Wei Shih-Yen, Chen Tzu-Hsuan, Kao Feng-Sheng, Hsu Yi-Jung, Chen Ying-Chieh
Department of Materials Science and Engineering, National Tsing Hua University, Hsinchu, Taiwan.
J Tissue Eng. 2022 Mar 11;13:20417314221084096. doi: 10.1177/20417314221084096. eCollection 2022 Jan-Dec.
The physically-crosslinked collagen hydrogels can provide suitable microenvironments for cell-based functional vascular network formation due to their biodegradability, biocompatibility, and good diffusion properties. However, encapsulation of cells into collagen hydrogels results in extensive contraction and rapid degradation of hydrogels, an effect known from their utilization as a pre-vascularized graft in vivo. Various types of chemically-crosslinked collagen-based hydrogels have been successfully synthesized to decrease volume contraction, retard the degradation rate, and increase mechanical tunability. However, these hydrogels failed to form vascularized tissues with uniformly distributed microvessels in vivo. Here, the enzymatically chemically-crosslinked collagen-Phenolic hydrogel was used as a model to determine and overcome the difficulties in engineering vascular networks. Results showed that a longer duration of inflammation and excessive levels of hydrogen peroxide limited the capability for blood vessel forming cells-mediated vasculature formation in vivo. Lowering the unreacted amount of crosslinkers reduced the densities of infiltrating host myeloid cells by half on days 2-4 after implantation, but blood vessels remained at low density and were mainly located on the edge of the implanted constructs. Co-implantation of a designed spacer with cell-laden hydrogel maintained the structural integrity of the hydrogel and increased the degree of hypoxia in embedded cells. These effects resulted in a two-fold increase in the density of perfused blood vessels in the hydrogel. Results agreed with computer-based simulations. Collectively, our findings suggest that simultaneous reduction of the crosslinker-induced host immune response and increase in hypoxia in hydrogen peroxide-triggered chemically-crosslinked hydrogels can effectively improve the formation of cell-mediated functional vascular networks.
物理交联的胶原蛋白水凝胶由于其生物可降解性、生物相容性和良好的扩散特性，可为基于细胞的功能性血管网络形成提供合适的微环境。然而，将细胞封装到胶原蛋白水凝胶中会导致水凝胶大量收缩和快速降解，这一现象在其作为体内预血管化移植物的应用中已为人所知。已经成功合成了各种类型的化学交联胶原蛋白基水凝胶，以减少体积收缩、延缓降解速率并提高机械可调性。然而，这些水凝胶在体内未能形成微血管均匀分布的血管化组织。在此，酶促化学交联的胶原蛋白-酚醛水凝胶被用作模型来确定和克服构建血管网络中的困难。结果表明，较长的炎症持续时间和过量的过氧化氢水平限制了体内血管形成细胞介导的脉管系统形成能力。降低交联剂的未反应量可使植入后第2至4天浸润的宿主髓样细胞密度减半，但血管密度仍然较低，且主要位于植入构建体的边缘。将设计的间隔物与载细胞水凝胶共同植入可维持水凝胶的结构完整性，并增加包埋细胞中的缺氧程度。这些作用导致水凝胶中灌注血管的密度增加了两倍。结果与基于计算机的模拟结果一致。总体而言，我们的研究结果表明，在过氧化氢触发的化学交联水凝胶中，同时降低交联剂诱导的宿主免疫反应并增加缺氧程度，可有效改善细胞介导的功能性血管网络的形成。
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