doi: 10.1016/j.actbio.2009.03.024. Epub 2009 Mar 27.

The nanocomposite scaffold of poly(lactide-co-glycolide) and hydroxyapatite surface-grafted with L-lactic acid oligomer for bone repair

Yang Cui 1, Yi Liu, Yi Cui, Xiabin Jing, Peibiao Zhang, Xuesi Chen

Affiliation

1State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Changchun 130022, People's Republic of China.

Abstract

Nanohydroxyapatite (op-HA) surface-modified with l-lactic acid oligomer (LAc oligomer) was prepared by LAc oligomer grafted onto the hydroxyapatite (HA) surface. The nanocomposite of op-HA/PLGA with different op-HA contents of 5, 10, 20 and 40wt.% in the composite was fabricated into three-dimensional scaffolds by the melt-molding and particulate leaching methods. PLGA and the nanocomposite of HA/PLGA with 10wt.% of ungrafted hydroxyapatite were used as the controls. The scaffolds were highly porous with evenly distributed and interconnected pore structures, and the porosity wasaround 90%. Besides the macropores of 100-300microm created by the leaching of NaCl particles, the micropores (1-50microm) in the pore walls increased with increasing content of op-HA in the composites of op-HA/PLGA. The op-HA particles could disperse more uniformly than those of pure HA in PLGA matrix. The 20wt.% op-HA/PLGA sample exhibited the maximum mechanical strength, including bending strength (4.14MPa) and compressive strength (2.31MPa). The cell viability and the areas of the attached osteoblasts on the films of 10wt.% op-HA/PLGA and 20wt.% op-HA/PLGA were evidently higher than those on the other composites. For the animal test, there was rapid healing in the defects treated with 10 and 20wt.% op-HA/PLGA, where bridging by a large bony callus was observed at 24weeks post-surgery. There was non-union of radius defects implanted with PLGA and in the untreated group. This was verified by the Masson's trichrome staining photomicrographs of histological analysis. All the data extrapolated that the composite with 10 and 20wt.% op-HA exhibited better comprehensive properties and were the optimal composites for bone repairing.

　文章简介

近年来，可吸收复合材料的开发一直是外科重建和骨组织工程中开发骨替代材料的关键课题。羟基磷灰石纳米粒子与聚乳酸（HA/PLA）或聚乳酸-共糖脂（HA/PLGA）的复合材料因其良好的骨传导性和生物降解性以及高机械强度而引起了广泛关注。特别是，越来越多的研究集中在PLGA材料上，因为它们的降解速率可以通过改变乳酸与乙醇酸的比例来调节。这是一个理想的特征，因为骨形成速率取决于缺陷的大小和部位[2]。然而，HA纳米粒子和PLGA基质之间缺乏粘附力导致HA-聚合物界面早期失效，从而降低了力学性能。因此，有必要开发具有更高机械强度的材料，以满足修复承重骨缺损的临床要求。

为了改善这种情况，已经开发了各种方法来提高HA与聚合物基质之间的粘附性，例如用硅烷偶联剂、锆盐、聚酸、十二烷醇、聚乙二醇和异氰酸酯对HA颗粒进行表面改性。在这些技术中，偶联剂分子与HA表面的羟基发生化学反应，从而显著提高了颗粒表面与PLA基质的亲和力。然而，如上所述的大多数接枝有机分子通常是有害的。

我们小组之前的工作主要集中在L-丙交酯（LLA）在HA颗粒表面的原位接枝开环聚合上。辛酸亚锡（Sn（Oct）2）因其低毒性和高反应性而被选为这些反应中的催化剂。HA/PLA或HA/PLGA与接枝HA颗粒的纳米复合材料的界面相容性、力学性能和生物相容性得到了改善。

为了研究其在骨科和组织工程中的进一步应用，通过熔融成型颗粒浸出法将不同op-HA比的op-HA/PLGA纳米复合材料制成三维（3D）支架，在体外和体内研究了复合材料的机械强度、生物相容性和成骨活性。对不同含量op-HA的复合材料的物理化学性能和生物性能进行了比较。

　中文摘要

通过将l-乳酸低聚物接枝到羟基磷灰石（HA）表面，制备了用l-乳酸低聚物（LAc低聚物）表面改性的纳米羟基磷灰石（op-HA）。不同op-HA含量为5、10、20和40wt.%的op-HA/PLGA纳米复合材料通过熔融成型和颗粒浸出方法将复合材料制成三维支架。PLGA和10wt%的HA/PLGA纳米复合材料未接枝羟基磷灰石作为对照。支架具有高度多孔性，孔结构均匀分布且相互连接，孔隙率约为90%。除了NaCl颗粒浸出产生的100-300微米的大孔外，孔壁中的微孔（1-50微米）随着op-HA/PLGA复合材料中op-HA含量的增加而增加。op-HA颗粒在PLGA基质中的分散比纯HA颗粒更均匀op HA/PLGA样品表现出最大的机械强度，包括抗弯强度（4.14MPa）和抗压强度（2.31MPa）。细胞活力和10wt%薄膜上附着成骨细胞的面积操作HA/PLGA和20重量%op-HA/PLGA明显高于其他复合材料。对于动物试验，用10和20wt.%处理的缺陷愈合迅速op-HA/PLGA，术后24周观察到大骨痂桥接。PLGA植入组和未治疗组桡骨缺损不愈合。组织学分析的Masson三色染色显微照片证实了这一点。所有数据均推断，复合物的重量百分比为10%和20%op-HA具有较好的综合性能，是骨修复的最佳复合材料。

Acta Biomater. 2009 Sep;5(7):2680-92.

Fig. 1. SEM micro-photographs of porous scaffolds of: PLGA (A), 5 wt.% op-HA/PLGA (B), 10 wt.% op-HA/PLGA (C), 20 wt.% op-HA/PLGA (D),40 wt.% op-HA/PLGA (E) and HA/PLGA (F) fabricated with the melt-molding particulate leaching method. Scale bar lengths are 200 lm (A and E),500 lm (B, C, D and F).

Fig. 9. Masson’s trichrome staining photomicrographs (400 magnification) for rabbit radius defects repair of: PLGA (A), 5 wt.% op-HA/PLGA (B),10 wt.% op-HA/PLGA (C), 20 wt.% op-HA/PLGA (D), 40 wt.% op-HA/PLGA (E) and HA/PLGA (F) 24 weeks postoperatively.