The native extracellular matrix (ECM) contains a host of matricellular proteins and bioactive factors that regulate cell behavior, and many ECM components have been leveraged to guide cell fate. However, the large size and chemical characteristics of these constituents complicate their incorporation into biomaterials without interfering with material properties, motivating the need for alternative approaches to regulate cellular responses. Mesenchymal stromal cells (MSCs) can promote osseous regeneration in vivo directly or indirectly through multiple means including (1) secretion of proangiogenic and mitogenic factors to initiate formation of a vascular template and recruit host cells into the tissue site or (2) direct differentiation into osteoblasts. As MSC behavior is influenced by the properties of engineered hydrogels, we hypothesized that the biochemical and biophysical properties of alginate could be manipulated to promote the dual contributions of encapsulated MSCs toward bone formation. We functionalized alginate with QK peptide to enhance proangiogenic factor secretion and RGD to promote adhesion, while biomechanical-mediated osteogenic cues were controlled by modulating viscoelastic properties of the alginate substrate. A 1:1 ratio of QK:RGD resulted in the highest levels of both proangiogenic factor secretion and mineralization in vitro. Viscoelastic alginate outperformed purely elastic gels in both categories, and this effect was enhanced by stiffness up to 20 kPa. Furthermore, viscoelastic constructs promoted vessel infiltration and bone regeneration in a rat calvarial defect over 12 weeks. These data suggest that modulating viscoelastic properties of biomaterials, in conjunction with dual peptide functionalization, can simultaneously enhance multiple aspects of MSC regenerative potential and improve neovascularization of engineered tissues.

中文翻译：

---

多肽呈递和水凝胶力学共同增强了被困基质细胞的治疗性双电势。

天然细胞外基质（ECM）包含许多基质细胞蛋白和调节细胞行为的生物活性因子，许多ECM成分已被用来指导细胞命运。然而，这些成分的大尺寸和化学特性使其在不干扰材料特性的情况下并入生物材料中变得复杂，从而激发了对调节细胞应答的替代方法的需求。间充质基质细胞（MSC）可以通过多种方式直接或间接促进体内骨再生，包括（1）促血管生成和促有丝分裂因子的分泌以启动血管模板的形成并将宿主细胞募集到组织部位，或（2）直接分化为成骨细胞。由于MSC的行为受工程水凝胶特性的影响，我们假设藻酸盐的生化和生物物理特性可以被操纵以促进封装的MSC对骨形成的双重作用。我们用QK肽功能化藻酸盐，以增强促血管生成因子的分泌，并用RGD促进黏附，而生物力学介导的成骨线索是通过调节藻酸盐底物的粘弹性来控制的。1：1的QK：RGD导致体外促血管生成因子分泌和矿化的最高水平。在这两个类别中，粘弹性藻酸盐的性能均优于纯弹性凝胶，而高达20 kPa的刚度可增强这种效果。此外，在12周内，粘弹性构建体促进了大鼠颅骨缺损中的血管浸润和骨再生。