A novel approach to therapeutic angiogenesis for patients with critical limb ischemia by sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel: an initial report of the phase I-IIa study.
BACKGROUND
Limb ischemia remains a challenge. To overcome shortcomings or limitations of gene therapy or cell transplantation, a sustained release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel has been developed.


RESULTS
A phase I-IIa study was performed, in which 7 patients had critical limb ischemia. They were intramuscularly injected with 200 microg of bFGF-incorporated gelatin hydrogel microspheres into the gastrocnemius of the ischemic limb. End-points were safety and feasibility of treatment after 4 and 24 weeks. One patient was excluded from the study for social reasons, but only after symptomatic improvements. In the evaluation of the other 6 patients, significant improvements were observed in the distance walked in 6 min (295+/-42 m vs 491+/-85 m for pretreatment vs after 24 weeks, p=0.023) and in transcutaneous oxygen pressure (53.5+/-5.2 mmHg vs 65.5+/-4.0 mmHg, p=0.03). The rest pain scale also improved (3.5+/-0.2 vs 1.0+/-0.6, p=0.022). The ankle-brachial pressure index improved at 4 weeks but not at 24 weeks. Among 5 patients who had a non-healing foot ulcer, the ulcer was completely healed in 3 patients, reduced in 1, and there was no change in 1 patient at 24 weeks. The blood levels of bFGF were undetected or within the normal level in all patients.


CONCLUSIONS
The sustained release of bFGF from gelatin hydrogel might be simple, safe, and effective to achieve therapeutic angiogenesis because it did not need genetic materials or collection of implanted cells, and because it did not have any general effects, which was supported by there being no elevation of the bFGF serum level.
Marui
Akira
A
Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, and Department of Pharmacy, Kyoto University Hospital, Japan.
Tabata
Yasuhiko
Y
Kojima
Shinsuke
S
Yamamoto
Masaya
M
Tambara
Keiichi
K
Nishina
Takeshi
T
Saji
Yoshiaki
Y
Inui
Ken-ichi
K
Hashida
Tohru
T
Yokoyama
Sumiko
S
Onodera
Rie
R
Ikeda
Tadashi
T
Fukushima
Masanori
M
Komeda
Masashi
M
D000328:Adult; D000368:Aged; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005121:Extremities / Q000473:pathology; D005240:Feasibility Studies; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000097:blood; D005780:Gelatin / Q000627:therapeutic use; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000627:therapeutic use; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D016896:Treatment Outcome
D003692:Delayed-Action Preparations; D016222:Fibroblast Growth Factor 2; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D005780:Gelatin