Development of a compliant and cytocompatible micro-fibrous polyethylene terephthalate vascular scaffold

Bioengineering approaches have been intensively applied to create small diameter vascular grafts using artificial materials. However, a fully successful, high performing and anti-thrombogenic structure has not been achieved yet. In this study, we have designed and fabricated a novel non-woven fibrous vascular graft with biomechanical properties closely resembling those of native vessels. Vascular cell growth, preservation of cell phenotype, retention of vasoactive properties, as well as the effect of gelatin coating on the cellular interaction with the scaffolds under static and shear stress conditions were investigated. The non-woven fibrous scaffolds were made from melt blown polyethylene terephthalate fiber webs stacked by means of a consolidation technique. The scaffold variables were fiber diameter distribution and the number of consolidated web stacks. SEM analysis confirmed various fiber diameter and pore size ranges corresponding to the different conditions. The scaffolds showed burst pressure values of ~1500 mmHg and compliance (8.4 6 \ub1 1.0 7 10\u207b\ub2% mmHg\u207b\ub9) very similar to those of native arteries (~8 7 10\u207b\ub2% mmHg\u207b\ub9). The structure with the smallest fiber diameter range (1\u20135 \ub5m) and pore size range (1\u201320 \ub5m) was the most suitable for the growth of human brain endothelial cells and aortic smooth muscle cells. The cells maintained their specific cell phenotype, expressed collagen and elastin and produced cAMP in response to \u3b1-calcitonin gene-related peptide. However, under shear stress conditions (0.9 dyne cm\u207b\ub2), only 30% of the cells were retained in both uncoated and gelatincoated scaffolds indicating the need for improving the cell retention capacity of these structures, which is our future research direction. This study indicates that the biomechanical and biocompatible properties of this novel vascular scaffold are promising for the development of a vascular graft with similar characteristics to those of native vessels.Peer reviewed: YesNRC publication: Ye

IGFBP-4 anti-angiogenic and anti-tumorigenic effects are associated with anti-cathepsin B activity

Insulin-like growth factor-binding protein 4 (IGFBP-4/IBP-4) has potent IGF-independent anti-angiogenic and antitumorigenic effects. In this study, we demonstrated that these activities are located in the IGFBP-4 C-terminal protein fragment (CIBP-4), a region containing a thyroglobulin type 1 (Tg1) domain. Proteins bearing Tg1 domains have been shown to inhibit cathepsins, lysosomal enzymes involved in basement membrane degradation and implicated in tumor invasion and angiogenesis. In our studies, CIBP-4 was shown to internalize and co-localize with lysosomal-like structures in both endothelial cells (ECs) and glioblastoma U87MG cells. CIBP-4 also inhibited both growth factor-induced EC tubulogenesis in Matrigel and the concomitant increases in intracellular cathepsin B (CatB) activity. In vitro assays confirmed CIBP-4 capacity to block recombinant CatB activity. Biodistribution analysis of intravenously injected CIBP-4-Cy5.5 in a glioblastoma tumor xenograft model indicated targeted accumulation of CIBP-4 in tumors. Most importantly, CIBP-4 reduced tumor growth in this animal model by 60%. Pleiotropic anti-angiogenic and anti-tumorigenic activities of CIBP-4 most likely underlie its observed therapeutic potential against glioblastoma. \ua9 2013 Neoplasia Press, Inc.Peer reviewed: YesNRC publication: Ye