Metzger Stéphanie, Blache Ulrich, Lienemann Philipp S, Karlsson Maria, Weber Franz E, Weber Wilfried, Ehrbar Martin
Department of Obstetrics, University and University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.
School of Engineering and Applied Sciences, Harvard University, 58 Oxford St., Cambridge, MA, 02138, USA.
Macromol Biosci. 2016 Nov;16(11):1703-1713. doi: 10.1002/mabi.201600223. Epub 2016 Aug 22.
Engineering in vitro tissue mimetics that resemble the corresponding living tissues requires the 3D arrangement of tissue progenitor cells and their differentiation by localized growth factor (GF) signaling cues. Recent technological advances open a large field of possibilities for the creation of complex GF arrangements. Additionally, cell-instructive biomaterials, which bind GFs by various mechanisms and release them with different kinetics depending on binding affinity, have become available. This paper describes the development of a matrix metalloproteinase (MMP)-degradable streptavidin-based linker module, which allows the release of immobilized GFs from synthetic biomimetic poly(ethylene glycol) hydrogels independently of the hydrogel degradation. The MMP-sensitive streptavidin linker is shown to efficiently bind biotinylated molecules, and as proof of concept, bone morphogenetic protein-2 (BMP-2) delivery via the MMP-degradable linker is used to induce osteogenic differentiation in C2C12 cells and mesenchymal stem cells. The results show a significantly increased net effect of proteolytically releasable BMP-2 in comparison to stably immobilized and soluble BMP-2. This study indicates that a GF delivery system directly responsive to cellular activity can have important implications for the synthesis of tissue mimetics and regenerative medicine, as it can influence the availability, the localization of effects, as well as efficacy of employed GFs.
构建类似于相应活组织的体外组织模拟物需要组织祖细胞的三维排列及其通过局部生长因子（GF）信号线索进行分化。最近的技术进步为创建复杂的GF排列开辟了广阔的可能性领域。此外，细胞指导性生物材料已可获得，这些材料通过各种机制结合GF，并根据结合亲和力以不同的动力学释放它们。本文描述了一种基于基质金属蛋白酶（MMP）可降解链霉亲和素的连接模块的开发，该模块允许从合成仿生聚乙二醇水凝胶中独立于水凝胶降解释放固定化的GF。MMP敏感的链霉亲和素连接体被证明能有效结合生物素化分子，作为概念验证，通过MMP可降解连接体递送骨形态发生蛋白-2（BMP-2）用于诱导C2C12细胞和间充质干细胞的成骨分化。结果表明，与稳定固定和可溶性BMP-2相比，蛋白水解可释放的BMP-2的净效应显著增加。这项研究表明，直接响应细胞活性的GF递送系统可能对组织模拟物的合成和再生医学具有重要意义，因为它可以影响所用GF的可用性、作用定位以及功效。
