Surgical lymphedema models in the mice hindlimb—A systematic review and quality assessment

Abstract

BackgroundLymphedema constitutes a major unsolved problem in plastic surgery. To identify novel lymphedema treatments, preclinical studies are vital. The surgical mouse lymphedema model is popular and cost‐effective; nonetheless, a synthesis and overview of the literature with evidence‐based guidelines is needed. The aim of this review was to perform a systematic review to establish best practice and support future high‐quality animal studies exploring lymphedema treatments.MethodsWe performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, searching four databases (PubMed, Embase, Web of Science, and Scopus) from inception–September 2022. The Animals in Research Reporting In Vivo Experiments 2.0 (ARRIVE 2.0) guidelines were used to evaluate reporting quality. Studies claiming to surgically induce lymphedema in the hindlimb of mice were included.ResultsThirty‐seven studies were included. Four main models were used. (1) Irradiation+surgery. (2) A variation of the surgery used by (1) + irradiation. (3) Surgery only (SPDF‐model). (4) Surgery only (PLND‐model). Remaining studies used other techniques. The most common measurement modality was the caliper. Mean quality coefficient was 0.57. Eighteen studies (49%) successfully induced sustained lymphedema. Combination of methods seemed to yield the best results, with an overrepresentation of irradiation, the removal of two lymph nodes, and the disruption of both the deep and superficial lymph vessels in the 18 studies.ConclusionSurgical mouse hindlimb lymphedema models are challenged by two related problems: (1) retaining lymphedema for an extended period, that is, establishing a (chronic) lymphedema model (2) distinguishing lymphedema from post‐operative edema.Most studies failed to induce lymphedema and used error‐prone measurements. We provide an overview of studies claiming to induce lymphedema and advocate improved research via five evidence‐based recommendations to use: (1) a proven lymphedema model; (2) sufficient follow‐up time, (3) validated measurement methods; (4) ARRIVE‐guidelines; (5) contralateral hindlimb as control.

Impact of Cervical Lymphatic Obstruction on Brain Pathophysiology in Cervical Lymphedema Animal Models

“…The rats were fed adaptively for 1 week before surgery, and all procedures involving animal experiments were conducted in specific designated areas. The development of animal models of lymphedema for preclinical research is still an actively researched area, but the fundamental surgical and radiation protocols followed the methods used for producing extremity lymphedema animal models [59][60][61][62] based on the research by Daneshgaran et al 63 . Before surgery, rats were anesthetized with a mixture of tiletamine/zolazepam (Zoletil 50) (50 mg/kg; Virbac, France) and xylazine (Rompun, Bayer Korea, Seoul, Republic of Korea) at a volume ratio of 5:1 after induction with 4% isoflurane gas.…”

Targeting lymphatic function in cardiovascular-kidney-metabolic syndrome: preclinical methods to analyze lymphatic function and therapeutic opportunities

“…The mouse tail lymphedema model has become a commonly used in vivo model of secondary lymphedema ( 88 ). This surgical procedure requires the circumferential excision of tail skin –2 cm below the base of the tail and injection of Evans Blue dye to visualize the two main collecting lymphatic vessels that run parallel to the lateral veins ( 89 ).…”

“…Aside from tail lymphedema, preclinical models of secondary lymphedema also include the removal of lymphatic vessels in the mouse hindlimb and popliteal lymph node (PLN) dissection ( 92 , 93 ). However, removal of the PLN alone often does not result in chronic edema ( 88 ). Variations of this surgical model have been developed including the removal of several lymph nodes (superficial inguinal lymph node, popliteal lymph node, and deep inguinal lymph node) and excision of the hindlimb femoral lymphatic vessel ( 94 ).…”