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Keywords:

  • tendinopathy;
  • platelet-derived growth factor-BB;
  • platelet-rich plasma;
  • corticosteroid;
  • biomechanics

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
  8. Supporting Information

This study compared the effect of intra-tendon (IT) delivery of recombinant human platelet-derived growth factor-BB (rhPDGF-BB), platelet-rich plasma (PRP) and corticosteroids in a rat tendinopathy model. Seven days after collagenase induction of tendinopathy, a 30-µl IT injection was administered. Treatments included: saline; 3 µg rhPDGF-BB; 10 µg rhPDGF-BB; PRP; and 300 µg triamcinolone acetonide (TCA). Outcomes were assessed 7 and 21 days after treatment. All groups exhibited good to excellent repair. Relative to saline, cell proliferation increased 65% in the 10 µg rhPDGF-BB group and decreased 74% in the TCA group; inflammation decreased 65% in the TCA group. At 7 days, maximum load-to-failure was increased in the 3 µg rhPDGF-BB group relative to saline, PRP, and TCA (p < 0.025). On day 21, maximum load-to-rupture was increased in the 10 µg rhPDGF-BB group relative to saline, PRP, and TCA (p < 0.035) and in the 3 µg rhPDGF-BB group compared to saline and TCA (p < 0.027). Stiffness in the 10 µg rhPDGF-BB group was increased compared to saline, PRP, and TCA (p < 0.038). Histology demonstrated similar repair in all groups. PRP and TCA did not improve mechanical properties compared to saline. Injections of rhPDGF-BB increased maximum load-to-failure (3 and 10 µg) and stiffness (10 µg) relative to controls and commonly used treatments. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:145–150, 2014.

Tendinopathy is a painful condition that develops as result of tendon degeneration[1, 2] and can affect tendons throughout the body (e.g., rotator cuff, Achilles). Tendinopathy leads to collagen degeneration, disorganization, increased mucoid ground substance, proliferation of capillaries and arterioles, loss of mechanical properties, and concomitant pain. These degenerative changes occur without macroscopic tearing of the tendon and may result from a failed healing response to sub-failure injuries.[1-3]

Current treatment options for tendinopathy including, but not limited to, exercise-based physical therapy, corticosteroid injections, non-steroidal anti-inflammatory drugs, extracorporeal shock wave therapy and surgical interventions[4-11] have met varying degrees of success. These therapies often treat the symptoms associated with the condition, but do not address the underlying cause resulting in persistence of the degeneration. While not considered a gold-standard treatment, corticosteroid injections are often administered for chronic tendinopathies. However, there are concerns about the long-term safety and efficacy of this therapy[8-10] due to adverse changes within the tendon.[12]

Growth factors have also been assessed to promote tendon healing. Autologous growth factors in the form of platelet-rich plasma (PRP) have been studied; however variability in the preparation and composition of PRP makes it difficult to compare results across studies.[13] Additionally, variable clinical outcomes following PRP treatment for tendinopathy have been reported.[14, 15] As an alternative to PRP, recombinant human platelet-derived growth factor-BB (rhPDGF-BB) is a readily available, off-the-shelf option that provides a consistent, therapeutic dose. Utilizing a variety of delivery methods, animal models of tendon injury have shown that rhPDGF-BB accelerates tendon healing by improving matrix remodeling, increased collagen synthesis, and increased cell proliferation.[16-22] We have previously reported that rhPDGF-BB is efficacious in a non-ruptured, degenerated, tendinopathy model.[23] In contrast to corticosteroids, rhPDGF-BB addresses chronic tendinopathies by inducing proliferation and migration of progenitor cells and tenocytes,[17, 24-26] which stimulate structural repair of the degenerated tendon.

As a consequence of the deficiencies in clinical outcome offered by contemporary therapies, the objective of this study was to compare the effect of intra-tendon (IT) delivery of rhPDGF-BB, PRP and corticosteroids in a rat Achilles tendinopathy model. We hypothesized that IT delivery of rhPDGF-BB would result in increased biomechanical strength and improved histological appearance compared to PRP and steroids.

MATERIALS AND METHODS

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
  8. Supporting Information

Animals

This study was approved by the Institutional Animal Care and Use Committee at Bolder BioPATH, Inc. Male Sprague-Dawley rats weighing approximately 315 g (Charles River Labs, St. Constant, Quebec) were used. Rats were housed four per cage under a 12:12-h light-dark cycle and food and water were provided ad libitum.

