title: Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy.
abstract: BACKGROUND
  Lymphedema is a frequent consequence of lymph node excision during breast cancer surgery. Current treatment options are limited mainly to external compression therapies to limit edema development. We investigated previously, post-surgical lymphedema in a sheep model following the removal of a single lymph node and determined that autologous lymph node transplantation has the potential to reduce or prevent edema development. In this report, we examine the potential of lymphangiogenic therapy to restore lymphatic function and reduce post-surgical lymphedema.
  
  
  METHODS
  Lymphangiogenic growth factors (vascular endothelial growth factor-C (VEGF-C) and angiopoitein-2 (ANG-2)) were loaded into a gel-based drug delivery system (HAMC; a blend of hyaluronan and methylcellulose). Drug release rates and lymphangiogenic signaling in target endothelial cells were assessed in vitro and vascular permeability biocompatibility tests were examined in vivo. Following, the removal of a single popliteal lymph node, HAMC with the growth factors was injected into the excision site. Six weeks later, lymphatic functionality was assessed by injecting (125)Iodoine radiolabelled bovine serum albumin ((125)I-BSA) into prenodal vessels and measuring its recovery in plasma. Circumferential leg measurements were plotted over time and areas under the curves used to quantify edema formation.
  
  
  RESULTS
  The growth factors were released over a two-week period in vitro by diffusion from HAMC, with 50% being released in the first 24 hours. The system induced lymphangiogenic signaling in target endothelial cells, while inducing only a minimal inflammatory response in sheep. Removal of the node significantly reduced lymphatic functionality (Nodectomy 1.9 ± 0.9, HAMC alone 1.7 ± 0.8) compared with intact groups (3.2 ± 0.7). There was no significant difference between the growth factor treatment group (2.3 ± 0.73) and the intact group. An increase in the number of regenerated lymphatic vessels at treatment sites was observed with fluoroscopy. Groups receiving HAMC plus growth factors displayed significantly reduced edema (107.4 ± 51.3) compared with non-treated groups (nodectomy 219.8 ± 118.7, and HAMC alone 162.6 ± 141).
  
  
  CONCLUSIONS
  Growth factor therapy has the potential to increase lymphatic function and reduce edema magnitude in an animal model of lymphedema. The application of this concept to lymphedema patients warrants further examination.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Baker
authors.forename: Harold
authors.initials: H
authors.lastname: Kim
authors.forename: John L
authors.initials: JL
authors.lastname: Semple
authors.forename: Dan
authors.initials: D
authors.lastname: Dumont
authors.forename: Molly
authors.initials: M
authors.lastname: Shoichet
authors.forename: Dalia
authors.initials: D
authors.lastname: Tobbia
authors.forename: Miles
authors.initials: M
authors.lastname: Johnston
mesh_terms: D042702:Angiopoietin-2 / Q000008:administration & dosage*; D000818:Animals; D001943:Breast Neoplasms / Q000601:surgery; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000601:surgery*; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000601:surgery; D008209:Lymphedema / Q000188:drug therapy* / Q000209:etiology*; D008408:Mastectomy; D011183:Postoperative Complications / Q000188:drug therapy; D012038:Regeneration / Q000187:drug effects; D012756:Sheep; D042582:Vascular Endothelial Growth Factor C / Q000008:administration & dosage*
chemical_list: D042702:Angiopoietin-2; D042582:Vascular Endothelial Growth Factor C
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