Rana Deepti, Rangel Vincent R, Padmanaban Prasanna, Trikalitis Vasileios D, Kandar Ajoy, Kim Hae-Won, Rouwkema Jeroen
Department of Biomechanical Engineering, Technical Medical Centre, University of Twente, Enschede, 7522NB, The Netherlands.
Institute of Tissue Regeneration Engineering, Dankook University, Cheonan, 31116, Republic of Korea.
Adv Healthc Mater. 2025 Jan;14(1):e2402302. doi: 10.1002/adhm.202402302. Epub 2024 Nov 1.
Dynamic growth factor presentation influences how individual endothelial cells assemble into complex vascular networks. Here, programmable bioinks are developed that facilitate dynamic vascular endothelial growth factor (VEGF) presentation to guide vascular morphogenesis within 3D-bioprinted constructs. Aptamer's high affinity is leveraged for rapid VEGF sequestration in spatially confined regions and utilized aptamer-complementary sequence (CS) hybridization to tune VEGF release kinetics temporally, days after bioprinting. It is shown that spatial resolution of programmable bioink, combined with CS-triggered VEGF release, significantly influences the alignment, organization, and morphogenesis of microvascular networks in bioprinted constructs. The presence of aptamer-tethered VEGF and the generation of instantaneous VEGF gradients upon CS-triggering restricted hierarchical network formation to the printed aptamer regions at all spatial resolutions. Network properties improved as the spatial resolution decreased, with low-resolution designs yielding the highest network properties. Specifically, CS-treated low-resolution designs exhibited significant vascular network remodeling, with an increase in vessel density(1.35-fold), branching density(1.54-fold), and average vessel length(2.19-fold) compared to non-treated samples. The results suggest that CS acts as an external trigger capable of inducing time-controlled changes in network organization and alignment on-demand within spatially localized regions of a bioprinted construct. It is envisioned that these programmable bioinks will open new opportunities for bioengineering functional, hierarchically self-organized vascular networks within engineered tissues.
动态生长因子的呈现方式会影响单个内皮细胞如何组装成复杂的血管网络。在此，开发了可编程生物墨水，其有助于动态呈现血管内皮生长因子（VEGF），以引导3D生物打印构建体内的血管形态发生。利用适体的高亲和力在空间受限区域快速隔离VEGF，并利用适体互补序列（CS）杂交在生物打印数天后随时间调节VEGF释放动力学。结果表明，可编程生物墨水的空间分辨率与CS触发的VEGF释放相结合，显著影响生物打印构建体中微血管网络的排列、组织和形态发生。适体连接的VEGF的存在以及CS触发时瞬时VEGF梯度的产生，在所有空间分辨率下都将分级网络的形成限制在打印的适体区域。随着空间分辨率的降低，网络特性得到改善，低分辨率设计产生最高的网络特性。具体而言，与未处理的样本相比，经CS处理的低分辨率设计表现出显著的血管网络重塑，血管密度增加（1.35倍）、分支密度增加（1.54倍）和平均血管长度增加（2.19倍）。结果表明，CS可作为一种外部触发因素，能够在生物打印构建体的空间局部区域内按需诱导网络组织和排列的时间控制变化。可以设想，这些可编程生物墨水将为在工程组织内生物工程功能性、分级自组织血管网络带来新的机遇。