Preparation of Platelet-Rich Plasma

PRP donor animals (n = 18) were sacrificed and each was used to treat two study animals (one sacrificed at 7 days and one sacrificed at 21 days post-treatment). PRP was prepared using a double-spin method.[27, 28] Briefly, 6.5 ml of blood was collected with 1.5 ml of acid citrate dextrose-A from the descending aorta and centrifuged at 220g for 20 min. The plasma was collected and centrifuged again at 480g for 20 min. The platelet-poor plasma was removed and the platelets were resuspended in 900 µl of platelet-poor plasma to form the PRP. Aliquots of whole blood, plasma, and PRP were collected for quantification of complete blood counts and of growth factors.

Analysis of Platelet-Rich Plasma

Immediately following preparation, complete blood counts were performed on samples of whole blood, plasma, and PRP using a Hemavet 950 FS system to determine red blood cell (RBC), white blood cell (WBC) and platelet (PLT) counts. Aliquots of plasma and PRP were frozen at −80°C for later quantification of growth factors. Enzyme-linked immunosorbent assays (ELISA) specific for rat PDGF-AB, PDGF-BB, vascular endothelial growth factor (VEGF), and transforming growth factor-β1 (TGF-β1) were used according to manufacturer's instructions (Quantikine Immunoassays, R&D Systems, Minneapolis, MN).

Experimental Protocol

On day-7, rats received an injection of collagenase (50 µl of 10 mg/ml Type IA in PBS, pH 7.4, 469 units/mg; Sigma, St. Louis, MO) into the right Achilles tendon near the osseo-tendinous junction using insulin syringes with 28.5 G needle as described previously.[23] Seven days following the collagenase injection (day 0), rats were randomized to one of five treatment groups (n = 18/time point/group): (i) saline (placebo control); (ii) 3 µg rhPDGF-BB (BioMimetic therapeutics, Inc., Franklin, TN); (iii) 10 µg rhPDGF-BB; (iv) 8.3 × 109–1.5 × 1012 platelets/L (PRP); or (v) 300 µg triamcinolone acetonide (TCA; Bristol-Myers Squibb Company, Princeton, NJ). These concentrations, adjusted for animal size, are consistent with other investigations of tendon rupture healing.[22, 29] Animals received an injection volume of 30 µl of the assigned treatment solution into the damaged Achilles tendon. Rats were anesthetized with isofluorane during the collagenase and subsequent treatment injections. Rats were euthanized 7 or 21 days following treatment. Additional animals (n = 18) were euthanized on the day of treatment (day 0) to establish the baseline damage from the collagenase treatment.

Histology

The calcaneous-Achilles tendon-muscle specimen (n = 5/time point/group), with skin removed, was fixed in 10% neutral buffered formalin and decalcified in 10% formic acid. Specimens were embedded in paraffin and serial sections (5 µm) were collected and stained with Hematoxylin and Eosin (H&E), Masson's trichrome or immunohistochemical staining for proliferating cell nuclear antigen (PCNA).

Histopathology

Histopathological assessment of inflammation, extent of damage, extent of repair and character of the repair were performed by a board-certified veterinary pathologist masked to treatment, according to criteria outlined in Table S1. Proliferating cells within the tendon, identified by PCNA immunoreactivity, were quantified using three consistent fields of an ocular micrometer (39.4 µm × 197 µm; 7,762 µm2). PCNA positive cell counts were normalized by the area of the field of view. Microscopic tendon thickness was measured with an ocular micrometer at the calcaneal attachment point and at the midsubstance of the tendon.

Biomechanical Analysis

At necropsy, the calcaneous-Achilles-gastrocnemius specimen was dissected from the surrounding tissues, wrapped in saline soaked gauze, and frozen at −20°C until testing. All treated ankles (n = 13/group/timepoint) were tested. Contralateral ankles (n = 13/timepoint) from the saline-treated group were used as uninjured controls. Samples were thawed in phosphate-buffered saline containing proteinase inhibitors (Roche Diagnostics, Indianapolis, IN) at 4°C for up to 4 h prior to mechanical testing. The muscle was dissected from the tendon and the soft tissue removed from the calcaneous to facilitate gripping. Specimen dimensions were measured using a custom contact-sensing micrometer. Mechanical testing was performed on a Bose EnduraTEC test system (Model 3200, Bose, Eden Prairie, MN) under displacement control. The resulting load was measured using a 100 N load cell. A 1 N tare load was applied to the specimens followed by 10 cycles of cyclic loading between 0.1 and 1 N at 0.138 Hz. A uniaxial tensile ramp-to-failure was then applied at a strain rate of 0.1%/s and the resultant load recorded. The samples were tested to failure (until fracture the measured load was <1 N).[23, 29, 30] All specimens were tested masked to treatment with no indication of identifiable group classification. The load–displacement curve was analyzed to determine linear stiffness and maximum load. The stress–strain curve was analyzed to determine modulus and ultimate stress.

