药物治疗骨质疏松动物模型的生物力学实验研究
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摘要
骨质疏松症是一种多发于绝经妇女及老年人的常见病,严重影响着老年人的生活质量和生存状况,目前已逐渐受到人们的重视。
国内外学者对预防和治疗骨质疏松做了大量研究,但是研究动物去势骨质疏松以中药、西药、VK、钙剂防治骨质疏松动物骨骼的骨密度,动物血液血磷、血钙、咸性磷酸酶指标,以扫描电镜观察动物骨组织显微结构,以图像分析系统观察,骨小梁周长、骨小梁相对体积,骨小梁平均厚度,骨小梁的两侧平均距离。对各种治疗方法动物骨骼的拉伸,压缩、弯曲、扭转、剪切、冲击力学性能和拉伸应力松驰、蠕变粘弹性(流变)性质未见报道。
鉴于相关研究和临床需要,作者设计了一组实验,将180只大鼠随机分成6组,分别设为正常对照组织30只,模型组30只,中药治疗组30只,西药治疗(阿伦膦酸纳)组30只、VK治疗组30只、钙剂治疗组30只,各组动物饲养15周周末在腹主动脉采血用于血钙、血磷、碱性磷酸酶测定,之后以腹主动脉放血法处死大鼠,取各组大鼠股骨、胫骨各8个试样,在骨中央切开测量骨密度。取各组大鼠胫骨各10个试样进行组织学观察,取各组大鼠骨进行拉伸、压缩、弯曲、扭转、剪切、冲击实验,并对各组大鼠骨进行拉伸应力松驰、蠕变实验。
得出了各组大鼠骨拉伸、压缩、弯曲、扭转、剪切、冲击力学性能指标;得出了各组大鼠应力松驰,蠕变数据和曲线,得出了各组大鼠骨应力松弛方程和蠕变方程。得出了各组大鼠骨的骨密度;得出了各组大鼠血清中血钙、血磷、碱性磷酸酶生化指标;得出了各组大鼠骨小梁周长、骨小梁相对体积、骨小梁平均厚度等指标,以期为骨质疏松的研究和临床提供理论基础。
Osteoporosis is a common disease in postmenopausal women and the elderly. It is characterized by reduction in bone mass, damage on micro-structure of bone tissue, the increasing of brittleness and bone fracture. At present, osteoporosis has been paid more attention for its dangerous and common chronic property, and serious impact on older people's life quality and living conditions. Over the past 30 years, with the further study on the ultrastructure of osteoporosis epidemiology, its etiology and pathogenesis has been much clear, and has confirmed that women are the main victims of this disease. The osteoporosis of senile is one of the three major diseases, which mostly occurred in postmenopausal women, as time increases after menopause, the incident of osteoporosis increased significantly, indicating that estrogen of ovarian has much infect on the osteoporosis and its development.
Many researches have been carried out about osteoporosis with bone mechanics methods at home and abroad. However, few experimental researches have been performed on the osteoporosis with new Chinese medicine treatment, animal bone tensile, compression, bending, torsion, impact, stress relaxation, creep, histology analysis, blood biochemistry, and bone mineral density as well.
In view of the actual clinical needs, a lot of experiments and systematic studies have been carried out to evaluate the postmenopausal osteoporosis systematically and objectively. The experiments are: the Chinese medicine, bisphosphonate, VK, and calcium dose are used in three models respectively, which are osteoporosis of ovariectomized rat model, normal rat model and osteoporosis of rat model, the aim is to investigate on the blood biochemistry, bone biomechanics, bone mineral density and bone tissue microstructure systematically. It is hoped to provide a theoretical basis of clinical practice.
In order to have a systematically study on biomechanical mechanism of the ovariectomized osteoporosis, osteoporosis of ovariectomized rat models were made to carry out the research. 180 rats are randomly divided into six groups, the experimental groups of rats were ovariectomized at 0 week, thereafter, the experimental groups were treated with Chinese medicine, bisphosphonate, VK, and calcium dose respectively. After 18 weeks feeding, the rats were killed with abdominal aortic blood method, the blood was centrifuged and the serum was preserved in the refrigerator, the rats were anatomized to extract the left and right femur, tibia and humerus. The extracted ones were wrapped with 0.9% saline gauze, the bone mineral density of lateral condyle, femoral intertrochanteric, and tibial plateau were measured respectively. Then, the femur, tibia, humerus were fixed in the mould with denture acrylic, thus the examples were made.
