纳米银局部给药治疗脊柱化脓性感染的实验研究
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摘要
第一章兔脊柱化脓性感染模型的建立
目的：建立兔脊柱化脓性感染模型。
实验方法：取雄性新西兰大白兔12只,随机分为4组,分别给予浓度103CFU/ml、102CFU/ml、10CFU/ml的金黄色葡萄球菌悬液及生理盐水。手术入路选择前外侧腹膜后入路,术中暴露出兔脊柱L1/2、L5/6椎间隙,切除大部分椎间盘,然后将不同浓度金黄色葡萄球菌悬浮液种植于椎间隙。术后2周抽静脉血培养并处死动物,取手术部位骨组织、肝脏做细菌培养,并取手术部位骨组织行组织学检查。
结果：应用浓度102CFU/ml(接种细菌数量为102CFU/mlx0.1ml)的金黄色葡萄球菌悬液成功的在100%(8/8)的种植部位诱导出脊柱感染,肝脏及血培养结果为阴性,排除全身系统性感染的可能。浓度10CFU/ml(接种细菌数量为10CFU/mlx0.1ml)的金黄色葡萄球菌悬液在33%(2/6)的种植部位诱导出脊柱感染。浓度103CFU/ml(接种细菌数量为103CFU/mlx0.1ml)的金黄色葡萄球菌悬液在100%(6/6)的种植部位诱导出脊柱感染,但有2只实验动物分别于术后7天、11天死亡。
结论：成功的建立了合适的兔脊柱化脓性感染模型,这种模型可应用于脊柱化脓性感染不同治疗手段干预的疗效比较。
第二章纳米银局部保留注射治疗兔脊柱感染的疗效观察
目的：探讨应用纳米银对脊柱化脓性感染的治疗效果。
实验方法：取新西兰大白兔24只,随机分为空白对照组、实验组A、实验组B,按前述方法制作脊柱感染模型,同时术中在手术部位留置导药管。术后第一日开始每日局部给药,实验组A给予0.1mg/Kg纳米银溶液,实验组B给予1mg/Kg纳米银溶液,空白对照组给予生理盐水。连续给药2周后抽静脉血做培养并处死动物,取手术部位骨组织行组织学检查及培养,另取肝脏组织做培养。处死动物前行脊柱X线、CT检查,观察影像学变化。
结果：接种部位骨组织细菌培养结果示实验组A感染阳性率75%(6/8),0死亡；实验组B感染阳性率25%(2/8),0死亡；空白对照组感染阳性率100%,1例死亡,2例双下肢瘫痪。实验组B与空白对照组感染阳性率结果比较有统计学差异(P<0.01),实验组A与空白对照组感染阳性率结果比较有统计学差异(P<0.01),证实了纳米银局部保留给药的有效性。X线、CT检查示感染动物细菌接种局部有骨质破坏、骨密度增高、椎间隙狭窄等表现,未感染动物没有发现异常结构变化。相应病检结果进一步证实影像学及培养阳性的动物椎体骨组织发生典型化脓性骨髓炎改变,骨髓组织溶解坏死,骨髓腔有化脓性渗出物和坏死物质,骨细胞大量坏死,成骨活性减低,死骨形成,周围有炎性肉芽组织。
结论：局部应用纳米银溶液治疗脊柱化脓性感染是有效的,纳米银溶液在体内内环境中的抗菌作用与给药浓度呈正相关。但纳米银局部给药治疗脊柱感染的作用不是决定性的,不能证实这种治疗方式可以完全替代全身应用抗生素。
第三章纳米银在动物体内的生物学分布
目的：初步分析纳米银在动物体内分布情况。
实验方法：取实验第二部分的动物静脉血清、肝、肾、脾、脊髓、睾丸器官标本,分组同实验第二部分,设为0.1mg/Kg组、1mg/Kg组、空白对照组。采用硝酸-高氯酸化学消化法,将待测标本消化为液态,用原子吸收法测定组织中银的含量。制作肝、肾、脾、脊髓、睾丸石蜡切片标本做组织学检查,观察有无病理变化,制作脊髓超薄切片,行透视电镜观察。
结果：1mg/Kg(?)内米银溶液组测得各组织银含量顺序脊髓>脾>肾>睾丸>肝>血清,0.1mg/kg纳米银组各组织银含量顺序为脊髓>肾>脾>肝>睾丸>血清。两实验组血清银含量与对照组比较,差别无统计学意义(P>0.05)；两实验组脊髓组织银含量与对照组比较,均有显著统计学差异(P<0.01)；1mg/Kg实验组肝、肾、脾、睾丸银含量与对照组比较,差别均有统计学意义(P<0.05)；0.1mg/Kg实验组肝、肾、脾、睾丸银含量与对照组比较,差别均无统计学意义(P>0.05)。结果表明1mg/Kg纳米银组除血清外,在脊髓、肝、肾、脾、睾丸组织均产生了蓄积,0.1 mg/Kg纳米银组仅在脊髓组织产生了蓄积。两实验组脊髓、肝、肾、脾、睾丸组织学检查均没有发现显著病理改变。
结论：纳米银溶液通过局部保留给药的方式,是安全有效的,但当给药量达到一定限值后,会在动物体内产生蓄积,其蓄积的过程主要通过血淋巴系统的转运和局部直接转移完成,蓄积作用最明显的靶组织为周围组织(脊髓)及免疫器官(脾),微量的蓄积不会导致组织器官的器质性和功能性损害。
Part I Establishment of Rabbit Pyogenic Spondylitis Model
Objective:Establish rabbit pyogenic spondylitis model.
