Riley Celeste M, Fuegy Peter W, Firpo Matthew A, Shu Xiao Zheng, Prestwich Glenn D, Peattie Robert A
Department of Chemical Engineering, Oregon State University, 103 Gleeson Hall, Corvallis, OR 97331, USA.
Biomaterials. 2006 Dec;27(35):5935-43. doi: 10.1016/j.biomaterials.2006.08.029. Epub 2006 Sep 6.
Crosslinked, chemically modified hyaluronan (HA) hydrogels pre-loaded with two cytokine growth factors, vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), were employed to elicit new microvessel growth in vivo, in both the presence and absence of heparin (Hp) in the gels. HA hydrogel film samples were surgically implanted in the ear pinnae of mice, and the ears were harvested at 7 or 14 days post-implantation. Analysis of neovascularization showed that each of the treatment groups receiving an implant, except for HA/Hp at day 14, demonstrated significantly more microvessel density than control ears undergoing surgery but receiving no implant (p<0.015). Treatment groups receiving either Ang-1 alone, or aqueous co-delivery of both Ang-1 and VEGF, were statistically unchanged with time. In contrast, film delivery of both growth factors produced continuing increases in vascularization from day 7 to day 14 in the absence of Hp, but decreases in its presence. However, presentation of both VEGF and Ang-1 in crosslinked HA gels containing Hp generated intact microvessel beds with well-defined borders. The HA hydrogels containing Ang-1+VEGF produced the greatest angiogenic response of any treatment group tested at day 14 (NI=7.44 in the absence of Hp and 4.67 in its presence, where NI is a neovascularization index). Even in the presence of Hp, this had 29% greater vessel density than the next largest treatment group receiving HA/Hp+VEGF (NI=3.61, p=0.04). New therapeutic approaches for numerous pathologies could be notably enhanced by the localized, sustained angiogenic response produced by release of both VEGF and Ang-1 from crosslinked HA films.
预先装载了两种细胞因子生长因子——血管内皮生长因子（VEGF）和血管生成素 -1（Ang-1）的交联化学修饰透明质酸（HA）水凝胶，被用于在体内引发新的微血管生长，凝胶中分别存在和不存在肝素（Hp）。将HA水凝胶薄膜样本通过手术植入小鼠耳廓，在植入后7天或14天收获耳朵。对新血管形成的分析表明，除了第14天的HA/Hp组外，每个接受植入的治疗组的微血管密度均显著高于接受手术但未植入的对照耳朵（p<0.015）。单独接受Ang-1治疗的组或同时接受Ang-1和VEGF水性共递送的组，其血管生成随时间无统计学变化。相比之下，在不存在Hp的情况下，两种生长因子的薄膜递送在第7天至第14天导致血管生成持续增加，但在存在Hp的情况下则减少。然而，在含有Hp的交联HA凝胶中同时呈现VEGF和Ang-1可产生边界清晰的完整微血管床。在第14天，含有Ang-1 + VEGF的HA水凝胶在所有测试治疗组中产生了最大的血管生成反应（在不存在Hp时新血管形成指数NI = 7.44，在存在Hp时NI = 4.67）。即使在存在Hp的情况下，该组的血管密度也比接受HA/Hp + VEGF的第二大治疗组高29%（NI = 3.61，p = 0.04）。交联HA薄膜释放VEGF和Ang-1所产生的局部、持续的血管生成反应，可能会显著增强针对多种病症的新治疗方法。
