<br>开发与骨诱导氧甾醇脂质体集成的生物材料支架，以增强刺猬信号传导和骨修复,Molecular Pharmaceutics

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开发与骨诱导氧甾醇脂质体集成的生物材料支架，以增强刺猬信号传导和骨修复
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-03-24 , DOI: 10.1021/acs.molpharmaceut.0c01136
Chung-Sung Lee ₁ , Ginny Ching-Yun Hsu ₂ , Takashi Sono ₂ , Min Lee _{1,

3} , Aaron W James _{2,

4}

Affiliation

骨修复需要对多种内在和外在细胞类型以及信号通路进行严格调控。 Hedgehog (Hh) 信号家族是膜骨和软骨内骨愈合中的正向调节信号通路之一。在此，通过将 Hh 激活胆固醇类似物与乳化剂自组装，并添加 Smoothened 激动剂 (SAG) 作为药物货物，开发了一种新型治疗性脂质体递送载体，用于增强骨再生中的 Hh 信号传导。使用仿生聚多巴胺粘合剂将载药的 Hh 信号传导纳米颗粒激动剂固定在小梁仿骨磷灰石涂层的 3D 支架上，以确保为细胞生长和局部治疗递送提供有利的微环境。结果表明，负载 SAG 的脂质体诱导 Hh 介导的成骨分化显着且呈剂量依赖性增加（如骨髓基质细胞的体外分析所证明的）和体内颅骨愈合（如使用所有放射照相参数和组织形态计量学分析所证明的）。此外，与护理标准（包括胶原海绵递送的 rBMP2 或同种异体移植骨）相比，取得了良好的结果。总之，本研究证明了使用纳米颗粒包装的 Hh 小分子作为广泛适用的骨移植替代品来实现稳健的骨修复。

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Development of a Biomaterial Scaffold Integrated with Osteoinductive Oxysterol Liposomes to Enhance Hedgehog Signaling and Bone Repair

Bone repair requires the tightly regulated control of multiple intrinsic and extrinsic cell types and signaling pathways. One of the positive regulatory signaling pathways in membranous and endochondral bone healing is the Hedgehog (Hh) signaling family. Here, a novel therapeutic liposomal delivery vector was developed by self-assembly of an Hh-activating cholesterol analog with an emulsifier, along with the addition of Smoothened agonist (SAG) as a drug cargo, for the enhancement of Hh signaling in bone regeneration. The drug-loaded nanoparticulate agonists of Hh signaling were immobilized onto trabecular bone-mimetic apatite-coated 3D scaffolds using bioinspired polydopamine adhesives to ensure favorable microenvironments for cell growth and local therapeutic delivery. Results showed that SAG-loaded liposomes induced a significant and dose-dependent increase in Hh-mediated osteogenic differentiation, as evidenced by in vitro analysis of bone marrow stromal cells, and in vivo calvarial bone healing, as evidenced using all radiographic parameters and histomorphometric analyses. Moreover, favorable outcomes were achieved in comparison to standards of care, including collagen sponge-delivered rBMP2 or allograft bone. In summary, this study demonstrates using a nanoparticle packaged Hh small molecule as a widely applicable bone graft substitute for robust bone repair.

更新日期：2021-04-05

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