Methods:Take 12 male New Zealand white rabbits, randomly divide into 4 groups and inject staphylococcus aureus suspension fluid with different concentration. Surgical approach selects anterolateral retroperitoneal approach. During the operation, exposure intervertebral space of rabbit spinal L1/2 and L5/6, remove part of intervertebral disc, destruct adjacent vertebral endplates, and then input the staphylococcus aureus suspension fluid with different concentration into destructed intervertebral space.2 weeks after the operation, draw venous blood for culturing and sacrifice the animal, take bone tissue of the surgical site and the liver for bacterial culturing, and take pathological examination to the bone tissue of the surgical site.
Result:Apply the staphylococcus aureus suspension fluid with the concentration of 102 CFU/ml to successfully induce spinal infection in 100%(8/8) planting site, the result of liver and blood culturing is negative, rule out the possibility of systemic infection. Apply the staphylococcus aureus suspension fluid with the concentration of 10CFU/ml to successfully induce spinal infection in 33%(2/6) planting area, Apply the staphylococcus aureus suspension fluid with the concentration of lOCFU/ml to successfully induce spinal infection in 100%(6/6) planting area, but only 2 experimental animals separately die 7 and 11 days after the operation.
Conclusion:It has successfully established appropriate rabbit pyogenic spondylitis model, which can be applicable to efficacy comparison of different anti-infection strategies.
Part II Experimental Study on Nano Silver Local Reserved Injection Treatment Rabbit Pyogenic Spondylitis
Objective:Discuss efficacy of Nano siiver treatment pyogenic spondylitis.
Materials & Methods:Take 24 New Zealand white rabbits; randomly divide into blank control group and experimental group A & B, make spinal infection model in accordance with the aforesaid methods, meanwhile indwell drug control guide in the surgical site during the operation. Since the first day after the operation, conduct local drug every day, inject 0.1mg/Kg Nano silver solution to Experimental Group A, inject 1mg/Kg Nano silver solution to Experimental Group B, and inject saline to Blank Control Group. After 2 weeks of consecutive drugging, draw venous blood for culturing and sacrifice the animal, take bone tissue of the surgical site for pathological examination and culturing, and take the liver tissue for culturing. Before sacrificing the animals, take spinal X-ray and CT examination and observe the changes of medical imageology.
Result:The bacteria culturing result of bone tissues in the inoculated site shows that the positive infection rate of Experimental Group A is 75%(6/8), zero death; the positive infection rate of Experimental Group B is 25%(2/8), zero death; the positive infection rate of Blank Control Group is 100%,1 death,2 cases paralysis of both lower extremities. The comparison of positive infection rate result of Experimental Group B and Blank Control Group has statistical difference (P＜0.01), as well as Experimental A and Blank Control Group (P＜0.01), which confirms the effectiveness of Nano silver local reserved drug.X-ray and CT examination indicate that the infectious animal bacterination partly has the changes involving bond destruction, bone mineral density increasing, and intervertebral space stenosis, and the uninfected animals have no abnormal structural change. The corresponding disease examination results further verify the imageology and animal centrum bone tissue of cultivating the positive have the changes of typical pyogenic osteomyelitis. The bone marrow tissue dissolves and necrotizes, the marrow cavity has pyogenic exudations and necrosis substances, the bone cells necrotize in quantity, the osteogenic activities reduce, and the sequestrum forms with the inflammatory granulation tissue around.
Conclusion:It is effective to apply Nano silver solution for treating the spinal column infection partly. The antibiotic action of Nano silver solution in the internal environment of the body shows the positive correlation with the dose concentration. But it is not decisive that Nano silver partly dosing treats the spinal column infection, which cannot verify this dosing method shall replace for the application antibiotic of the whole body.
