Dose–response effect of an intra‐tendon application of recombinant human platelet‐derived growth factor‐BB (rhPDGF‐BB) in a rat Achilles tendinopathy model

Shah, Vivek; Bendele, Alison M.; Dines, Joshua S.; Kestler, Hans K.; Hollinger, Jeffrey O.; Chahine, Nadeen O.; Hee, Christopher K.

doi:10.1002/jor.22222

Cited by 35 publications

(40 citation statements)

References 37 publications

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“…Other concentrations have not shown a significant difference compared to the normal untreated control (Shah et al, 2013). On the other hand, ultimate tensile stress was only significantly higher, compared to the other groups, in the 1.02 μg of PDGF group.…”

Section: Single Bolus Injectionmentioning

confidence: 70%

“…From the literature covered in this review and the observations existing so far, it can be concluded that from the available delivery strategies, a single bolus injection of 10 µg of PDGF-BB one week post-operation (Shah et al, 2013) or a fibrin-based PDGF-BB delivery system loaded with much larger amounts than reported, e.g. 10 µg instead of only 0.5 µg (Thomopoulos et al, 2009), would probably be the most promising approaches.…”

Section: Resultsmentioning

confidence: 96%

“…When the healing tissue was analysed histologically for cellularity, collagen fibre orientation and density, inflammation and vascularisation, it was found that different amounts of single bolus applied at the wound site had different dose-dependent effects. Furthermore, biomechanical strength, 1 and 3 weeks post-administration, was also influenced by PDGF-BB (Shah et al, 2013).…”

Section: Single Bolus Injectionmentioning

confidence: 95%

“…3 weeks post-application, inflammatory reaction and vascularisation were significantly increased only at the highest dose (102 μg of PDGF). Furthermore, assessment of biomechanics revealed that only the highest dose group had significantly larger failure loads at 1 and 3 weeks, compared to the other treated groups -indicating a biphasic dosedependence and the need for an exact evaluation of the optimum growth factor amount (Shah et al, 2013). Solchaga et al (2014) also worked with a single injection of PDGF-BB.…”

Section: Single Bolus Injectionmentioning

confidence: 99%

“…Only higher doses (~ 500 ng) of PDGF-BB delivered in the same way resulted in beneficial effects (Thomopoulos et al, 2009). On the other hand, when single bolus injections (Shah et al, 2013) or different scaffolds/carriers are used for delivery (Kovacevic et al, 2015), much larger amounts (1-10 µg) might be needed to have any effect on the biomechanics of the tendons. With the current studies suggesting higher dosages of PDGF-BB as promising, a systematic study in one in vivo model, with different delivery methods and dosages and the possibility to track the release profile of the growth factor in vivo is missing.…”

Section: Current Limitations and Future Workmentioning

confidence: 99%

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In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

Evrova

Buschmann

2017

eCM

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To promote and support tendon healing, one viable strategy is the use or administration of growth factors at the wound/rupture site. Platelet derived growth factor-BB (PDGF-BB), together with other growth factors, is secreted by platelets after injury. PDGF-BB promotes mitogenesis and angiogenesis, which could accelerate tendon healing. Therefore, in vitro studies with PDGF-BB have been performed to determine its effect on tenocytes and tenoblasts. Moreover, accurate and sophisticated drug delivery devices, aiming for a sustained release of PDGF-BB, have been developed, either by using heparin-binding and fibrin-based matrices or different electrospinning techniques.In this review, the structure and composition, as well as the healing process of tendons, are described. Part A deals with in vitro studies. They focus on the multiple effects evoked by PDGF-BB on the cellular level. Moreover, they address strategies for the sustained delivery of PDGF-BB. Part B focuses on animal models used to test different delivery strategies for PDGF-BB, in the context of tendon reconstruction. These studies showed that dosage and timing of PDGF-BB application are the most important factors for deciding which delivery device should be applied for a specific tendon laceration.

