A New Experimental Lymphedema Model Reevaluating the Efficacy of Rat Models and Their Clinical Translation for Chronic Lymphedema Studies

Abstract

Background Our aim was to create a new rodent hind limb lymphedema model lacking the fibrosis effect induced by radiotherapy and subjected to the inhibition of lymphangiogenesis via sirolimus (rapamycin) to maintain a chronic lymphedema model and investigate its reliability for human treatment modalities. Methods Forty-two Sprague-Dawley rats were randomly assigned to 7 groups: (1) surgery control, (2) vehicle-surgery control, (3) vehicle control, (4) rapamycin control, (5) surgery with 1 mg/kg per day rapamycin, (6) surgery with 1.5 mg/kg per day rapamycin, and (7) surgery with 2 mg/kg per day rapamycin. All surgeries were performed on the right hind limbs, with the left hind limbs also considered as a control. The drug and its solvent were administered daily into the relevant groups intraperiteonally. The presence of lymphedema was investigated by weekly limb circumference measurements, microcomputed tomography, fluorescence lymphography using indocyanine green dye, and microscopic evaluation at the end of the sixth week to determine any histological changes in the hind limbs. Results In group 1, lymphedema was observed for 2 weeks (P = 0.032), whereas in groups 5, 6, and 7, lymphedema lasted for 3 weeks (P 3 weeks. Because of the rapid neolymphangiogenesis in murines and a different wound healing mechanism, they should not be considered as an appropriate model for research on human lymphedema in first place.