In vivo biocompatibility of carbodiimide-crosslinked collagen matrices: Effects of crosslink density, heparin immobilization, and bFGF loading.
In vivo biocompatibility of carbodiimide-crosslinked collagen matrices: Effects of crosslink density, heparin immobilization, and bFGF loading.
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DOI：
10.1002/1097-4636(20010605)55:3
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发表时间：
2001-06
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通讯作者：
P. V. van Wachem;J. Plantinga;M. Wissink;R. Beernink;A. Poot;G. Engbers;T. Beugeling;W. van Aken;J. Feijen;M. V. van Luyn
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作者：
P. V. van Wachem;J. Plantinga;M. Wissink;R. Beernink;A. Poot;G. Engbers;T. Beugeling;W. van Aken;J. Feijen;M. V. van Luyn
使用N-（3-二甲基氨基丙基）-N '-乙基碳二亚胺（E）和N-羟基琥珀酰亚胺（N）交联的胶原基质先前被开发为小直径血管移植物的内皮细胞接种的基质。在本研究中，各种EN交联胶原基质的生物相容性进行了评价后，皮下植入大鼠长达10周。研究了交联密度（称为每1，000个氨基酸残基（EN 10、EN 14、EN 18或EN 22）中游离伯氨基的数量）、固定于EN 14的肝素量以及用碱性成纤维细胞生长因子（bFGF）预加载肝素化EN 14对诱导的组织反应的影响。EN-交联的胶原在早期和晚期时间间隔都是生物相容的，并且具有高交联密度的基质（即，EN 14、EN 10）与非交联胶原相比，尤其显示出抗原应答显著降低。此外，增加交联导致降解速率降低。将肝素固定到EN 14上导致与EN 14（因此没有肝素）类似或稍微减少的组织反应，但纤维蛋白形成和血管化随着固定肝素量的增加而增加。基质预载bFGF也表现出良好的生物相容性，特别是在结合较高量的固定化肝素。后一种基质[具有高肝素和bFGF的EN 14，因此EN 14-H（0.4）F和EN 14-H（1.0）F]显示血管形成显著增加，持续时间长达3周。肝素固定和bFGF预载均未诱导抗原应答增加。可以得出结论，本研究的结果证明了bFGF预载，肝素固定的EN 14胶原蛋白，作为实验动物内皮细胞接种的基质的进一步评价。
Collagen matrices, crosslinked using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (E) and N-hydroxysuccinimide (N), were previously developed as a substrate for endothelial cell seeding of small-diameter vascular grafts. In the present study, the biocompatibility of various EN-crosslinked collagen matrices was evaluated following subcutaneous implantation in rats for periods up to 10 weeks. The effects of the crosslink density, referred to as the number of free primary amino groups per 1,000 amino acid residues (EN10, EN14, EN18, or EN22), the amount of heparin immobilized to EN14, and the effect of preloading heparinized EN14 with basic fibroblast growth factor (bFGF) on the induced tissue reaction were studied. EN-crosslinked collagen was biocompatible at both early and late time intervals, and matrices with high crosslink densities (i.e., EN14, EN10) especially demonstrated a significantly decreased antigenic response when compared to noncrosslinked collagen. Furthermore, increased crosslinking resulted in a decreased degradation rate. Immobilization of heparin onto EN14 resulted in a similar to EN14 (thus without heparin) or somewhat reduced tissue reaction, but fibrin formation and vascularization were increased with increasing quantities of immobilized heparin. Matrices preloaded with bFGF also demonstrated good biocompatibility, especially in combination with higher amounts of immobilized heparin. The latter matrices [EN14 with high heparin and bFGF, thus EN14-H (0.4)F and EN14-H(1.0)F] demonstrated significantly increased vascularization for periods up to 3 weeks. Neither heparin immobilization nor bFGF preloading induced an increased antigenic response. It is concluded that the results of this study justify further evaluation of bFGF preloaded, heparin immobilized EN14 collagen, as a matrix for endothelial cell seeding in experimental animals.