Multi-layered PLLA-nanosheets loaded with FGF-2 induce robust bone regeneration with controlled release in critical-sized mouse femoral defects
Multi-layered PLLA-nanosheets loaded with FGF-2 induce robust bone regeneration with controlled release in critical-sized mouse femoral defects
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DOI：
10.1016/j.actbio.2018.12.031
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发表时间：
2019-02-01
影响因子：
9.7
通讯作者：
Saito, Taku
中科院分区：
文献类型：
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作者：
Murahashi, Yasutaka;Yano, Fumiko;Saito, Taku
为了克服由大面积骨缺损和随后的骨不连引起的临床问题，已经研究了各种骨再生方法，包括组织工程、生物材料、干细胞和药物筛选。以前，我们开发了一个独立的可生物降解的聚合物纳米片组成的聚（L-乳酸）（PLLA），使用一个简单的制造过程，包括旋涂和剥离技术。我们报道了负载重组人骨形态发生蛋白-2（rhBMP-2）的β-型PLLA纳米片显示出持久的、持续的rhBMP-2释放，并显著增强小鼠颅骨缺损的骨再生。在这里，我们制作了多层纳米片加载成纤维细胞生长因子-2（FGF-2），并研究了它们在长骨再生中的应用。皮下植入的三层PLLA纳米片显示负载的rhFGF-2持续释放约2周。接下来，我们准备了临界大小的小鼠股骨缺损，并植入单层或三层纳米片，或含有rhFGF-2的明胶水凝胶。在这些条件中，三层纳米片最有效地诱导骨再生。事实上，即使在三层纳米片组中4周后，骨再生也得到了增强，并且伴随着FGFR 1活化和随后的成骨细胞分化。负载rhFGF-2的多层PLLA纳米片可能对骨再生医学有用。此外，多层PLLA纳米片结构可能被应用作为一个有效的缓释carrier.Statements的SignificanceHere，我们描述了多层聚（L-乳酸）（PLLA）纳米片加载重组人成纤维细胞生长因子-2（rhFGF-2）作为一个修改的缓释载体骨再生。体内成像系统分析显示，皮下植入的三层PLLA纳米片显示负载的rhFGF-2持续释放2周。在临界尺寸的小鼠股骨缺损中，装载rhFGF-2的三层纳米片最有效地诱导骨再生。值得注意的是，即使在三层纳米片组中4周后，骨再生也得到了增强，并且伴随着FGFR 1活化和随后的成骨细胞分化。负载rhFGF-2的多层PLLA纳米片可用于骨再生医学。此外，多层PLLA纳米片结构可能被潜在地用作有效的缓释载体。(C)2018 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
To overcome clinical issues caused by large bone defects and subsequent nonunion, various approaches to bone regeneration have been researched, including tissue engineering, biomaterials, stem cells and drug screening. Previously, we developed a free-standing biodegradable polymer nanosheet composed of poly(L-lactic acid) (PLLA) using a simple fabrication process consisting of spin-coating and peeling techniques. We reported that sandwich-type PLLA nanosheets loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) displayed long-lasting, sustained release of rhBMP-2, and markedly enhanced bone regeneration in mouse calvarial bone defects. Here, we fabricated multi-layered nanosheets loaded with fibroblast growth factor-2 (FGF-2), and investigated their application for long bone regeneration. Subcutaneously implanted tri-layered PLLA nanosheets displayed sustained release of loaded rhFGF-2 for about 2 weeks. Next, we prepared critical-sized mouse femoral defects and implanted mono- or tri-layered nanosheets, or a gelatin hydrogel with rhFGF-2. Amongst these conditions, the tri-layered nanosheet most efficiently induced bone regeneration. Indeed, bone regeneration was enhanced even after 4 weeks in the tri-layered nanosheet group, and was accompanied by FGFR1 activation and subsequent osteoblast differentiation. Multi-layered PLLA nanosheets loaded with rhFGF-2 may be useful for bone regenerative medicine. Furthermore, the multi-layered PLLA nanosheet structure may potentially be applied as a potent sustained-release carrier.Statements of SignificanceHere, we describe multi-layered poly(L-lactic acid) (PLLA) nanosheets loaded with recombinant human fibroblast growth factor-2 (rhFGF-2) as a modified sustained-release carrier for bone regeneration. In vivo imaging system analysis revealed that subcutaneously implanted tri-layered PLLA nanosheets displayed sustained release of loaded rhFGF-2 for 2 weeks. In critical-sized mouse femoral defects, tri-layered nanosheets loaded with rhFGF-2 most efficiently induced bone regeneration. Notably, bone regeneration was enhanced even after 4 weeks in the tri-layered nanosheet group, and was accompanied by FGFR1 activation and subsequent osteoblast differentiation. Multi-layered PLLA nanosheets loaded with rhFGF-2 may be useful for bone regenerative medicine. Furthermore, the multi-layered PLLA nanosheet structure may potentially be applied as a potent sustained-release carrier. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.