Injectable hydrogels provide a powerful and non-invasive approach for numerous applications in cell transplantation, growth factor delivery, tissue regeneration and so forth. The properties of injectable hydrogels should be well-tuned for specific applications, where their overall design should ensure biocompatibility, non-toxicity, robust mechanical properties, and most importantly the ability to promote vascularization and integration with the host tissue/organ. Among these criteria, vascularization remains a key design element in the development of functional therapeutic hydrogels for successful translation into clinical settings. To that end, there is still a critical need for the development of the next generation of injectable hydrogels with precisely tuned biophysical and biochemical properties which could simultaneously promote tissue vascularization. In this work, we developed a temperature responsive, dual-crosslinking, biohybrid hydrogels, modified with a vasculogenic peptide for applications in regenerative medicine, specifically tissue vascularization. The synthesized hydrogels consisted of poly(N-isopropylacrylamide)-based copolymer, functionalized gelation and angiogenic VEGF-mimetic QK peptide with enhanced shear-thinning and injectability properties. QK peptide is a VEGF-mimetic vasculogenic peptide which binds to VEGF receptors and activates intercellular pathway for vascularization. Apart from the presence of QK peptide, the mechanical properties of the hydrogels were precisely tuned by altering the polymer concentration, enabling successful assembly and endothelial cell network formation. Extended in vitro studies demonstrated successful encapsulation and homogeneous distribution of endothelial cells within the three-dimensional (3D) environment of the hydrogel matrix with significantly enhanced vascularization in presence of the QK peptide as early as 3 days of culture. A small, preliminary in vivo study in mice showed a trend of increased blood vessel formation in hydrogels that incorporated the QK peptide. Overall, our study presents the design and characterization of injectable, dual-crosslinking and vasculogenic hydrogels with controlled properties which could be utilized for numerous applications in regenerative medicine, minimally invasive cell and drug delivery as well as fundamental studies on tissue vascularization and angiogenesis. STATEMENT OF SIGNIFICANCE: In this work, we synthesized a new class of temperature responsive, dual-crosslinking, biohybrid injectable hydrogels with enhanced vascularization properties for broad applications in regenerative medicine and minimally invasive cell/drug delivery. The developed hydrogels properly accommodated 3D culture, assembly and network formation of endothelial cells, as evidenced by in vitro and in vivo studies.

中文翻译：

---

基于聚（N-异丙基丙烯酰胺）的双交联生物混合可注射水凝胶用于血管生成。

可注射的水凝胶为细胞移植，生长因子递送，组织再生等方面的众多应用提供了强大而无创的方法。注射用水凝胶的特性应针对特定应用进行适当调整，其整体设计应确保生物相容性，无毒，鲁棒的机械特性，最重要的是具有促进血管生成和与宿主组织/器官整合的能力。在这些标准中，血管形成仍然是功能性治疗水凝胶开发中关键设计要素，以成功转化为临床环境。为此，仍然迫切需要开发具有可精确调节的生物物理和生化特性，同时促进组织血管形成的下一代可注射水凝胶。在这项工作中，我们开发了一种具有温度响应性的双交联生物杂交水凝胶，并用血管生成肽进行了修饰，可用于再生医学，特别是组织血管生成。合成的水凝胶由聚（N-异丙基丙烯酰胺）基共聚物，官能化凝胶和血管生成性VEGF模拟QK肽组成，具有增强的剪切稀化和可注射性。QK肽是一种可模拟VEGF的血管生成肽，可与VEGF受体结合并激活细胞间通路以实现血管形成。除了存在QK肽外，通过改变聚合物浓度可以精确调节水凝胶的机械性能，从而能够成功组装并形成内皮细胞网络。扩展的体外研究表明，早在培养3天时，在存在QK肽的情况下，内皮细胞在水凝胶基质的三维（3D）环境中的成功封装和均匀分布，血管形成显着增强。一项小型的体内初步研究显示，掺入QK肽的水凝胶中血管形成增加的趋势。总体而言，我们的研究提出了具有可控特性的可注射，双交联和血管生成水凝胶的设计和表征，这些凝胶可用于再生医学的众多应用，微创细胞和药物输送以及组织血管形成和血管生成的基础研究。重大意义声明：在这项工作中，我们合成了一类新型的具有温度响应性，双交联性，可增强血管生成特性的生物混合可注射水凝胶，广泛用于再生医学和微创细胞/药物输送。体外和体内研究证明，开发的水凝胶可适当适应内皮细胞的3D培养，组装和网络形成。具有增强的血管形成特性的生物混合可注射水凝胶，广泛用于再生医学和微创细胞/药物输送。体外和体内研究证明，开发的水凝胶可适当适应内皮细胞的3D培养，组装和网络形成。具有增强的血管形成特性的生物混合可注射水凝胶，广泛用于再生医学和微创细胞/药物输送。体外和体内研究证明，已开发的水凝胶可适当适应内皮细胞的3D培养，组装和网络形成。