Statistical Analysis

Statistical analyses were performed using SigmaPlot 12.0. A one-way ANOVA on ranks with a Tukey's post-hoc test was used for analysis of the complete blood counts. A one-tailed t-test was used for comparison of the growth factor concentration. Two-way ANOVA with interaction and a Fisher's LSD post-hoc test was used for analysis of the biomechanical data. Non-parametric data (histopathology scores) were analyzed using a Kruskal–Wallis test. All results are presented as mean ± SEM. The level of significance was set at p < 0.05.

RESULTS

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
  8. Supporting Information

PRP Analysis

RBCs were present in whole blood only (Table 1). WBCs were present in whole blood and their numbers were significantly diminished in plasma and PRP. PLTs were concentrated 3.3-fold in PRP samples compared to whole blood (p < 0.05). Platelet concentration in plasma was not different from whole blood. VEGF was not detected in any sample. The concentrations of PDGF-AB, PDGF-BB, and TGF-β1 (Table 2) were significantly increased in the PRP relative to plasma (p < 0.001). A positive correlation (p < 0.001) was observed between growth factor concentration and platelet count.

Table 1. Mean Blood Cell Counts for Whole Blood, Plasma, and PRP
 RBC (×106 cells/µl)WBC (×103 cells/µl)PLT (×103 cells/µl)
  • Mean ± SD.

  • *

    Different from whole blood; p < 0.05.

  • #

    Different from plasma; p < 0.05.

Whole blood5.7 ± 0.26.5 ± 1.2926.3 ± 85.8
Plasma0.0 ± 0.00.1 ± 0.1*1.146.4 ± 212.7
PRP0.0 ± 0.00.5 ± 0.8*3.018.4 ± 482.3*,#
Table 2. Average Growth Factor Content in Plasma and PRP Samples
 PDGF-AB (pg/ml)PDGF-BB (ng/ml)TGF-β1 (ng/ml)VEGF (pg/ml)
  • Mean ± SD.

  • BLQ, below the limit of quantitation.

  • *

    Different from plasma; p < 0.001.

Plasma168.2 ± 45.45.0 ± 1.5145.4 ± 23.1BLQ
PRP651.1 ± 180.9*15.4 ± 5.1*342.3 ± 63.5*BLQ

Histopathology

Histopathology scores are presented as the median and range of five specimens (Table 3) evaluated by a single masked histopathologist. On day 7, the TCA-treated specimens presented decreased tendon thickness at insertion and midsubstance; decreased cell proliferation and decreased inflammation relative to saline treatment; the 10 µg rhPDGF-BB dose group presented increased cell proliferation compared to saline; no differences were observed in the extent and character of the repair among the treatment groups. On day 21 no differences were observed in any of the elements of assessment among the treatment groups.

Table 3. Histopathology Scores at Baseline, 7, and 21 Days Post-Treatment
 InflammationExtent of DamageExtent of RepairCharacter of Repair
Day 0Day 7Day 21Day 0Day 7Day 21Day 0Day 7Day 21Day 0Day 7Day 21
  1. Mean ± SEM; n = 5.

Baseline2.0 ± 0.04.4 ± 0.25.0 ± 0.03.4 ± 0.2
Saline1.7 ± 0.31.0 ± 0.34.0 ± 0.63.2 ± 1.04.6 ± 0.43.6 ± 1.04.4 ± 0.24.5 ± 0.3
PRP1.8 ± 0.41.3 ± 0.34.2 ± 0.62.6 ± 0.94.6 ± 0.43.0 ± 0.94.4 ± 0.24.2 ± 0.4
rhPDGF-BB (3 µg)2.0 ± 0.00.9 ± 0.14.1 ± 0.94.4 ± 0.44.4 ± 0.65.0 ± 0.04.0 ± 0.05.6 ± 0.2
rhPDGF-BB (10 µg)1.8 ± 0.21.0 ± 0.04.1 ± 0.92.1 ± 0.84.6 ± 0.43.0 ± 0.64.8 ± 0.24.8 ± 0.2
TCA0.6 ± 0.41.8 ± 0.62.4 ± 0.93.8 ± 1.02.3 ± 0.63.4 ± 1.05.0 ± 0.03.8 ± 0.3
Contralateral0.0 ± 0.00.1 ± 0.10.0 ± 0.00.0 ± 0.00.1 ± 0.10.1 ± 0.10.0 ± 0.00.0 ± 0.0

