Division of Advanced Prosthodontics, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Division of Diagnostic and Surgical Sciences, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Sci Adv. 2020 Apr 22;6(17):eaaz7822. doi: 10.1126/sciadv.aaz7822. eCollection 2020 Apr.
Biomaterial delivery of bioactive agents and manipulation of stem cell fate are an attractive approach to promote tissue regeneration. Here, smoothened agonist sterosome is developed using small-molecule activators [20-hydroxycholesterol (OHC) and purmorphamine (PUR)] of the smoothened protein in the hedgehog pathway as carrier and cargo. Sterosome presents inherent osteoinductive property even without drug loading. Sterosome is covalently immobilized onto three-dimensional scaffolds via a bioinspired polydopamine intermediate to fabricate a hybrid scaffold for bone regeneration. Sterosome-immobilized hybrid scaffold not only provides a favorable substrate for cell adhesion and proliferation but also delivers bioactive agents in a sustained and spatially targeted manner. Furthermore, this scaffold significantly improves osteogenic differentiation of bone marrow stem cells through OHC/PUR-mediated synergistic activation of the hedgehog pathway and also enhances bone repair in a mouse calvarial defect model. This system serves as a versatile biomaterial platform for many applications, including therapeutic delivery and endogenous regenerative medicine.
生物活性物质的生物材料传递和干细胞命运的操纵是促进组织再生的一种有吸引力的方法。在这里，我们使用 Hedgehog 通路中 smoothened 蛋白的小分子激活剂[20-羟基胆固醇（OHC）和 purmorphamine（PUR）]作为载体和有效载荷来开发 smoothened 激动剂 sterosome。即使没有药物负载，sterosome 也具有内在的成骨诱导特性。sterosome 通过生物启发的聚多巴胺中间物共价固定在三维支架上，以制造用于骨再生的混合支架。sterosome 固定的混合支架不仅为细胞黏附和增殖提供了有利的基质，而且还以持续和空间靶向的方式输送生物活性物质。此外，该支架通过 OHC/PUR 介导的 Hedgehog 通路协同激活显著促进骨髓干细胞的成骨分化，并增强小鼠颅骨缺损模型中的骨修复。该系统可作为一种多功能生物材料平台，适用于包括治疗药物传递和内源性再生医学在内的多种应用。
