Treatment of leg ischemia with biodegradable gelatin hydrogel microspheres incorporating granulocyte colony-stimulating factor.
Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenic factor. We hypothesized that G-CSF-immersed gelatin hydrogel microspheres (G-CSF-GHMs) injected into the ischemic legs might continuously release a small amount of G-CSF to locally stimulate angiogenesis without unfavorable systemic effects. Just after ligation of the right femoral artery of BALB/c mice, recombinant human G-CSF (100-μg/kg)-immersed GHM was injected into the right hindlimb muscles; the controls included a saline-injected group, an intramuscularly injected G-CSF group, a subcutaneously injected G-CSG group, and an empty GHM-injected group. Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the G-CSF-GHM group compared with any of the control groups. Despite there being no increase in the serum concentration of G-CSF, in peripheral granulocytes, or in circulating endothelial progenitor cells, not only capillary but also arteriolar density was significantly increased in this group. Next, we started treatment with G-CSF-GHM 4 weeks after ligation to examine whether the treatment is effective if performed during the chronic stage of ischemia. The late treatment was also found to effectively improve blood flow in the ischemic leg. In conclusion, G-CSF-GHM administration is suggested to be a promising and readily usable approach to treating peripheral artery disease, applicable even during the chronic stage.
Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Itta
I
Kawamura
Genzou
G
Takemura
Akiko
A
Tsujimoto
Takatomo
T
Watanabe
Hiromitsu
H
Kanamori
Masayasu
M
Esaki
Hiroyuki
H
Kobayashi
Toshiaki
T
Takeyama
Tomonori
T
Kawaguchi
Kazuko
K
Goto
Rumi
R
Maruyama
Takako
T
Fujiwara
Hisayoshi
H
Fujiwara
Yasuhiko
Y
Tabata
Shinya
S
Minatoguchi
D000818:Animals; D004195:Disease Models, Animal; D005780:Gelatin / Q000737:chemistry; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D006801:Humans; D020100:Hydrogels; D007273:Injections, Intramuscular; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D058729:Peripheral Arterial Disease / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins; D013997:Time Factors
D020100:Hydrogels; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D005780:Gelatin