Biomechanical Strength

Structural mechanical properties (maximum load, tensile extension, and stiffness) are presented in Table 4. The maximum load for the 3 µg rhPDGF-BB dose group was significantly increased (p ≤ 0.025) compared to the saline, PRP, and TCA groups at day 7 and significantly increased (p ≤ 0.027) compared to the saline and TCA groups at day 21. The maximum load (p ≤ 0.035) and stiffness (p ≤ 0.038) were significantly increased in the 10 µg rhPDGF-BB group compared to the saline, PRP, and TCA groups at day 21. Material mechanical properties (ultimate stress, tensile strain, and modulus) are presented in Table 5. The ultimate stress was significantly increased in the 3 µg rhPDGF-BB dose group compared to the saline, PRP, and TCA groups at day 7 (p ≤ 0.025) and compared to the PRP group at day 21 (p ≤ 0.025). The ultimate stress (p ≤ 0.025) and modulus (p 0.046) were significantly increased in the 10 µg rhPDGF-BB dose group compared to the saline, PRP, and TCA groups at day 21.

Table 4. Summary of Structural Biomechanical Properties at Baseline, 7, and 21 Days Post-Treatment
 Maximum LoadTensile Extension at Maximum LoadRamping Stiffness
Day 0Day 7Day 21Day 0Day 7Day 21Day 0Day 7Day 21
  1. Mean ± SEM; n = 13.

Baseline12.0 ± 3.21.4 ± 0.29.5 ± 2.4
Saline12.5 ± 2.915.7 ± 4.41.5 ± 0.31.8 ± 0.310.8 ± 2.611. 7 ± 2.9
PRP10.3 ± 2.014.5 ± 2.31.4 ± 0.22.1 ± 0.28.4 ± 1.88.7 ± 1.3
rhPDGF-BB (3 µg)24.5 ± 4.321.4 ± 2.32.0 ± 0.12.4 ± 0.217.1 ± 3.712.8 ± 1.5
rhPDGF-BB (10 µg)15.2 ± 2.530.1 ± 5.52.0 ± 0.21.9 ± 0.211.2 ± 2.523.4 ± 4.7
TCA12.1 ± 3.512.2 ± 2.41.3 ± 0.11.6 ± 0.210.4 ± 3.19.1 ± 2.0
Intact Controls38.3 ± 2.342.1 ± 2.31.6 ± 0.031.6 ± 0.133.8 ± 1.936.5 ± 2.0
Table 5. Summary of Material Biomechanical Properties at Baseline, 7, and 21 Days Post-Treatment
 Ultimate Tensile StressTensile Strain at Maximum StressRamping Modulus
Day 0Day 7Day 21Day 0Day 7Day 21Day 0Day 7Day 21
  1. Mean ± SEM; n = 13.

Baseline1.8 ± 0.40.2 ± 0.0211.3 ± 2.9
Saline1.7 ± 0.42.4 ± 0.80.2 ± 0.030.2 ± 0.0312.3 ± 3.314.0 ± 4.9
PRP1.7 ± 0.51.1 ± 0.20.2 ± 0.020.3 ± 0.0211.1 ± 3.35.6 ± 0.8
rhPDGF-BB (3 µg)3.8 ± 0.92.1 ± 0.30.3 ± 0.020.3 ± 0.0320.9 ± 5.610.2 ± 1.6
rhPDGF-BB (10 µg)2.0 ± 0.44.2 ± 0.90.2 ± 0.020.2 ± 0.0312.7 ± 3.124.7 ± 5.6
TCA2.0 ± 0.82.0 ± 0.50.2 ± 0.020.2 ± 0.0213.2 ± 4.812.2 ± 3.3
Intact controls10.9 ± 0.711.4 ± 0.60.2 ± 0.010.2 ± 0.0172.6 ± 5.074.4 ± 3.8

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
  8. Supporting Information

In this study, we compared rhPDGF-BB with corticosteroids and PRP in a rat model of tendinopathy. This collagenase-induced model[23, 31-34] presents aspects that are similar to human tendinopathy such as hypercellularity, loss of matrix organization, and lack of inflammatory cell infiltration, however, its main drawback is that it causes a healing response which is often absent in tendinopathy patients.[35, 36] This healing response can mask the effects of the treatments applied if the time points for assessment are not carefully defined. Guided by our previous experience,[23] we chose relatively short follow-up that would allow us to assess the effect and, potentially, the mechanism of action of the treatments applied.

