Quantification of Chronic Lymphedema in a Revised Mouse Model

Jørgensen, Mads Gustaf; Toyserkani, Navid Mohamadpour; Hansen, Christian Rønn; Hvidsten, Svend; Baun, Christina; Hejbøl, Eva Kildall; Sørensen, Jens Ahm

doi:10.1097/sap.0000000000001537

Cited by 20 publications

(44 citation statements)

References 35 publications

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“…The sample of mice is divided into two groups "High quality" and "Low quality" each with two subgroups "lymphedema hindlimb" and "control hindlimb". The model that was used for inducing secondary lymphedema has previously been described 18 . The model comprised three steps:…”

Section: Methodsmentioning

confidence: 99%

“…The scans chosen for analysis stem from a pool of approximately 576 scans of 81 mice. The mice were part of two prior experiments in which secondary lymphedema was induced in one hindlimb of each mouse using the previously described method 18,25 . During these experiments µCT scans were made every week after surgery to measure the hindlimb volume of the lymphedema hindlimb and control hindlimb.…”

Section: Methodsmentioning

confidence: 99%

“…In recent studies, three-dimensional (3D) image analysing software has been used to quantify tissue volume in the hindlimb of rodents using both µCT- [17][18][19] and magnetic resonance imaging (MRI) 17,20 . It has been shown that both µCT and MRI analysis provide reliable measurements of hindlimb volume when compared to conventional measuring techniques, such as caliper-measured paw thickness 17 .…”

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confidence: 99%

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Quantification of tissue volume in the hindlimb of mice using microcomputed tomography images and analysing software

Wiinholt

Gerke

Dalaei

et al. 2020

Sci Rep

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When studying illnesses that cause disturbance in volume such as lymphedema, reliable quantification of tissue volume is important. Lymphedema results in swelling and enlargement of extremities and can be both physically and psychologically stressful to the patient. Experiments in rodent models provide a cost-effective research platform and are important for preclinical research on lymphedema. When performing such research, it can be crucial to measure the changes in tissue volume. Researchers must ensure that the risk of measurement error, when measuring the tissue volume, is as low as possible. The main goal of this article was to perform a comprehensive examination of the intra-and interrater agreement and hereby assess the risk of measurement error when using microcomputed tomography (µCT) images to measure hindlimb volume. We examined the agreement between four raters with different levels of prior experience and found that the risk of measurement error is extremely low when using this method. The main limitation of this method is that it is relatively expensive and timeconsuming. The main advantages of this method are that it is easily learned and that it has a high intraand interrater agreement, even for raters with no prior measuring experience. The core function of the lymphatic system is to collect excess interstitial fluid from the soft tissue and return it to the venous system 1. Impairment of the lymphatic system leads to accumulation of fluid containing macromolecules such as proteins. The stasis of the protein rich interstitial fluid and subsequent inflammation will over time lead to chronic swelling due to adipose deposition and tissue fibrosis, this condition is known as lymphedema 2. One of the most common problems originating from lymphedema is that the swelling of limbs or genitalia causes deformity which lowers the patients' self-esteem and leads to poor quality of life 2,3. Furthermore patients with lymphedema have a higher risk of infection 4 , and the complications of chronic lymphedema lead to a high cost of patient care and an increased disease burden on society 5,6. In developed countries the most common cause of lymphedema is oncological therapy such as lymph node dissection and adjuvant radiotherapy 7. It has been suggested that 21% of women diagnosed with breast cancer will develop lymphedema 8. Animal models are being used to research novel treatment options for lymphedema, but the lack of standardized parameters to objectively measure lymphedema has been described as a major problem 9. Various animal models have been used in research on lymphedema, of which the rodent hindlimb model is one of the most frequently used 10. The rodent tail model is also frequently used but the hindlimb model has previously been described as appearing to be the most eligible and cost-effective model to investigate the reconstruction of lymphatic function 9. Conventional measurement techniques for hindlimb volume in mice include techniques such as water displacement 11,12 , paw thickness 13 or circumfer...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Quantification of tissue volume in the hindlimb of mice using microcomputed tomography images and analysing software

Wiinholt

Gerke

Dalaei

et al. 2020

Sci Rep

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“…Indeed, the VLNT outcome relies on the survival of the lymphatic graft, on the quality of the recipient site (after radiation and/or surgery), and on the stage of the patient disease in correlation with the deposition of fibrosis and adipose tissue. 23 As many studies refine lymphedema animal models in an ongoing process to recapitulate the hallmark features of acquired lymphedema in humans, 6,24,25 we implemented a VLNT animal model performing, to the best of our knowledge, the first contralateral VLNT mouse model. The 3-month follow-up eradicate the possibility that this results can be the consequence of a Paw volume evaluated by magnetic resonance imaging (MRI) measurement at day 67 after lymphedema induction.…”

Section: Discussionmentioning

confidence: 99%

“…Because of their cost efficiency, mice models are constantly under revision and improvement. 6 One of the major limitations in performing a VLNT hindlimb mouse model is the small size of the vascular pedicle of the lymph node flap, which represents a technical limitation to the achievement of a free vascular anastomosis, in contrast to what has been recently performed on a rat model 7 and what is routinely performed in humans. Until now, to overcome this limitation, VLNT in mice was realized as a pedicle flap harvesting VLNT from inguinal (also called "abdominal") to popliteal in the same paw.…”

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confidence: 99%

Contralateral Vascularized Lymph Node Transfer: An Optimized Mouse Model

Vottero

Morfoisse

Durré

et al. 2019

J Reconstr Microsurg Open

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Background Vascularized lymph node transfer (VLNT) is one of the surgical options in the treatment of lymphedema, but its mechanism of action has not yet been firmly clarified. In the VLNT mouse models described so far, the lymph node flap is performed between two different sites in the same lymphedematous paw. In this study, we describe an optimized VLNT mouse model using the contralateral paw as donor site, thus removing the bias of transferring a lymph node already damaged by irradiation and/or surgery required to induce lymphedema. Methods A lymphedema was induced on the left posterior paw in four experimental groups of mice (n = 8). Two weeks later, group 1 was the sham one, group 2 underwent a VLNT from the right inguinal region to the left, in group 3 a vascular endothelial growth factor (VEGF)-C sponge was placed alone in the left inguinal region, and in group 4 a VEGF-C sponge was associated to the VLNT. The 32 mice were followed during 3 months. Outcomes included paws volume, skin quality, inflammation in the lymphedematous tissue, and lymphatic network density and function. Results Group 4 displayed significantly higher (p < 0.05) lymphedema regression compared with the other three groups. Conclusions This optimized mouse model of VLNT shows to be handy and effective. It could be exploited to perform further experimental studies about the influence of VLNT on lymphedema. Moreover, the local association between VLNT and biological compounds in this model allows it to be a good preclinical model to identify new potential drugs in lymphedema.

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

Bucan,

Frendø,

Ngo

et al. 2023

Microsurgery

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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.

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Quantification of Chronic Lymphedema in a Revised Mouse Model

Cited by 20 publications

References 35 publications

Quantification of tissue volume in the hindlimb of mice using microcomputed tomography images and analysing software

Quantification of tissue volume in the hindlimb of mice using microcomputed tomography images and analysing software

Contralateral Vascularized Lymph Node Transfer: An Optimized Mouse Model

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

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