title: Hemoglobin vesicles improve wound healing and tissue survival in critically ischemic skin in mice.
abstract: Local hypoxia, as due to trauma, surgery, or arterial occlusive disease, may severely jeopardize the survival of the affected tissue and its wound-healing capacity. Initially developed to replace blood transfusions, artificial oxygen carriers have emerged as oxygen therapeutics in such conditions. The aim of this study was to target primary wound healing and survival in critically ischemic skin by the systemic application of left-shifted liposomal hemoglobin vesicles (HbVs). This was tested in bilateral, cranially based dorsal skin flaps in mice treated with a HbV solution with an oxygen affinity that was increased to a P(50) (partial oxygen tension at which the hemoglobin becomes 50% saturated with oxygen) of 9 mmHg. Twenty percent of the total blood volume of the HbV solution was injected immediately and 24 h after surgery. On the first postoperative day, oxygen saturation in the critically ischemic middle flap portions was increased from 23% (untreated control) to 39% in the HbV-treated animals (P < 0.05). Six days postoperatively, flap tissue survival was increased from 33% (control) to 57% (P < 0.01) and primary healing of the ischemic wound margins from 6.6 to 12.7 mm (P < 0.05) after HbV injection. In addition, higher capillary counts and endothelial nitric oxide synthase expression (both P < 0.01) were found in the immunostained flap tissue. We conclude that left-shifted HbVs may ameliorate the survival and primary wound healing in critically ischemic skin, possibly mediated by endothelial nitric oxide synthase-induced neovascularization.
authors: Department of Plastic and Hand Surgery, Inselspital, University of Bern, CH-3010 Bern, Switzerland. jan.plock@insel.ch
authors: Jan A
authors: JA
authors: Plock
authors: Nassim
authors: N
authors: Rafatmehr
authors: Dubravko
authors: D
authors: Sinovcic
authors: Jonas
authors: J
authors: Schnider
authors: Hiromi
authors: H
authors: Sakai
authors: Eishun
authors: E
authors: Tsuchida
authors: Andrej
authors: A
authors: Banic
authors: Dominique
authors: D
authors: Erni
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D001802:Blood Substitutes / Q000494:pharmacology*; D062109:Dermatologic Surgical Procedures; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000494:pharmacology*; D000860:Hypoxia / Q000473:pathology / Q000628:therapy; D007511:Ischemia / Q000473:pathology* / Q000628:therapy*; D008081:Liposomes / Q000494:pharmacology; D051379:Mice; D008833:Microcirculation; D009336:Necrosis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000473:pathology; D013524:Surgical Flaps / Q000098:blood supply / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D001802:Blood Substitutes; D006454:Hemoglobins; D008081:Liposomes; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D010100:Oxygen