Biologically active ligands (e.g., RGDS from fibronectin) play critical roles in the development of chemically defined biomaterials. However, recent decades have shown only limited progress in discovering novel extracellular matrix–protein–derived ligands for translational applications. Through motif analysis of evolutionarily conserved RGD-containing regions in laminin (LM) and peptide-functionalized hydrogel microarray screening, we identified a peptide (a1) that showed superior supports for endothelial cell (EC) functions. Mechanistic studies attributed the results to the capacity of a1 engaging both LM- and Fn-binding integrins. RNA sequencing of ECs in a1-functionalized hydrogels showed ~60% similarities with Matrigel in “vasculature development” gene ontology terms. Vasculogenesis assays revealed the capacity of a1-formulated hydrogels to improve EC network formation. Injectable alginates functionalized with a1 and MMPQK (a vascular endothelial growth factor–mimetic peptide with a matrix metalloproteinase–degradable linker) increased blood perfusion and functional recovery over decellularized extracellular matrix and (RGDS + MMPQK)–functionalized hydrogels in an ischemic hindlimb model, illustrating the power of this approach.

生物活性配体（例如纤连蛋白的 RGDS）在化学成分确定的生物材料的开发中发挥着关键作用。然而，近几十年来，在发现用于转化应用的新型细胞外基质蛋白衍生配体方面仅取得有限进展。通过对层粘连蛋白 (LM) 中进化保守的含有 RGD 的区域进行基序分析和肽功能化水凝胶微阵列筛选，我们鉴定了一种肽 (a1)，它对内皮细胞 (EC) 功能显示出卓越的支持。机制研究将结果归因于 a1 结合 LM 和 Fn 整合素的能力。a1 功能化水凝胶中 EC 的 RNA 测序显示，在“脉管系统发育”基因本体论术语中，其与 Matrigel 相似约 60%。血管生成测定揭示了 a1 配制的水凝胶改善 EC 网络形成的能力。在缺血后肢模型中，与脱细胞细胞外基质和 (RGDS + MMPQK) 功能化水凝胶相比，用 a1 和 MMPQK（一种具有基质金属蛋白酶可降解接头的血管内皮生长因子模拟肽）功能化的可注射海藻酸盐增加了血液灌注和功能恢复，说明这种方法的力量。