Part III Biological Distribution of Nano Silver in the Body of the Animal
Objective:Analyze the distribution conditions of Nano sliver in the body of the animal preliminarily.
Methods and Materials:Take the venous blood, liver, kidney, spleen, spinal cord, and testis organs specimen of the animals in Part II of the experiment. The grouping is the same as Part II of the experiment, involving 0.1 mg/Kg group,1 mg/Kg group and blank control group. Adopt the nitric acid-perchloric acid chemical digestion method, digest the specimen to be tested into the liquid state, and measure Ag content of the tissue with the atomic absorption method upon the constant volume. Make the liver, kidney, spleen, spinal cord, and testis paraffin section specimen as the histology examination and observe whether it has the pathologic change. Make the spinal marrow ultra thin section and observe with the transmission electron microscopy.
Results:1 mg/Kg Nano silver solution group measures the silver content sequences of each tissue as spinal cord> spleen> kidney> testis> liver> blood serum, and as for 0.1 mg/kg group, the silver content sequences of each tissue is spinal cord> kidney> spleen> liver> testis> blood serum. The silver content differences of the blood serum in two experimental groups and control group have no statistics significance (P>0.05). The silver content differences of the spinal marrow tissue in two experimental groups and control group have the statistics significance (P<0.01). The silver content differences of liver, kidney, spleen and testis in 1 mg/Kg experimental group and control group have the statistics significance (P<0.05). The silver content differences of liver, kidney, spleen and testis in 0.1 mg/Kg experimental group and control group have no statistics significance (P＜0.05). The result indicates that 1 mg/Kg Nano silver group produces the accumulation in spinal cord, liver, kidney, spleen and testis tissues except for the blood serum, and 0.1 mg/Kg Nano silver group only produces the accumulation in spinal cord tissue. The histology examination of spinal cord, liver, kidney, spleen and testis of two experimental groups has no obvious pathological change.
Conclusion:Nano silver solution is safe and effective by the way of partly retaining for dosing, however, the dose shall accumulate in the body of the animal after reaching the established limit values. The accumulating process is accomplished mainly through the transfer of hemolymph system and direct jump of the part. The most obvious target tissue of the accumulative action is the peripheral tissue (spinal cord) and immune organ (spleen). The micro accumulation shall not result in the organic and functional damages of the tissue and organ.
目的：建立兔脊柱化脓性感染模型。
实验方法：取雄性新西兰大白兔12只,随机分为4组,分别给予浓度103CFU/ml、102CFU/ml、10CFU/ml的金黄色葡萄球菌悬液及生理盐水。手术入路选择前外侧腹膜后入路,术中暴露出兔脊柱L1/2、L5/6椎间隙,切除大部分椎间盘,然后将不同浓度金黄色葡萄球菌悬浮液种植于椎间隙。术后2周抽静脉血培养并处死动物,取手术部位骨组织、肝脏做细菌培养,并取手术部位骨组织行组织学检查。
结果：应用浓度102CFU/ml(接种细菌数量为102CFU/mlx0.1ml)的金黄色葡萄球菌悬液成功的在100%(8/8)的种植部位诱导出脊柱感染,肝脏及血培养结果为阴性,排除全身系统性感染的可能。浓度10CFU/ml(接种细菌数量为10CFU/mlx0.1ml)的金黄色葡萄球菌悬液在33%(2/6)的种植部位诱导出脊柱感染。浓度103CFU/ml(接种细菌数量为103CFU/mlx0.1ml)的金黄色葡萄球菌悬液在100%(6/6)的种植部位诱导出脊柱感染,但有2只实验动物分别于术后7天、11天死亡。
