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

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) incorporating125 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 m in diameter, whereas Ϸ80% of radioactivity was counted in the ischemic limb after administration of 29-or 59-m-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-m-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-m-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.

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

“…Vascular regenerative therapy improves the flow of blood to ischemic tissues by inducing neovascularization in patients with vascular occlusive diseases (1)(2)(3)(4)(5)(6)(7)(8). Therapeutic methods include the direct delivery of vascular growth factors including vascular endothelial growth factor, basic fibroblast growth factor (bFGF) and hepatocyte growth factor, the delivery of genes into host cells for the on-site production of vascular growth factors and the direct delivery of somatic stem cells capable of generating new vessels (9)(10)(11)(12)(13).…”

Enhanced Neovascular Formation in a Novel Hydrogel Matrix Consisting of Citric Acid and Collagen

“…It is, therefore, desirable that the TSC-AlCol gel enables induction of the process of arteriogenesis in addition to angiogenesis and/ or vasculogenesis. Since bFGF is known to induce angiogenesis and arteriogenesis, 6,28) it is an ideal angiogenic factor for increasing the effect of vascular development in the TSC-AlCol gel. Further, it might be important that bFGF associated with the TSC-AlCol gel.…”

“…The combination of bFGF significantly increased vessel density and length in TSC [3]-AlCol [15], TSC [6]AlCol [7.5, 10] and TSC [10]-AlCol [7.5], as compared with those in untreated gels (Fig. 3A and 3B).…”

“…4) Delivery of angiogenic growth factors or endothelial precursor cells potentially promotes these mechanisms of neovascularization, and this strategy has been applied for the treatment of vascular occlusive disease, such as ischemic heart disease and chronic limb ischemia. [6][7][8] However, to induce vessel formation in regenerative tissue, it is also important that the tissue is suitably furnished with a scaffold structure for newlyformed vessels, since it is essential for vessels in vivo to have a surrounding extracellular matrix (ECM) as a natural scaffold.…”

Controlled Release Strategy Based on Biodegradable Microspheres for Neurodegenerative Disease Therapy

“…GDNF has been used to prepare sustained release microspheres and to use for the treatment of Parkinson's disease [19,21,23,25,40]. Basic fibroblast growth factor (bFGF) has been used to formulate bFGF-loaded microshperes and use to treat ischemic hindlimb [27,41,42]. In central nervous system, different neurons have express different receptors and react with different neurotrophic factors.…”