Summary

PARP-1 inhibition is beneficial for the healing after acute rotator cuff repair

Abstract

Introduction

Repair of rotator cuff tears (RCT) have a high retear rate due to the formation of mechanical inferior scar tissue during the healing period and so far there is no way to improve it therapeutically. It was shown that PARP-1 is a key regulator in orchestrating the molecular and cellular mechanisms after rotator cuff tear (RCT). However, knowledge on how PARP-1 influences the healing after repair is missing. We hypothesized that PARP-1 inhibition improves biomechanical and histological properties of the repair in a rat model of acute rotator cuff repair.

Methods

24 Sprague Dawley rats were randomly allocated into an Inhibitor and Control group (n = 12 each). In all rats the tendon of the supraspinatus muscle was sharply detached from its insertion at the humeral head and immediately repaired with a single transosseous suture. Starting one day prior to surgery the rats of the Inhibitor group received 12.5mg/kg/d Veliparib in their drinking water (ABT-888, APExBio, TX, USA) during the recovery period. The water uptake was monitored to assure accurate uptake of the inhibitor. The animals were sacrificed 8 weeks after surgery and analyzed utilizing macroscopic, biomechanical (n = 6 per group) and histological (n = 6 per group) methods. The the groups were analyzed utilizing a two-tailed ANOVA and Fisher’s LSD post-hoc test.

Results

Macroscopically muscle cross section was significantly higher in the Inhibitor group (p=0.034). In the histological total grading of longitudinal joint sections the Inhibitor group had a significant lower mean scoring than the Control group (Inhibitor: 8.0 ±1.9 vs. Control: 11.9 ±1.9, p=0.022). The histological crossection of the SSP muscle was divided into four quadrants to measure fiber cross sections. Fiber cross section was significantly higher in quadrant 1 (41.2±2.5mm2 vs. 34.9±3.8mm2, p=0.0004) and near significant higher in total (p=0.061) and quadrant 2 and 4 (p=0.09 and p=0.072 respectively). The difference in the relative amount of myosin type I muscle fibers was not significant in any quadrant. During biomechanical testing most of the specimens in the Inhibitor group failed in the tendon midsubstance (n=4/6), whereas most of the Controls failed at the entheses (n=4/6). Biomechanical testing revealed a higher yield load in the Inhibitor group compared to the Control group (Inhibitor: 22.3±8.5N vs. Control: 18.2±7.4N, p>0.05) and higher stiffness (Inhibitor: 21.9±2.9MPa vs. Control: 18.7±4.6N, p=0.034). The difference in ultimate load was not significant (Inhibitor: 27.5±4N vs. 25.4±5.7N, p>0.05), nor for the energy absorbed to failure (Inhibitor: 27.7±8.9Nmm vs. Control: 24.3±7.7Nmm, p>0.05).

Conclusions

Inhibition of PARP-1 activity leads to improved healing of the RCT repair with better histological healing of the neo-entheses and less scar tissue formation, which leads to failure at the tendon midsection during biomechanical testing; although biomechanical properties were not significantly different between the groups due to being underpowered, the PARP-1 inhibitor group showed a general trend of improvement. Together with reduced atrophy and higher muscle fiber diameter we conclude that PARP-1 inhibition is beneficial for the healing after acute rotator cuff repair.