结论：成功的建立了合适的兔脊柱化脓性感染模型,这种模型可应用于脊柱化脓性感染不同治疗手段干预的疗效比较。
第二章纳米银局部保留注射治疗兔脊柱感染的疗效观察
目的：探讨应用纳米银对脊柱化脓性感染的治疗效果。
实验方法：取新西兰大白兔24只,随机分为空白对照组、实验组A、实验组B,按前述方法制作脊柱感染模型,同时术中在手术部位留置导药管。术后第一日开始每日局部给药,实验组A给予0.1mg/Kg纳米银溶液,实验组B给予1mg/Kg纳米银溶液,空白对照组给予生理盐水。连续给药2周后抽静脉血做培养并处死动物,取手术部位骨组织行组织学检查及培养,另取肝脏组织做培养。处死动物前行脊柱X线、CT检查,观察影像学变化。
结果：接种部位骨组织细菌培养结果示实验组A感染阳性率75%(6/8),0死亡；实验组B感染阳性率25%(2/8),0死亡；空白对照组感染阳性率100%,1例死亡,2例双下肢瘫痪。实验组B与空白对照组感染阳性率结果比较有统计学差异(P<0.01),实验组A与空白对照组感染阳性率结果比较有统计学差异(P<0.01),证实了纳米银局部保留给药的有效性。X线、CT检查示感染动物细菌接种局部有骨质破坏、骨密度增高、椎间隙狭窄等表现,未感染动物没有发现异常结构变化。相应病检结果进一步证实影像学及培养阳性的动物椎体骨组织发生典型化脓性骨髓炎改变,骨髓组织溶解坏死,骨髓腔有化脓性渗出物和坏死物质,骨细胞大量坏死,成骨活性减低,死骨形成,周围有炎性肉芽组织。
结论：局部应用纳米银溶液治疗脊柱化脓性感染是有效的,纳米银溶液在体内内环境中的抗菌作用与给药浓度呈正相关。但纳米银局部给药治疗脊柱感染的作用不是决定性的,不能证实这种治疗方式可以完全替代全身应用抗生素。
第三章纳米银在动物体内的生物学分布
目的：初步分析纳米银在动物体内分布情况。
实验方法：取实验第二部分的动物静脉血清、肝、肾、脾、脊髓、睾丸器官标本,分组同实验第二部分,设为0.1mg/Kg组、1mg/Kg组、空白对照组。采用硝酸-高氯酸化学消化法,将待测标本消化为液态,用原子吸收法测定组织中银的含量。制作肝、肾、脾、脊髓、睾丸石蜡切片标本做组织学检查,观察有无病理变化,制作脊髓超薄切片,行透视电镜观察。
结果：1mg/Kg(?)内米银溶液组测得各组织银含量顺序脊髓>脾>肾>睾丸>肝>血清,0.1mg/kg纳米银组各组织银含量顺序为脊髓>肾>脾>肝>睾丸>血清。两实验组血清银含量与对照组比较,差别无统计学意义(P>0.05)；两实验组脊髓组织银含量与对照组比较,均有显著统计学差异(P<0.01)；1mg/Kg实验组肝、肾、脾、睾丸银含量与对照组比较,差别均有统计学意义(P<0.05)；0.1mg/Kg实验组肝、肾、脾、睾丸银含量与对照组比较,差别均无统计学意义(P>0.05)。结果表明1mg/Kg纳米银组除血清外,在脊髓、肝、肾、脾、睾丸组织均产生了蓄积,0.1 mg/Kg纳米银组仅在脊髓组织产生了蓄积。两实验组脊髓、肝、肾、脾、睾丸组织学检查均没有发现显著病理改变。
结论：纳米银溶液通过局部保留给药的方式,是安全有效的,但当给药量达到一定限值后,会在动物体内产生蓄积,其蓄积的过程主要通过血淋巴系统的转运和局部直接转移完成,蓄积作用最明显的靶组织为周围组织(脊髓)及免疫器官(脾),微量的蓄积不会导致组织器官的器质性和功能性损害。
Part I Establishment of Rabbit Pyogenic Spondylitis Model
Objective:Establish rabbit pyogenic spondylitis model.
Methods:Take 12 male New Zealand white rabbits, randomly divide into 4 groups and inject staphylococcus aureus suspension fluid with different concentration. Surgical approach selects anterolateral retroperitoneal approach. During the operation, exposure intervertebral space of rabbit spinal L1/2 and L5/6, remove part of intervertebral disc, destruct adjacent vertebral endplates, and then input the staphylococcus aureus suspension fluid with different concentration into destructed intervertebral space.2 weeks after the operation, draw venous blood for culturing and sacrifice the animal, take bone tissue of the surgical site and the liver for bacterial culturing, and take pathological examination to the bone tissue of the surgical site.
Result:Apply the staphylococcus aureus suspension fluid with the concentration of 102 CFU/ml to successfully induce spinal infection in 100%(8/8) planting site, the result of liver and blood culturing is negative, rule out the possibility of systemic infection. Apply the staphylococcus aureus suspension fluid with the concentration of 10CFU/ml to successfully induce spinal infection in 33%(2/6) planting area, Apply the staphylococcus aureus suspension fluid with the concentration of lOCFU/ml to successfully induce spinal infection in 100%(6/6) planting area, but only 2 experimental animals separately die 7 and 11 days after the operation.
Conclusion:It has successfully established appropriate rabbit pyogenic spondylitis model, which can be applicable to efficacy comparison of different anti-infection strategies.
