Osseointegration of chitosan coated porous titanium alloy implant by reactive oxygen species-mediated activation of the PI31K/AKT pathway under diabetic conditions
Osseointegration of chitosan coated porous titanium alloy implant by reactive oxygen species-mediated activation of the PI31K/AKT pathway under diabetic conditions
复制标题
糖尿病条件下通过活性氧介导的 PI3K/AKT 通路激活来实现壳聚糖涂层多孔钛合金植入物的骨整合
DOI：
10.1016/j.biomaterials.2014.09.012
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发表时间：
2015-01-01
期刊：
影响因子：
14
通讯作者：
Wang, Lin
中科院分区：
文献类型：
--
作者：
Li, Xiang;Ma, Xiang-Yu;Wang, Lin
壳聚糖包覆多孔钛合金种植体（CTI）是提高纯多孔钛合金种植体（TI）骨整合能力的一种很有前途的方法。由于壳聚糖已被证明具有抗氧化活性，我们提出CTI可能改善ROS过量产生，从而扭转糖尿病条件下骨整合不良，并研究其潜在机制。在TI和CTI上孵育的原代大鼠成骨细胞分别受到正常血清（NS）、糖尿病血清（DS）、DS + NAC（一种有效的ROS抑制剂）和DS + LY294002（一种PI3K/ akt特异性抑制剂）的影响。在糖尿病羊髂嵴骨缺损中植入TI或CTI进行了体内研究。结果表明，糖尿病诱导的ROS过量产生导致成骨细胞功能障碍和凋亡，并伴有TI底物上成骨细胞AKT的抑制。而CTI通过ROS衰减刺激AKT磷酸化，从而逆转成骨细胞功能障碍，表现为改善成骨细胞粘附，增加增殖和ALP活性，降低细胞毒性和凋亡率，这与NAC处理T1具有相同的效果。Micro-CT和组织学检查进一步证实了CFI体内骨整合的改善。此外，通过添加LY294002阻断PI3K/AKT通路，CTI的上述促进作用被消除。这些结果表明，壳聚糖涂层通过ros介导的PI3K/AKT通路的再激活，显著改善了糖尿病诱导的TI生物性能受损，这为改善糖尿病患者钛种植体的临床性能提供了一种新的表面功能化策略。(C) 2014 Elsevier Ltd.版权所有。
Chitosan coated porous titanium alloy implant (CTI) is demonstrated a promising approach to improve osseointegration capacity of pure porous titanium alloy implant (TI). Since chitosan has been demonstrated to exhibit antioxidant activity, we propose CTI may ameliorate the ROS overproduction, thus reverse the poor osseointegration under diabetic conditions, and investigate the underlying mechanisms. Primary rat osteoblasts incubated on the TI and the CTI were subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and DS + LY294002 (a PI3K/AKT-specific inhibitor). In vivo study was performed on diabetic sheep implanted with TI or CTI into the bone defects on crista iliaca. Results showed that diabetes-induced ROS overproduction led to osteoblast dysfunction and apoptosis, concomitant with the inhibition of AKT in osteoblasts on the TI substrate. While CTI stimulated AKT phosphorylation through ROS attenuation, thus reversed osteoblast dysfunction evidenced by improved osteoblast adhesion, increased proliferation and ALP activity, and decreased cytotoxicity and apoptotic rate, which exerted same effect to NAC treatment on the T1. These effects were further confirmed by the improved osseointegration within the CFI in vivo evidenced by Micro-CT and histological examinations. In addition, the aforementioned promotive effects afforded by CTI were abolished by blocking PI3K/AKT pathway with addition of LY294002. These results demonstrate that the chitosan coating markedly ameliorates diabetes-induced impaired bio-performance of TI via ROS-mediated reactivation of PI3K/AKT pathway, which elicits a new surface functionalization strategy for better clinical performance of titanium implant in diabetic patients. (C) 2014 Elsevier Ltd. All rights reserved.