Abstract：
Although several bioactive 3D-printed bone scaffolds loaded with multiple kinds of biomolecules for enhanced bone regeneration have been recently developed, the manipulation of on-demand release profiles of different biomolecules during bone regeneration remains challenging. Herein, a 3D-printed dual-drug-loaded biomimetic scaffold to regulate the host stem cell recruitment and osteogenic differentiation in a two-stage process for bone regeneration was successfully fabricated. First, a chemotactic small-molecule drug, namely, simvastatin (SIM) was directly incorporated into the hydroxyapatite/collagen bioink for printing and could be rapidly released during the early stage of bone regeneration. Further, near-infrared (NIR)-light-responsive polydopamine-coated hydroxyapatite nanoparticles were designed to deliver the osteogenic drug, i.e., pargyline (PGL) in a controllable manner. Together, our scaffold displayed an on-demand sequential release of those two drugs and could optimize their therapeutic effects to align with the stem cell recruitment and osteoblastic differentiation, thereby promoting bone regeneration. The results confirmed the suitable mechanical strength, high photothermal conversion efficiency, good biocompatibility of our scaffold. The scaffold loaded with SIM could efficiently accelerate the migration of stem cells. In addition, the scaffold with on-demand sequential release promoted alkaline phosphatase (ALP) activity, significantly upregulated gene expression levels of osteogenesis-related markers, and enhanced new-bone-formation capabilities in rabbit cranial defect models. Altogether, this scaffold not only offers a promising strategy to control the behavior of stem cells during bone regeneration but also provides an efficient strategy for controllable sequential release of different biomolecule in bone tissue engineering.
摘要：
尽管最近已经开发了几种装有多种生物分子的生物活性3D打印骨支架，以增强骨再生，骨再生过程中不同生物分子的按需释放曲线的操作仍然具有挑战性。在这里，成功制造了一种3D打印的双载药仿生支架,用于在骨再生的两阶段过程中调节宿主干细胞募集和成骨分化.首先,一种趋化性小分子药物,即,辛伐他汀（SIM）直接掺入羟基磷灰石/胶原生物墨水中进行打印，并可在骨再生的早期快速释放。Further,近红外（NIR）光响应型聚多巴胺涂层羟基磷灰石纳米颗粒被设计用于递送成骨药物，即，pargyline(PGL)以可控的方式。一起,我们的支架显示按需顺序释放这两种药物，并可以优化其治疗效果，以配合干细胞募集和成骨细胞分化，从而促进骨再生。结果证实了合适的机械强度，光热转换效率高，我们的支架具有良好的生物相容性。负载有SIM的支架可以有效地加速干细胞的迁移。此外,按需顺序释放促进碱性磷酸酶（ALP）活性的支架，显著上调成骨相关标志物的基因表达水平，增强兔颅骨缺损模型的新骨形成能力。总之,这种支架不仅为骨再生过程中干细胞行为的控制提供了有前景的策略，而且为骨组织工程中不同生物分子的可控顺序释放提供了有效的策略。
