Development of a method for the evaluation of wound tensile strength in cynomolgus macaques.
BACKGROUND
Numerous in vivo wound healing models have been developed to evaluate the potential of drugs to affect the processes involved in wound healing, including angiogenesis. The majority of these models are frequently conducted in rodents, rabbits, and pigs and are terminal in nature. Due to the species specificity of many biotherapeutic molecules under development a non-terminal model in the cynomolgus monkey was evaluated in this study.


METHODS
To evaluate wound tensile strength, 3 full thickness skin incisions (2 cm long and 3 mm deep) were created on each side of the midline with a micro-fine surgical scalpel. Wounds were closed with SteriStrips applied over Mastisol, and covered with Tegaderm. The animals were then fitted with primate jackets. In Study 1, 3 male macaques per group received daily intramuscular injections of saline or dexamethasone (1 mg/kg) from Day-1 through Day 11. In Study 2, 3 males macaques per treatment group received a single intravenous injection of saline or anti-VEGF mAb (20 mg/kg) on Day-1. In Studies 1 and 2 wounds were created on Day 1. In Study 3, 3 males and 3 female macaques per treatment group received anti-VEGF mAb (20 mg/kg) on Days 1, 8, 15 and 22. In study 3, wounds were created on Day 12. On Days 4, 8, and 11 relative to wound creation, two randomized incisions per animal were evaluated with a Biomechanical Tissue Characterization System.


RESULTS
In Study 1, there was a statistically significant reduction in wound strength in the dexamethasone treated group on Day 11 as compared to saline negative control. There was a statistically significant reduction in wound strength in the anti-VEGF mAb treated animals on Day 8 as compared to saline in Study 2. Statistical evaluation of wound strength between saline treated animals and the anti-VEGF mAb treated animals showed a significant reduction in wound strength in the anti-VEGF mAb treatment group on Day 8 (Fig. 3). In all studies there were open wound sites at the time of evaluation, which ranged from 6 to 50% on Day 4, 3 to 17% on Day 8, and 6% on Day 11.


CONCLUSIONS
These studies demonstrate a potential method for evaluating the strength of sterile incisional wounds in the cynomolgus monkey, which allows for multiple evaluations of wound strength within an animal over time in a non-terminal model. Dexamethasone and anti-VEGF mAb produced significant reductions in wound healing on Day 11 and 8, respectively. It was inconclusive whether the number of open incisional sites was related to the test article, incomplete closure at the time of surgery, or movement of the animals in the primate jacket.
Cornacoff
Joel B
JB
Department of Toxicology and Investigational Pharmacology, Centocor Research and Development, Radnor, Pennsylvania 19087, USA. jcornaco@cntus.jnj.com
Howk
Kreg
K
Pikounis
Bill
B
Mendenhall
Vince
V
Martin
Pauline
P
D000818:Animals; D000911:Antibodies, Monoclonal; D001696:Biomechanical Phenomena; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D015203:Reproducibility of Results; D013718:Tensile Strength; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries
D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D042461:Vascular Endothelial Growth Factor A; D003907:Dexamethasone