Gelatin Hydrogel Microspheres Enable Pinpoint Delivery of Basic Fibroblast Growth Factor for the Development of Functional Collateral Vessels

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Abstract
Background— Various growth factors promote collateral vessel development and are regarded as promising for the treatment of vascular occlusive diseases. However, an efficacious delivery system for them has yet to be established. We devised a strategy to augment functional collateral vessels by using acidic gelatin hydrogel microspheres (AGHMs) incorporating basic fibroblast growth factor (bFGF). The aim of the present study was to investigate the hypothesis that by intra-arterial (IA) administration of bFGF-impregnated AGHMs, bFGF could be delivered from AGHMs trapped in distal small-diameter vessels and thereby induce functional collateral vessels with an assured blood supply through the process of arteriogenesis. Methods and Results— Various sizes of AGHMs (3 mg) incorporating 125 I-labeled bFGF were injected into the left internal iliac artery of a rabbit model of hindlimb ischemia. Less than 50% of radioactivity accumulated in the ischemic hindlimb after injection of AGHMs that were 10 μm in diameter, whereas ≈80% of radioactivity was counted in the ischemic limb after administration of 29- or 59-μm-diameter AGHMs. Calf blood pressure ratio and the ratio of regional blood flow of the bilateral hindlimbs immediately before and after IA administration of 29-μm–diameter AGHMs showed no significant change. Then we evaluated the function of the developed collateral vessels 28 days after IA administration of bFGF-impregnated, 29-μm-diameter AGHMs. IA administration of bFGF-impregnated AGHMs induced marked collateral vessel improvement compared with IA administration of phosphate buffered saline–treated AGHMs and intramuscular administration of bFGF-impregnated AGHMs. Conclusions— IA administration of bFGF-impregnated, 29-μm-diameter AGHMs strongly induced functional collateral vessels without worsening ischemia, indicating the possible therapeutic usefulness of this approach.

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