局部应用辛伐他汀促进大鼠脊柱融合。
Locally Applied Simvastatin as an Adjunct to Promote Spinal Fusion in Rats.
机构信息
Hospital for Special Surgery, New York, NY.
Weill Cornell Medical College, New York, NY.
出版信息
Spine (Phila Pa 1976). 2019 Aug 1;44(15):1042-1048. doi: 10.1097/BRS.0000000000003020.
STUDY DESIGN
Basic Science.
OBJECTIVE
To determine if locally delivered simvastatin can enhance bone formation in a rat spinal fusion model.
SUMMARY OF BACKGROUND DATA
The bone-anabolic properties of statins in fracture healing are well established, however, few studies have evaluated the impact of locally delivered statins in spinal fusion.
METHODS
We formulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles by adapting previously published techniques. Two types of nanoparticles were created: simvastatin nanoparticles (SimNP) and nanoparticles without simvastatin (BlankNP). Drug elution from SimNP was characterized. Osteoblastic differentiation was analyzed using MC3T3-E1 cells cultured in differentiation medium containing SimNP or BlankNP. Forty male 12 week old outbred Wistar rats underwent uninstrumented posterolateral fusion using iliac crest bone graft and BlankNP, SimNP or simvastatin drug. X-rays to assess bone formation were obtained at 4 weeks and 9 weeks post-operatively. Spines were explanted at 9 weeks for micro-CT analysis, and a blinded manual assessment of fusion (MAF).
RESULTS
SimNP achieved a release efficiency of 74.1% with ∼50% release occurring in the first day. Simvastatin and SimNP treated cells showed significantly greater expression of osteopontin (OPN) and osteocalcin (OCN). On micro-CT analysis, SimNP animals had higher bone volume and percent bone volume (bone volume/total volume) than control animals. SimNP rats had higher X-ray scores at 4 weeks (p=0.010) and 9 weeks (p<0.001) relative to BlankNP. MAF showed that SimNP had a higher fusion rate than BlankNP (42.9% vs. 0%, p=0.006).
CONCLUSION
We were able to validate that sustained release of simvastatin via a PLGA nanoparticle. SimNP was able to induce an increase in mineralization as well as an increase in markers of bone formation. X-ray analysis, micro-CT quantification, and MAF assessment of SimNP treated rats showed significantly greater bone formation and fusion mass strength relative to vehicle treated animals. Simvastatin may be a safe, cost-effective bone anabolic agent for use in spinal fusion.
LEVEL OF EVIDENCE
N/A.
研究设计
基础科学。
目的
确定局部递送辛伐他汀是否可以增强大鼠脊柱融合模型中的骨形成。
背景资料概要
他汀类药物在骨折愈合中的骨合成特性已得到充分证实，但是，很少有研究评估局部递送他汀类药物对脊柱融合的影响。
方法
我们通过采用先前发表的技术来制备聚（乳酸-共-乙醇酸）（PLGA）纳米粒子。创建了两种类型的纳米粒子：辛伐他汀纳米粒子（SimNP）和不含辛伐他汀的纳米粒子（BlankNP）。对 SimNP 的药物洗脱进行了表征。使用含 SimNP 或 BlankNP 的分化培养基培养 MC3T3-E1 细胞，分析成骨细胞分化。40 只 12 周龄雄性杂交 Wistar 大鼠采用髂嵴骨移植物和 BlankNP、SimNP 或辛伐他汀药物进行非器械性后路融合。术后 4 周和 9 周进行 X 射线评估骨形成。9 周时取出脊柱进行 micro-CT 分析和融合的盲法手动评估（MAF）。
结果
SimNP 的释放效率达到 74.1%，其中约 50%的药物在第 1 天释放。辛伐他汀和 SimNP 处理的细胞表现出明显更高的骨桥蛋白（OPN）和骨钙素（OCN）表达。在 micro-CT 分析中，SimNP 动物的骨体积和骨体积百分比（骨体积/总体积）高于对照动物。SimNP 大鼠在 4 周（p=0.010）和 9 周（p<0.001）时的 X 射线评分均高于 BlankNP。MAF 显示 SimNP 的融合率高于 BlankNP（42.9%比 0%，p=0.006）。
结论
我们能够验证通过 PLGA 纳米粒子的持续释放辛伐他汀。SimNP 能够诱导矿化增加以及骨形成标志物增加。SimNP 处理大鼠的 X 射线分析、micro-CT 定量和 MAF 评估显示，与载体处理动物相比，骨形成和融合质量强度明显增加。辛伐他汀可能是一种安全、具有成本效益的骨合成代谢药物，可用于脊柱融合。
证据水平
N/A。
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