club. Data derived from closed questions to the patients based on a simplified construct of Cincinnati As shown in Table 1, sports activities were different function scales30 were used to define the elapsed time between the 2 groups, and patients in the PRGF group had to get back to sporting activities, normal training, and a higher demand of running and jumping. Figure 2 shows the differences in the functional recovery of both groups.
2007 American Orthopaedic Society for Sports Medicine. All rights reserved. Not for commercial use or unauthorized distribution.
Enhanced Tendon Healing With Autologous Plasma are particularly important because the growth factors aredirectly implicated in the healing process. For this aim,growth factor concentration was determined in the PRGFobtained from a total of 21 donors. The PRGF prepared asdescribed resulted in an increase in platelet concentration.
In fact, the count of platelets in peripheral blood rangedfrom 142 × 103 to 379 × 103 (mean, 223 × 103 ± 71 × 103platelets/µL) and from 421 × 103 to 1314 × 103 (mean, 634 × 103 ± 217 × 103) in the PRGF. These data reflect thatPRGF had a 3.10-fold (SD, 0.58) increase in the meanplatelet concentration. Furthermore, the leukocyte contentwas also determined in the whole blood and in the PRGF.
Results showed that white blood cell content in PRGF was Figure 2. Differences in the functional recovery of 6 athletes
below the detection limit of the coulter, confirming the treated with preparation rich in growth factors (PRGF) during absence of leukocytes in the PRGF, which improves the surgical reconstruction and a matched group that followed homogeneity of the product and reduces donor-to-donor conventional surgical procedure. Indices of functional out- variability. The content of growth factors released from the come: time necessary to reach total motion, take up gentle activated PRGF was also measured for each donor. Mean running, and resume training activities (mean ± SD). *P < .05.
levels of EGF, VEGF, and HGF were 481.5 ± 187.5 pg/mL,383.0 ± 374.9 pg/mL, and 593.87 ± 155.8 pg/mL, respectively.
All 3 indices of functional outcome (attainment of full On the other hand, mean IGF-I, PDGF, and TGF-β concen- range of ankle motion, time needed to be able to run gen- trations were higher than the above-mentioned factors, tly, and time to resume normal training activities) were reaching 94.53 ± 32.84 ng/mL, 35.62 ± 14.57 ng/mL, and significantly faster in the PRGF-treated group. At the indi- 74.99 ± 27.48 ng/mL, respectively. Another feature vidual level, 2 professional athletes (soccer and basketball) of this therapy is the significant positive correlation found treated with PRGF returned to competition at a level sim- between platelet count and the levels of TGF-β1 (r = .6157, ilar to preinjury within 14 weeks after surgery. Two of the P = .003), PDGF-AB (r = .6831, P < .001), VEGF (r = .5966, P= amateur athletes in the PRGF group (soccer and basket- .023), EGF (r = .5910, P = .029), and HGF (r = .6544, ball) attained preinjury level by 6 months, whereas the 2 P = .008). Interestingly, IGF-I showed a significant inverse remaining athletes (soccer) retired from competitive sports correlation with age (r = –.6897, P < .001).
for reasons other than the injury; however, their level ofactivity was high (level 1 to 2, Cincinnati Scale). Beforeinjury, the Cincinnati Sports Activity Scale30 was similar for control (90 ± 12 points) and PRGF athletes (88 ± 11 Surgical repair of the foot and ankle is now advancing points). PRGF patients attained the same sports activity toward minimally invasive surgery that tends to allow for scores at 14 weeks (range, 2 weeks), while control athletes a more rapid recovery with less pain. If operative treat- scored 82 ± 11 points at 22 weeks (range, 8 weeks). In the ment is the right solution, the goal is to minimize compli- control group, 1 amateur athlete (basketball) returned to cations related to the surgery and promote healing with competitive participation and 5 athletes retired; this was a early functional recovery that does not compromise repair.
common feature in Achilles tendon repairs during this In clinical conditions such as Achilles tendon tears, the period. Despite retiring from competitive participation, all operative treatment offers a significant reduction in the subjects reported they were in good fitness and continued risk of rerupture and produces better functional results performing in sport activities at a lower level and did not when compared with nonoperative treatment, rendering surgery the most recommended option in athletes.3,9However, the number of complications has been estimated as 15% to 20%, rising in parallel with the increasing inci- dence of ruptures in active people.3,18,21,26 Concerns about unpredictable impairment in healing In both groups, the cross-sectional area of the operated led us to treat tendon tears combining the principles of tendon was significantly greater than the contralateral biology and surgery by applying an autologous platelet- tendons. The mean increase in cross-sectional area of the rich fibrin during the operative treatment. The delivery of repaired Achilles tendon 4 to 5 cm from the insertion in the a complex pool of factors and proteins from the fibrin calcaneus was 298% ± 90% and 499% ± 91% for the PRGF matrix seeks to better meet the expected need for the and the control group, respectively (t = 3.44, P = .009).
