Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis.
Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis.
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DOI：
10.1016/j.actbio.2014.11.002
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发表时间：
2015-02
影响因子：
9.7
通讯作者：
Liu, Xiaohua
中科院分区：
文献类型：
--
作者：
Li, Zhe;Qu, Tiejun;Ding, Chen;Ma, Chi;Sun, Hongchen;Li, Shirong;Liu, Xiaohua
可注射生物材料对于软组织再生很有吸引力，因为它们以微创方式处理，并且可以轻松适应复杂的缺陷。然而，可注射结构的血管化不足长期以来一直是一个障碍，导致植入后坏死或体积减少。在这项工作中，我们开发了一种三步法来合成可注射的明胶衍生水凝胶，该水凝胶能够控制生长因子的递送以诱导血管生成。在我们的方法中，酪胺首先被引入明胶链中，为注射后凝胶形成提供酶促交联点。接下来，肝素（一种具有许多生长因子结合域的多糖）与酪胺修饰的明胶共价连接。最后，通过与明胶衍生物中的肝素结合，将血管内皮生长因子（VEGF）掺入明胶衍生物中，并通过过氧化氢（H2O2）和辣根过氧化物酶（HRP）的酶催化反应形成VEGF受控释放的注射凝胶。凝胶的胶凝时间、机械性能和降解很容易通过明胶浓度和 H2O2/HRP 比率来调整。 VEGF 与肝素结合可稳定该生长因子，保护其免于变性和蛋白水解降解，从而延长持续释放时间。体外释放研究和生物活性测定表明，VEGF持续释放，具有高生物活性，持续时间超过3周。此外，还进行了鸡绒毛尿囊膜（CAM）测定和动物实验，以评估水凝胶释放的 VEGF 的体内生物活性。在CAM上孵育5天后，肝素修饰水凝胶周围的血管数量比对照组增加了2.4倍。在小鼠背侧皮下注射两周后，与对照组相比，肝素修饰明胶/VEGF凝胶中观察到更深、更致密的细胞浸润和血管生成。有趣的是，即使没有掺入VEGF，肝素修饰的明胶衍生物仍然具有一定程度的诱导血管生成的能力。我们的结果表明明胶衍生物/VEGF 是一种用于诱导软组织再生血管生成的优秀注射递送系统。
Injectable biomaterials are attractive for soft tissue regeneration because they are handled in a minimally invasive manner and can easily adapt to complex defects. However, inadequate vascularization of the injectable constructs has long been a barrier, leading to necrosis or volume reduction after implantation. In this work, we developed a three-step process to synthesize injectable gelatin-derived hydrogels that are capable of controlling growth factor delivery to induce angiogenesis. In our approach, tyramine was first introduced into gelatin chains to provide enzymatical crosslinking points for gel formation after injection. Next, heparin, a polysaccharide with binding domains to many growth factors, was covalently linked to the tyramine-modified gelatin. Finally, vascular endothelial growth factor (VEGF) was incorporated into the gelatin derivative by binding with the heparin in the gelatin derivative, and an injectable gel with controlled VEGF release was formed by an enzymatic catalytic reaction with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The gelation time, mechanical properties and degradation of the gel was readily tailored by the gelatin concentration and the ratio of H2O2/HRP. Binding VEGF to heparin stabilizes this growth factor, protects it from denaturation and proteolytic degradation, and subsequently prolongs the sustained release. An in vitro release study and bioactivity assay indicated that the VEGF was released in a sustained manner with high bioactivity for over 3 weeks. Furthermore, a chicken chorioallantoic membrane (CAM) assay and animal experiments were performed to evaluate in vivo bioactivity of the VEGF released from the hydrogels. After 5 days of incubation on CAM, the number of blood vessels surrounding the heparin-modified hydrogels was 2.4-fold increase than that of the control group. Deeper and denser cell infiltration and angiogenesis in the heparin-modified gelatin/VEGF gels were observed than in the controls after being subcutaneously injected in the dorsal side of the mice for 2 weeks. Interestingly, even without the incorporation of VEGF, the heparin-modified gelatin derivative still had the capability to induce angiogenesis to a certain degree. Our results suggest that the gelatin derivative/VEGF is an excellent injectable delivery system for induced angiogenesis of soft tissue regeneration.
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