SLR - March 2018 - Eric So
Therapeutic Effects of Doxycycline on the Quality of Repaired and Unrepaired Achilles Tendons
Reference: Nguyen QT, Norelli JB, Graver A, Akstein C, Schwartz J, Chowdhury F, Drakos MC, Grande DA, Chahine NO. Therapeutic Effects of Doxycycline on the Quality of Repaired and Unrepaired Achilles Tendons. Am J Sports Med. 2017;45(12):2872–2881.
Scientific Literature Review
Reviewed By: Eric So, DPM
Residency Program: Grant Medical Center, Columbus, OH
Podiatric Relevance: Achilles tendon injuries are among the most common sports-related injuries of the foot and ankle. Operative treatment of Achilles tendon ruptures has been shown to decrease rerupture rates and to allow earlier rehabilitation compared to nonoperative treatment. However, other studies have shown that nonoperative treatment may result in outcomes similar to surgical repair. In light of this ongoing debate, recent literature has brought attention of the deleterious effects of matrix metalloproteinases (MMP) for tendon healing. The mechanism of action of Doxycycline is a potent tetracycline MMP inhibitor and has been used to treat various MMP-mediated disease processes. Thus, this article hypothesizes that Doxycycline would enhance the histological, molecular and biomechanical quality of Achilles tendons.
Methods: The Achilles tendons of 288 adult, live, male two- to three-month-old rats were used. The right and left leg were alternated as the site of injury with the contralateral Achilles tendon serving as an uninjured control. After anesthetic administration, the midsubstance of each Achilles tendon was excised. The tendons were either left unrepaired or surgically repaired with 4-0 Vicryl. The rats were allowed unrestricted activity after surgery. Daily administration of 10 mg/kg Doxycycline began Day 1 in half of all surgically repaired and unrepaired subjects. The control group did not receive Doxycycline. At 1.5, three, six and nine weeks after injury, the animals were euthanized and Achilles tendons were harvested for analysis of histology, gene expression and biomechanical properties.
Results: In the surgically repaired specimens, Doxycycline significantly improved collagen organization with tendons at nine weeks exhibiting the most organized tissue structure (P=0.0014). Genes expression of MMP-3, MMP-9, and TIMP1 were significantly reduced in the Doxycycline group. Doxycycline treatment increased the dynamic modulus at six weeks but not at nine weeks after injury (P<0.001). Doxycycline did not have an effect on the histology or biomechanics of unrepaired tendons.
Conclusions: The findings of this study suggest that the administration of Doxycycline in surgically repaired Achilles tendons improves collagen organization and biomechanical properties by inhibiting gene expression of MMPs. The clinical impact would effectuate more aggressive rehabilitation protocols, potentially improving functional performance. This study raises the question of whether Doxycycline ought to be included as part of the immediate postoperative protocol. The results also suggest that in patients who are treated nonoperatively, the addition of Doxycycline would not provide its intended therapeutic benefit. Due to this study’s design, the true clinical application of Doxycycline in human subjects is still largely unproven. In clinical practice, patients are nonweightbearing for a period of time; however, the protocol to allow the animal subjects unrestricted activity after surgery may have influenced the clinical significance of this study. Furthermore, the optimum dosage and frequency of Doxycycline administration was not elucidated. Lastly, the foot and ankle surgeon must decide whether the potential benefits of Doxycycline for Achilles tendon injuries outweigh the risks of its side effects, particularly in the absence of infection. Despite these limitations, this study provides a scientific foundation upon which future clinical studies may be based.