The idea of using fibrin as a therapeutic tool is not new.
Taking advantage of its adhesive properties was proposed years ago as an alternative to suturing in Achilles tendonruptures.32 However, clinical results indicated that the Initially, a full characterization of the main growth factors procedure was not good enough to be recommended in released from activated PRGF was performed. These data 2007 American Orthopaedic Society for Sports Medicine. All rights reserved. Not for commercial use or unauthorized distribution.
The American Journal of Sports Medicine Concepts that have evolved since the development of fibrin as matrix metalloproteinase-8, and release reactive oxygen glues have given rise to the new platelet-rich technology that species that destroy surrounding injured or healthy cells.6 overcomes some of the drawbacks associated with fibrin Because part of this therapeutic strategy is to increase glues. Although fibrin glues provide adhesive properties and growth factor concentration at the injured site, we have scaffolding function, they lack signaling factors. In fact, they assessed the most relevant growth factors to tendon heal- are prepared by polymerization of homologous lyophilized ing.24 Although some of the individual roles of these factors fibrinogen through the addition of massive thrombin. In con- have been described in the scientific literature, their func- trast, PRGF provides a bioactive scaffold offering a highly tions could be modified by the presence of other molecules.
complex pool of signaling factors critical to ensure cell acti- For example, the presence of TGF-β1 could provide some vation and the successful growth of healthy tissue. In previ- concerns about application of this therapeutic strategy, as ous studies, we showed that tendon cells seeded on this protein is associated with excessive collagen deposi- autologous PRGF proliferate and synthesize type I collagen, tion and scar tissue formation, damaging the mechanical in contrast to fibrin glue. Moreover, tenocytes elicited an properties of the repaired tissue. We addressed this issue angiogenic response by synthesizing VEGF and HGF.8 in previous experimental studies and showed that the Assuming these effects, PRGF treatment would enhance the effect of TGF-β1 on collagen synthesis was counteracted quality of tendon repair and the time of healing.
by the presence of other platelet-secreted molecules.7 We explored the relevance of applying PRGF during Furthermore, when several doses of this plasma were open surgery in a group of athletes. The treatment con- injected weekly in Achilles tendons in sheep, no signs of sisted of replacing the natural hematoma, containing a fibrosis were observed, implying that the use of fibrin bulk of red blood cells (about 94%) and a little proportion matrices may be a safe strategy to initiate and promote of platelets (6%) and <1% leukocytes, with PRGF, which healing in damaged tendons.8 Supporting these findings, merely contains platelets embedded in a fibrin matrix.
our preliminary clinical evidence with PRGF resulted in The fact that tendons are often subjected to high or less increase in width and cross-sectional area in platelet- unusual loads during sports participation reflects better rich–treated tendons in contrast with the control group, the functional efficacy of this novel procedure. Our study indicating a more physiologic repair with less scar tissue.
population included 12 carefully matched athletes with In addition, it has been reported that platelets also store total tears of the Achilles tendon. The functional results antibacterial and fungicidal proteins that could prevent using this surgical repair and postoperative rehabilitation infection, although this has yet to be proved.19 protocol were within the reported outcomes for this The method described for the preparation of PRGF is injury.22,25 Despite the fact that all athletes did well with easy to implement and to handle and is applied in a sim- Achilles repair, the PRGF group required a shorter time in ple way. The risk of disease transmission or an antigenic the recovery of motion and return to sporting activities; the reaction is nonexistent because autologous blood is not latter was a decision that came solely from the sports med- mixed with any other component of animal or human icine staff rather than the operating surgeons.
We report 100% healing without any delayed wound Based on this preliminary study, we suggest that the healing, sural nerve injury, or superficial or deep infection operative management of Achilles tendon tears associated in the PRGF-treated group. In contrast, minor complica- with the application of autologous platelet-rich fibrin could tions including 1 superficial infection and 2 keloids were present new possibilities for enhanced healing and func- described in the control group. Although this study is tional recovery. Although these preliminary results need merely observational, the reported results are in accor- confirmation in a large cohort of patients, they provide dance with the proven efficacy of platelet-rich derived useful information about the safety of this new surgical therapies in other clinical areas,4 including the treatment procedure and open new perspectives in the area of sports of chronic leg ulcers,23 articular cartilage surgery,29 and medicine, where acceleration of healing is paramount.
anterior cruciate ligament reconstruction.28 Our study has some inherent weaknesses. It is a retro- spective study, and although it represents the first descrip- tion of tendon treatment with an autologous platelet- The authors are grateful to Dr Yangüela and Dr Orive for rich preparation reported in the literature, the number of their magnetic resonance imaging and ultrasonography patients is small. Further clinical studies are needed to expertise. The work of this group is partially funded by the determine the validity of the procedure.
Fully understanding the influence of platelet-rich therapy on healing is an area of developing research.
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