title: Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia.
abstract: As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I-IIa study that analyzed 10 CLI patients following a 200-μg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p < 0.01) showed significant improvement. Regarding secondary endpoints, the distance walked in 6 min (255 ± 105 vs. 318 ± 127 m, p = 0.02), the Rutherford classification (4.4 ± 0.5 vs. 3.1 ± 1.4, p = 0.02), the rest pain scale (1.7 ± 1.0 vs. 1.2 ± 1.3, p = 0.03), and the cyanotic scale (2.0 ± 1.1 vs. 0.9 ± 0.9, p < 0.01) also showed improvement. The blood levels of bFGF were within the normal range in all patients. A subanalysis of patients with arteriosclerosis obliterans (n = 7) or thromboangiitis obliterans (Buerger's disease) (n = 3) revealed that TcO2 had significantly improved in both subgroups. TcO2 did not differ between patients with or without chronic kidney disease. The sustained release of bFGF from biodegradable gelatin hydrogel may offer a safe and effective form of angiogenesis for patients with CLI.
authors: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Motoyuki
authors: M
authors: Kumagai
authors: Division of Cardiovascular Surgery, Tenri Hospital, Nara, Japan.|Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Akira
authors: A
authors: Marui
authors: Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors: Yasuhiko
authors: Y
authors: Tabata
authors: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.|Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Takahide
authors: T
authors: Takeda
authors: Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors: Masaya
authors: M
authors: Yamamoto
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
authors: Atsushi
authors: A
authors: Yonezawa
authors: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.|Department of Data Science, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Shiro
authors: S
authors: Tanaka
authors: Department of Cardiovascular Surgery, Kumamoto Central Hospital, Kumamoto, Japan.
authors: Shigeki
authors: S
authors: Yanagi
authors: Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Toshiko
authors: T
authors: Ito-Ihara
authors: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Takafumi
authors: T
authors: Ikeda
authors: Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Toshinori
authors: T
authors: Murayama
authors: Department of Biostatistics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Satoshi
authors: S
authors: Teramukai
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
authors: Toshiya
authors: T
authors: Katsura
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
authors: Kazuo
authors: K
authors: Matsubara
authors: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.|Department of Data Science, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Koji
authors: K
authors: Kawakami
authors: Department of Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Masayuki
authors: M
authors: Yokode
authors: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors: Akira
authors: A
authors: Shimizu
authors: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. sakatar@kuhp.kyoto-u.ac.jp.
authors: Ryuzo
authors: R
authors: Sakata
mesh_terms: D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D055109:Ankle Brachial Index; D001785:Blood Gas Monitoring, Transcutaneous; D016638:Critical Illness; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D005780:Gelatin / Q000737:chemistry*; D006801:Humans; D020100:Hydrogels; D007273:Injections, Intramuscular; D007511:Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D007564:Japan; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010147:Pain Measurement; D058729:Peripheral Arterial Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D020127:Recovery of Function; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D043925:Angiogenesis Inducing Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020100:Hydrogels; D016222:Fibroblast Growth Factor 2; D005780:Gelatin
keywords: Angiogenesis; Basic fibroblast growth factor; Critical limb ischemia; Drug delivery system