Attenuation of limb loss in an experimentally induced hindlimb ischemic model by fibroblast growth factor-2/fragmin/protamine microparticles as a delivery system.
Fibroblast growth factor-2 (FGF-2) is a well-characterized protein that is used in the treatment of healing-impaired wounds. We previously reported that fragmin/protamine microparticles (F/P MPs) are useful as biodegradable carriers for the controlled release of cytokines. We examined the ability of FGF-2-containing (FGF-2/) F/P MPs to prevent limb loss in an experimentally induced ischemic hindlimb model using adult Balb/c-nu/nu male mice. One day after inducing ischemia, intramuscular injections of 100 μL of FGF-2/F/P MPs turbid suspension (10 μg/mL FGF-2 and 6 mg/mL F/P MPs) were administered into eight sites of the ischemic hindlimb. A 100-μL suspension of each of the following-10 μg/mL FGF-2, 6 mg/mL F/P MPs, and phosphate-buffered saline (PBS; the control)-was similarly injected into the hindlimb. From 5 days onward after the injections, recovery from ischemia was observed in the FGF-2/F/P MP-treated group, but only partial recovery occurred in the FGF-2-treated group. The F/P MP-treated and PBS-treated groups (i.e., control) exhibited no recovery from the ischemia. The histological evaluations of the hindlimbs also confirmed that the capillary (i.e., mature vessels) density was significantly higher in the FGF-2/F/P MP-treated group than in the other groups. The mice injected with FGF-2/F/P MPs also recovered hindlimb blood flow, as reflected by oxygen saturation and surface temperature evaluation. Our present approach using FGF-2/F/P MPs could be considered a valuable option for the therapeutic treatment of peripheral ischemic diseases.
Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan. snaka@ndmc.ac.jp
Shingo
S
Nakamura
Masayuki
M
Ishihara
Megumi
M
Takikawa
Satoko
S
Kishimoto
Susumu
S
Isoda
Masanori
M
Fujita
Masahiro
M
Sato
Tadaaki
T
Maehara
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D017985:Dalteparin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D007511:Ischemia / Q000473:pathology*; D023821:Limb Salvage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D011479:Protamines / Q000008:administration & dosage / Q000494:pharmacology*; D013817:Thermography; D013997:Time Factors
D011479:Protamines; D016222:Fibroblast Growth Factor 2; D017985:Dalteparin; D010100:Oxygen