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

Marui, Akira; Tabata, Yasuhiko; Kojima, Shinsuke; Yamamoto, Masaya; Tambara, Keiichi; Nishina, Tomohiro; Saji, Yoshiaki; Inui, Ken Ichi; Hashida, Tohru; Yokoyama, Sumiko; Onodera, Rie; Ikeda, Tadashi; Fukushima, Masanori; Komeda, Masashi

doi:10.1253/circj.71.1181

Cited by 118 publications

(77 citation statements)

References 34 publications

(55 reference statements)

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“…Certain institutions are already practicing vascular regeneration therapy and the outcome is believed to be best determined by assessing the degree of symptom improvement (2,17,18) by, for example, perfusion study using CT or MRI, contrast-enhanced ultrasonography or optical CT. We did not include angiographic findings in our efficacy evalua- A B C tion as our earlier study suggested that their quantification was affected by the ROI used and thus there were variations in the ratios of vascular regeneration. Several previous studies have reported on how bFGF bonds to GMS and is slowly released from GMS (19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

Vascular regeneration by pinpoint delivery of growth factors using a microcatheter reservoir system in a rabbit hind-limb ischemia model

Nitta

Nitta-Seko

Sonoda

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. The purpose of this study was to compare the results of delivering low doses of growth factor iteratively (20 µg x5) via a reservoir system with results obtained following a single administration of 100 µg of growth factor. The delivery systems using gelatin microspheres (GMS) facilitate the controlled release of drugs. The controlled release of growth factors at specific sites is essential for vascular regeneration. An ischemic hind-limb model was established in nine rabbits. A reservoir system was implanted in each rabbit. GMS impregnated with basic fibroblast growth factor (bFGF) through an indwelling 2-Fr catheter was infused in the reservoir system. The rabbits were divided into three equal groups: group 1 received 20 µg iteratively (x5) via the reservoir, a single dose of 100 µg growth factor was administered to group 2 and group 3 was the saline control. The therapeutic effects were evaluated by measuring the thigh temperature, blood pressure and blood flow. An immunohistological analysis was also performed for CD31. No significant difference was observed between preand post-treatment (4 weeks following bFGF infusion) in the thigh temperature, blood pressure and blood flow results from each group. Pathological analysis revealed that the number of regenerated vessels was significantly higher in the group treated iteratively with low-dose bFGF.

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Section: Discussionmentioning

confidence: 99%

Vascular regeneration by pinpoint delivery of growth factors using a microcatheter reservoir system in a rabbit hind-limb ischemia model

Nitta

Nitta-Seko

Sonoda

et al. 2012

Experimental and Therapeutic Medicine

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“…[1][2][3][4][5][6][7][8]19,20 Briefly, gelatin hydrogelmicrospheres were prepared by crosslinking glutaraldehyde of gelatin in the dispersed state. Human recombinant bFGF was incorporated into the gelatin microspheres by dropping 20 l of bFGF solution at various concentrations into 2 mg of freeze-dried gelatin microspheres; the microspheres were then left at room temperature for 3 h. At use, the bFGF containing gelatin hydrogel microspheres were dispersed in 100 l of phosphate buffer saline, aspirated into a 1-ml syringe attached with a 27-G needle (TERUMO, Tokyo, Japan), and injected into the 5 sites of ischemic thigh muscles of mice hindlimb.…”

Section: Preparation Of Gelatin Hydrogel Microspheres Incorporating Bfgfmentioning

confidence: 99%

“…31,32 We have shown the efficacy of sustained release of bFGF in several animal and clinical studies. [1][2][3][4][5][6][7][8] We used gelatin hydrogel as a sustained-release carrier for bFGF instead of genetic materials. There have been concerns about the unpredictable duration and level of gene expression or immunity of inflammatory responses of viral vectors.…”

Section: Sustained Release Of Bfgf From Biodegradable Gelatin Hydrogelmentioning

confidence: 99%

Sustained Release of Prostaglandin E1 Potentiates the Impaired Therapeutic Angiogenesis by Basic Fibroblast Growth Factor in Diabetic Murine Hindlimb Ischemia

Huang

Marui

Sakaguchi

et al. 2008

Circ J

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“…Furthermore, when the results were classified by seed type, the largest group of 35 (60.3%), used autologous somatic stem cells; 7 (12.1%) used growth factor genes; 6 (10.3%), growth factor peptides; 5 (8.6%), allogeneic somatic stem cells; 3 (5.2%) used devices; and 2 (3.5%) were other types of seed ( Table 2). Because early-phase (＜phase Ⅱ) seeds are in the majority (43 seeds; 82.7%), revascularization seeds for CLI are still in the competitive development phase and promising seeds can be expected to appear in the near future 23) . Apart from the phase or endpoint, the main difference between trials is whether they allow the inclusion of patients with gangrene.…”

Section: International Randd Status Of Regenerative Medicine For CLImentioning

confidence: 99%

Regenerative Medicine in Critical Limb Ischemia

Ohno

Kaneda

Nagai

et al. 2012

JAT

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Critical limb ischemia (CLI) is commonly caused by atherosclerotic arterial obstruction or stenosis in the leg, as demonstrated by rest pain, skin ulcers and gangrene (Fontaine Ⅲ or Ⅳ), often fails to respond to conservative treatments, and carries a high risk for limb amputation, with a particularly dismal prognosis. Although surgical revascularization techniques may be used for certain CLI patients, such techniques are not indicated for most CLI patients due to the diffuse nature of the responsible lesions, distal location of the obstruction, or coexisting systemic comorbidities. For such CLI patients with no alternative treatments, the potential utility of cell therapies has been investigated. Indeed many clinical trials are being carried out by academic sectors, and their achievements will facilitate clinical development by pharmaceutical companies. In order to understand the situation regarding competitive international R&D of revascularization seeds for CLI, we surveyed the status of clinical trials. As a result, we identified 58 clinical trials on revascularization for CLI, with the majority in the early phase (＜phase Ⅱ: 82.7%). Revascularization seeds for CLI are in the development and competition phase, and promising seeds are expected to appear in the near future. In this review, we discuss how to develop optimal regenerative medicine concerning the selection of cell origin, cell type, combination with growth factor, and the influence of concomitant disease.

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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

Cited by 118 publications

References 34 publications

Vascular regeneration by pinpoint delivery of growth factors using a microcatheter reservoir system in a rabbit hind-limb ischemia model

Vascular regeneration by pinpoint delivery of growth factors using a microcatheter reservoir system in a rabbit hind-limb ischemia model

Sustained Release of Prostaglandin E1 Potentiates the Impaired Therapeutic Angiogenesis by Basic Fibroblast Growth Factor in Diabetic Murine Hindlimb Ischemia

Regenerative Medicine in Critical Limb Ischemia

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