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Section: Single Bolus Injectionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 96%

Section: Single Bolus Injectionmentioning

confidence: 95%

Section: Single Bolus Injectionmentioning

confidence: 99%

Section: Current Limitations and Future Workmentioning

confidence: 99%

See 3 more Smart Citations

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

Evrova

Buschmann

2017

eCM

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Comparison of the effect of intra‐tendon applications of recombinant human platelet‐derived growth factor‐BB, platelet‐rich plasma, steroids in a rat achilles tendon collagenase model

Solchaga

Bendele

Shah

et al. 2013

Journal Orthopaedic Research

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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-ml IT injection was administered. Treatments included: saline; 3 mg rhPDGF-BB; 10 mg rhPDGF-BB; PRP; and 300 mg 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 mg 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 mg rhPDGF-BB group relative to saline, PRP, and TCA (p < 0.025). On day 21, maximum load-to-rupture was increased in the 10 mg rhPDGF-BB group relative to saline, PRP, and TCA (p < 0.035) and in the 3 mg rhPDGF-BB group compared to saline and TCA (p < 0.027). Stiffness in the 10 mg 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 loadto-failure (3 and 10 mg) and stiffness (10 mg) relative to controls and commonly used treatments. Keywords: tendinopathy; platelet-derived growth factor-BB; platelet-rich plasma; corticosteroid; biomechanics 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][2][3] Current treatment options for tendinopathy including, but not limited to, exercise-based physical therapy, corticosteroid injections, non-steroidal antiinflammatory 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 goldstandard 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 ...

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Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline

Kessler

Barr

Greenwald

et al. 2013

Journal Orthopaedic Research

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Collagenases or matrix metalloproteinases (MMPs) have been shown to play an important role in the matrix degradation cascade associated with Achilles tendon rupture and disease. The goal of this study was to examine the effects of daily administration of doxycycline (Doxy) through oral gavage on MMP activity and on the repair quality of Achilles tendons in vivo. Our findings indicate that Achilles tendon transection resulted in increasing MMP-8 activity from 2 to 6 weeks post-injury, with peak increases in activity occurring at 4 weeks post-injury. Doxy adiministration at clinically relevant serum concentrations was found to significantly inhibit MMP activity after continuous treatment for 4 weeks, but not for continuous administration for shorter durations (96 h or 2 weeks). Extended doxy administration was also associated with improved collagen fibril organization, and enhanced biomechanical properties (stiffness, ultimate tensile strength, maximum load to failure, and elastic toughness). Our findings indicate that a temporal delay exists between Achilles tendon transection and associated increases in MMP-8 activity in situ. Our findings suggest that inhibition of MMP-8 at its peak activity levels ameliorates fibrosis development and improves biomechanical properties of the Achilles tendon. Keywords: achilles tendon; matrix metalloproteinase; doxycycline; tendon rupture and repair Achilles tendon tears are devastating injuries, and have unpredictable outcomes with respect to return to function.1,2 Collagenases or matrix metalloproteinases (MMPs) have been shown to play an important role in the enzymatic matrix degradation cascade associated with tendon injury and disease.3-6 Tendon degeneration is an active, cell-mediated process that may result from a failure to regulate specific MMP activities in response to repeated injury or mechanical strain. After tendon rupture, increased activity of MMPs and increased matrix turnover have been associated with further deterioration in the quality of the collagen network.7-13 Downregulation of tissue inhibitors of MMPs (TIMPS) is also associated with disregulation of the ratio of MMP to TIMP activity, and has been implicated in the pathogenesis of tendinopathy. [8][9][10][11][12][13][14][15][16] Tenocyte production of MMP-1 and -3 underscores the potential for non-lymphocyte mediated cytokine production of proteases inducing local matrix changes. 17 Tetracyclines, through a mechanism independent of their antibiotic effects, have been shown to substantially inhibit the action of MMPs, such as collagenase.18-21 Specifically, doxycycline (doxy) is considered to be the most potent tetracycline MMP inhibitor, whose activity is mediated both by direct and indirect mechanisms of action, and has been applied therapeutically in a variety of clinical applications.18-21 The use of doxy in tendon repair had been previously explored in vivo, though contradictory findings regarding its efficacy have been reported. [22][23][24] Consequently, MMP inhibitors and their activity ...

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Dose–response effect of an intra‐tendon application of recombinant human platelet‐derived growth factor‐BB (rhPDGF‐BB) in a rat Achilles tendinopathy model

Cited by 35 publications

References 37 publications

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

Comparison of the effect of intra‐tendon applications of recombinant human platelet‐derived growth factor‐BB, platelet‐rich plasma, steroids in a rat achilles tendon collagenase model

Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline

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