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EXPERIMENTAL STUDY

Biodegradable gelatin hydrogel potentiates the angiogenic effect of fibroblast growth factor 4 plasmid in rabbit hindlimb ischemia

Hirofumi Kasahara, MD^*, Etsuro Tanaka, MD, PhD, Naoto Fukuyama, MD, PhD, Eriko Sato, MD^*, Hiromi Sakamoto, PhD^||, Yasuhiko Tabata, PhD^¶, Kiyoshi Ando, MD, PhD, Harukazu Iseki, MD, PhD, Yoshiro Shinozaki, BS, Koji Kimura, MD^*, Eriko Kuwabara, MD^*, Shirosaku Koide, MD, PhD^*, Hiroe Nakazawa, MD, PhD and Hidezo Mori, MD, PhD^#,*

^* Cardiovascular Surgery, Tokai University School of Medicine, Isehara, Japan
Physiology, Tokai University School of Medicine, Isehara, Japan
Internal Medicine, Tokai University School of Medicine, Isehara, Japan
Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Isehara, Japan
^|| Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
^¶ Research Center for Biomedical Engineering, Kyoto University, Kyoto, Japan
^# Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Japan

Manuscript received December 30, 2001; revised manuscript received July 2, 2002, accepted November 5, 2002.

^* Reprint requests and correspondence: Dr. Hidezo Mori, Department of Cardiac Physiology, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita 565-8565, Japan.
hidemori{at}ri.ncvc.go.jp

OBJECTIVES: We investigated the potentiation of gene therapy using fibroblast growth factor 4 (FGF4)-gene by combining plasmid deoxyribonucleic acid (DNA) with biodegradable gelatin hydrogel (GHG).

BACKGROUND: Virus vectors transfer genes efficiently but are biohazardous, whereas naked DNA is safer but less efficient. Deoxyribonucleic acid charges negatively; GHG has a positively charged structure and is biodegradable and implantable; FGF4 has an angiogenic ability.

METHODS: The GHG-DNA complex was injected into the hindlimb muscle (63 mice and 55 rabbits). Gene degradation was evaluated by using ¹²⁵I-labeled GHG-DNA complex in mice. Transfection efficiency was evaluated with reverse-transcription nested polymerase chain reaction and X-Gal histostaining. The therapeutic effects of GHG-FGF4-gene complex (GHG-FGF4) were evaluated in rabbits with hindlimb ischemia.

RESULTS: Gelatin hydrogel maintained plasmid in its structure, extending gene degradation temporally until 28 days after intramuscular delivery, and improving transfection efficiency. Four weeks after gene transfer, hindlimb muscle necrosis was ameliorated more markedly in the GHG-FGF4 group than in the naked FGF4-gene and GHG-beta-galactosidase (control) groups (p < 0.05, Kruskal-Wallis test). Synchrotron radiation microangiography (spatial resolution, 20 µm) and flow determination with microspheres confirmed significant vascular responsiveness to adenosine administration in the GHG-FGF4 group, but not in the naked FGF4-gene and the control.

CONCLUSIONS: The GHG-FGF4 complex promoted angiogenesis and blood flow regulation of the newly developed vessels possibly by extending gene degradation and improving transfection efficiency without the biohazard associated with viral vectors.

Abbreviations and Acronyms   ANOVA   analysis of variance   cDNA   complementary deoxyribonucleic acid   DNA   deoxyribonucleic acid   FGF4   fibroblast growth factor 4   GHG   gelatin hydrogel   lacZ   beta-galactosidase   NIH   National Institute of Health   PBS   phosphate-buffered saline   pI   isoelectric point   RNA   ribonucleic acid   RT-nested PCR   reverse transcription-nested polymerase chain reaction

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