Part II Experimental Study on Nano Silver Local Reserved Injection Treatment Rabbit Pyogenic Spondylitis
Objective:Discuss efficacy of Nano siiver treatment pyogenic spondylitis.
Materials & Methods:Take 24 New Zealand white rabbits; randomly divide into blank control group and experimental group A & B, make spinal infection model in accordance with the aforesaid methods, meanwhile indwell drug control guide in the surgical site during the operation. Since the first day after the operation, conduct local drug every day, inject 0.1mg/Kg Nano silver solution to Experimental Group A, inject 1mg/Kg Nano silver solution to Experimental Group B, and inject saline to Blank Control Group. After 2 weeks of consecutive drugging, draw venous blood for culturing and sacrifice the animal, take bone tissue of the surgical site for pathological examination and culturing, and take the liver tissue for culturing. Before sacrificing the animals, take spinal X-ray and CT examination and observe the changes of medical imageology.
Result:The bacteria culturing result of bone tissues in the inoculated site shows that the positive infection rate of Experimental Group A is 75%(6/8), zero death; the positive infection rate of Experimental Group B is 25%(2/8), zero death; the positive infection rate of Blank Control Group is 100%,1 death,2 cases paralysis of both lower extremities. The comparison of positive infection rate result of Experimental Group B and Blank Control Group has statistical difference (P＜0.01), as well as Experimental A and Blank Control Group (P＜0.01), which confirms the effectiveness of Nano silver local reserved drug.X-ray and CT examination indicate that the infectious animal bacterination partly has the changes involving bond destruction, bone mineral density increasing, and intervertebral space stenosis, and the uninfected animals have no abnormal structural change. The corresponding disease examination results further verify the imageology and animal centrum bone tissue of cultivating the positive have the changes of typical pyogenic osteomyelitis. The bone marrow tissue dissolves and necrotizes, the marrow cavity has pyogenic exudations and necrosis substances, the bone cells necrotize in quantity, the osteogenic activities reduce, and the sequestrum forms with the inflammatory granulation tissue around.
Conclusion:It is effective to apply Nano silver solution for treating the spinal column infection partly. The antibiotic action of Nano silver solution in the internal environment of the body shows the positive correlation with the dose concentration. But it is not decisive that Nano silver partly dosing treats the spinal column infection, which cannot verify this dosing method shall replace for the application antibiotic of the whole body.
Part III Biological Distribution of Nano Silver in the Body of the Animal
Objective:Analyze the distribution conditions of Nano sliver in the body of the animal preliminarily.
Methods and Materials:Take the venous blood, liver, kidney, spleen, spinal cord, and testis organs specimen of the animals in Part II of the experiment. The grouping is the same as Part II of the experiment, involving 0.1 mg/Kg group,1 mg/Kg group and blank control group. Adopt the nitric acid-perchloric acid chemical digestion method, digest the specimen to be tested into the liquid state, and measure Ag content of the tissue with the atomic absorption method upon the constant volume. Make the liver, kidney, spleen, spinal cord, and testis paraffin section specimen as the histology examination and observe whether it has the pathologic change. Make the spinal marrow ultra thin section and observe with the transmission electron microscopy.
Results:1 mg/Kg Nano silver solution group measures the silver content sequences of each tissue as spinal cord> spleen> kidney> testis> liver> blood serum, and as for 0.1 mg/kg group, the silver content sequences of each tissue is spinal cord> kidney> spleen> liver> testis> blood serum. The silver content differences of the blood serum in two experimental groups and control group have no statistics significance (P>0.05). The silver content differences of the spinal marrow tissue in two experimental groups and control group have the statistics significance (P<0.01). The silver content differences of liver, kidney, spleen and testis in 1 mg/Kg experimental group and control group have the statistics significance (P<0.05). The silver content differences of liver, kidney, spleen and testis in 0.1 mg/Kg experimental group and control group have no statistics significance (P＜0.05). The result indicates that 1 mg/Kg Nano silver group produces the accumulation in spinal cord, liver, kidney, spleen and testis tissues except for the blood serum, and 0.1 mg/Kg Nano silver group only produces the accumulation in spinal cord tissue. The histology examination of spinal cord, liver, kidney, spleen and testis of two experimental groups has no obvious pathological change.
Conclusion:Nano silver solution is safe and effective by the way of partly retaining for dosing, however, the dose shall accumulate in the body of the animal after reaching the established limit values. The accumulating process is accomplished mainly through the transfer of hemolymph system and direct jump of the part. The most obvious target tissue of the accumulative action is the peripheral tissue (spinal cord) and immune organ (spleen). The micro accumulation shall not result in the organic and functional damages of the tissue and organ.
引文
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