The effect of granulocyte-colony stimulating factor on rotator cuff healing after injury and repair.
BACKGROUND
The failure rate of tendon-bone healing after repair of rotator cuff tears remains high. A variety of biologic- and cell-based therapies aimed at improving rotator cuff healing have been investigated, and stem cell-based techniques have become increasingly more common. However, most studies have focused on the implantation of exogenous cells, which introduces higher risk and cost. We aimed to improve rotator cuff healing by inducing endogenous stem cell mobilization with systemic administration of granulocyte-colony stimulating factor (G-CSF).


OBJECTIVE
We asked: (1) Does G-CSF administration increase local cellularity after acute rotator cuff repair? (2) Is there histologic evidence that G-CSF improved organization at the healing enthesis? (3) Does G-CSF administration improve biomechanical properties of the healing supraspinatus tendon-bone complex? (4) Are there micro-MRI-based observations indicating G-CSF-augmented tendon-bone healing?


METHODS
After creation of full-thickness supraspinatus tendon defects with immediate repair, 52 rats were randomized to control or G-CSF-treated groups. G-CSF was administered for 5 days after repair and rats were euthanized at 12 or 19 postoperative days. Shoulders were subjected to micro-MR imaging, stress relaxation, and load-to-failure as well as blinded histologic and histomorphometric analyses.


RESULTS
G-CSF-treated animals had significantly higher cellularity composite scores at 12 and 19 days compared with both control (12 days: 7.40 ± 1.14 [confidence interval {CI}, 5.98-8.81] versus 4.50 ± 0.57 [CI, 3.58-5.41], p = 0.038; 19 days: 8.00 ± 1.00 [CI, 6.75-9.24] versus 5.40 ± 0.89 [CI, 4.28-6.51], p = 0.023) and normal animals (12 days: p = 0.029; 19 days: p = 0.019). There was no significant difference between G-CSF-treated animals or control animals in ultimate stress (MPa) and strain, modulus (MPa), or yield stress (MPa) and strain at either 12 days (p = 1.000, p = 0.104, p = 1.000, p = 0.909, and p = 0.483, respectively) or 19 days (p = 0.999, p = 0.964, p = 1.000, p = 0.988, and p = 0.904, respectively). There was no difference in MRI score between G-CSF and control animals at either 12 days (2.7 ± 1.8 [CI, 1.08-4.24] versus 2.3 ± 1.8 [CI, 0.49-4.17], p = 0.623) or 19 days (2.5 ± 1.4 [CI, 1.05-3.94] versus 2.3 ± 1.5 [CI, 0.75-3.91], p = 0.737). G-CSF-treated animals exhibited significantly lower relative bone volume compared with normal animals in the entire humeral head (24.89 ± 3.80 [CI, 20.17-29.60) versus 32.50 ± 2.38 [CI, 29.99-35.01], p = 0.009) and at the supraspinatus insertion (25.67 ± 5.33 [CI, 19.04-32.29] versus 33.36 ± 1.69 [CI, 31.58-35.14], p = 0.027) at 12 days. Further analysis did not reveal any additional significant relationships with respect to regional bone volume or trabecular thickness between groups and time points (p > 0.05).


CONCLUSIONS
Postoperative stem cell mobilization agents may be an effective way to enhance rotator cuff repair. Future studies regarding the kinetics of mobilization, the homing capacity of mobilized cells to injured tissues, and the ability of homing cells to participate in regenerative pathways are necessary.
Department of Orthopaedic Surgery, Beaumont Health System, Royal Oak, MI, USA.
David
D
Ross
Tristan
T
Maerz
Michael
M
Kurdziel
Joel
J
Hein
Shashin
S
Doshi
Asheesh
A
Bedi
Kyle
K
Anderson
Kevin
K
Baker
D000818:Animals; D001696:Biomechanical Phenomena; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D020127:Recovery of Function; D017006:Rotator Cuff / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical; D013708:Tendon Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D013997:Time Factors; D016474:Weight-Bearing; D014945:Wound Healing / Q000187:drug effects*
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim