Spontaneous Reanastomosis of Cutaneous Capillary Lymphatic Vessels after Tissue Transfer
Alan Yan, MD, Tomer Avraham, MD, Jamie C. Zampell, MD, Nicolas W. Clavin, MD, Babak J. Mehrara, MD.
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
BACKGROUND: Lymphedema is the chronic swelling of an extremity that occurs when the capacity of the lymphatic is exceeded. As many as 50% of patients treated with lymph node dissection go on to develop lymphedema and have frequent infections, pain, and cosmetic deformity. Although recent clinical case studies have shown remarkable improvements in limb edema after tissue transfer, the mechanisms responsible for lymphatic reanastomosis remain unknown. The purpose of these experiments was therefore to determine the mechanisms that regulate lymphatic regeneration after tissue transfer.
METHODS: In order to induce acute lymphedema in mouse tails, a circumferential full thickness skin excision ligating the superficial and deep lymphatics was performed in nude mice. Experimental wounds were repaired with full thickness skin grafts (FTSG) from either 1) transgenic mice that express GFP protein or 2) mice that are deficient in lymphatic vessel endothelial hyaluronan receptor (LYVE-1). Control animals underwent excision only without repair since we have previously shown that this treatment results in tail lymphedema for 10-12 weeks postoperatively. Lymphatic function was assessed at various time points with tail volume measurements, lymphoscintigraphy for in vivo lymphatic imaging, and immunohistochemistry.
RESULTS: Mice treated with FTSG had significantly more rapid restoration of lymphatic function with markedly decreased tail volumes, brisk lymphatic drainage by lymphoscintigraphy, and collapsed lymphatic vessels on histology as compared with control animals that underwent excision only. Treatment with tissue transfer improved lymphatic regeneration by increasing migration and proliferation of lymphatic endothelial cells, decreasing local inflammation, and increasing macrophage infiltration with resultant expression of vascular endothelial growth factor-C (VEGF-C). Interestingly, in the early postoperative period, nearly 100% of lymphatic vessels present in the graft were donor-derived (i.e. GFP+) and appeared to spontaneously anastomose with host lymphatics (GFP-). By 6 weeks, new lymphatics from the recipient had infiltrated the edges of the skin graft both proximally and distally, and lymphatics within the skin grafted area took on a chimeric appearance expressing both donor and recipient proteins.
CONCLUSIONS: Lymphatic regeneration after tissue transfer occurs as a result of three processes: spontaneous reanastomosis of existing recipient lymphatic channels, proliferation and inosculation from graft lymphatics, and de novo lymphatic regeneration in recipient wounded tissue. These events occur rapidly (<6 weeks) and bypass damaged lymphatics, thus leading to significant improvement in lymphedema.
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