Although there are concerns about their long-term safety and efficacy,[8-10] corticosteroid injections are often administered for chronic tendinopathies. Growth factors have also been used to promote tendon healing in the form of PRP; however variability in the preparation and composition of PRP makes it difficult to compare results across studies[13] and it is likely responsible for the variability in the clinical outcomes reported with this therapy.[14, 15] Several preclinical studies demonstrate that regenerative healing of tendons and ligaments can be accomplished by exploiting the biological properties of the platelet-derived growth factor (PDGF) family of growth factors.[37-44] The safety profile of rhPDGF-BB has been well-established[45, 46] and the Food and Drug Administration has approved rhPDGF-BB-containing formulations (Regranex® Gel and GEM 21S®) for wound healing and periodontal regeneration.

The results of this study confirm our previous findings that a 10 µg IT injection of rhPDGF-BB, promoted cellular proliferation and improved mechanical properties of collagenase-treated tendons.[23] Consistent with our previous study, this treatment resulted in early cellular proliferation at day 7 and improved strength at day 21 compared to the placebo controls.

The mechanism of action of corticosteroid treatment is very different from that of the PRP and rhPDGF-BB. Corticosteroids target the pain caused by local inflammation of the damaged tendon tissue[6, 8] while PDGF-BB and the growth factors contained in PRP are chemotactic and mitogenic triggering recruitment and proliferation of tenocytes to the injured tendon that may improve the conditions for repair.[47] As a result, corticosteroids predictably and significantly reduced inflammation.

Corticosteroid treatment, consistent with the proposed mechanism of action, significantly reduced inflammation, tendon thickness and cell proliferation at day 7. However, these early effects did not result in biomechanical improvement over the control group indicating that this therapy addresses the pain associated with tendinopathy albeit not its root cause and lacks long-term efficacy.[48] PRP and low dose (3 µg) rhPDGF-BB had little impact on cell proliferation and tendon thickness and they also lacked sustained improvement in biomechanical properties suggesting that low doses of growth factors are insufficient to trigger a successful repair.

The platelet content and RBC depletion achieved in the preparation of the PRP for this study are similar to those achieved by commercially available systems.[13] The growth factor content in PRP compared with whole blood correlated strongly with the platelet enrichment attained in the PRP preparation. The concentration of PDGFs in PRP are, however, orders of magnitude below the dose that was found to be efficacious in this and in our previous study.[23] As such, the lack of improvement of biomechanical properties in these groups suggests that the level of concentration of platelets/growth factors necessary for impacting tendon function is not achievable with the PRP concentration method studied.

In conclusion, the improved biomechanical strength of the tendons treated with 10 µg of rhPDGF-BB support the hypothesis that rhPDGF-BB stimulates tendon repair in this model, resulting in improvements in the mechanical function. The other treatments (3 µg of rhPDGF-BB, PRP, and TCA) did not yield biomechanical improvements compared to the placebo (saline) group. Although this model has some intrinsic shortcomings and does not lend itself to long-term follow-up and assessment of the longevity of the repair, taken together, the results of this study indicate that rhPDGF-BB, at the correct concentration, may have benefit as a therapy for tendinopathy. Future investigations will examine the clinical impact of rhPDGF-BB on pain abrogation and restoration of activity following treatment.

ACKNOWLEDGMENTS

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
  8. Supporting Information

We thank Dr. Jeffery O. Hollinger (assistance with study design), Jack Ratliff (histologic processing), and Patricia Ward (growth factor analysis).

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. ABSTRACT
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
  8. Supporting Information

Additional supporting information may be found in the online version of this article at the publisher's web-site.

FilenameFormatSizeDescription
jor22483-sm-0001-SupTable-S1.doc24KTable S1. Description of the Histopathology Scoring System for Inflammation, Extent of Damage, Extent of Repair and Character of Repair

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