The biomechanical researches were performed on the rat bone examples, which include, three-point bending, tensile, compression, torsion, impact and shear mechanical properties. The mechanical characteristics of stress relaxation and creep were also examined. The data such as bone tensile, compression, bending, stress, strain, modulus of elasticity were obtained, the torque, the torsion angle and the torsion shear stress were obtained, and the impact energy and impact toughness as well, the maximum bone shear load, shear stress, and also drew the stress relaxation and creep under 7200S load, hence to establish a three-parameter model of rat bone stress relaxation, creep equation.
All the femoral head cancellous bone were decalcification with 2.5% EDTA for a month, pre-fixed with 2.5% glutaraldehyde, post-fixed with 1% osmium tetroxide, dehydrated with acetaldehyde, embedded with epon 812 epoxy resin, sliced with LKB-Ⅲultra-thin slicing machine, double-stained with uranyl acetate and citric acid, finally observed the morphology by scanning electron microscopy.
Blood biochemical testing results are, serum phosphorus, serum phosphorus, alkaline phosphatase of the normal group and Chinese medicine groups have no significant, the normal group and model group have significant differences (P<0.01), calcium group have significant difference between the normal group, calcium group have little difference with the model group.
As for bone mineral density measurement, the normal group and Chinese medicine group, western medicine group have little differences, calcium group and model group have little difference.
The experiment tensile on bone were performed on Shimadzu AG-10TA Automatic Control Electronics Universal Testing Machine, loaded 20 times repeatedly. The specimen was clamped on to the testing machine, the tensile stress imposed on rat femur at a loading speed of 5mm/min , femur fracture more than the backbone, a small number of faults in the epiphysis. Tensile stress and strain and elastic modulus of normal group were greatly higher than that of model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The majority of each group for the cross-sectional fracture are transverse, a small number of them are oblique.
The three-point bending experiments on femur were performed on the same machine as tensile experiments. The specimens were placed on the supporter of the machine, the supporter span is 20mm, the specimens were imposed with bending moment speed of the 5mm/min. the bending moment, bending stress, damage load, and elastic modulus of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The majority of each group for the tension-sectional fracture are transverse, and the compression section are oblique.
The compression experiments were performed on the same machine as tensile experiments, Automatic Control Electronics Universal Testing Machine. The specimen was clamped on to the testing machine, the tensile stress imposed on rat femur at a loading speed of 5mm/min. The damage load, stress, strain, and elastic modulus of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The damage on most samples are oblique fracture damage, and presents a brittle fracture morphology of the damage.
The torsion experiments were performed on the torsion machine, the samples were clamped to the machine chuck, then drive the machine to impose torque on them. The torque, the torsion angle and the torsion shear stress of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The damage on most samples are oblique fracture damage.
The impact experiments were performed on the impact testing machine, the pendulum was swung up to impact on the sample. The impact energy and impact toughness of the normal group were greatly higher then that of the model group(P﹤0.01). There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The damage on most samples are mostly comminuted fracture.
The shear experiments were performed on Automatic Control Electronics Universal Testing Machine. The specimen was clamped on to the testing machine, the shear stress imposed on the specimen at a loading speed of 5mm/min. All the index of the normal group were greatly higher then that of the model group(P﹤0.05). There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group(P﹤0.05).
The stress relaxation experiments on femur were performed on the same machine as tensile experiments. The stress relaxation under 7200S load was greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group.
The creep experiments on femur were performed on the same machine as stress relaxation experiments. The creep under 7200S load was greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group.
Scanning with electron microscope, the trabecular bone was close arranged in the normal group, and which of the model group disorganized and with pores, the trabecular bone of Chinese medicine group and western medicine group were also close arranged, and with no obvious abnormalities.
The bone tensile, compression, bending, impact and torsion mechanical properties of normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
The blood biochemistry index of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
The bone mineral density of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
The stress relaxation and creep under 7200S of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
国内外学者对预防和治疗骨质疏松做了大量研究,但是研究动物去势骨质疏松以中药、西药、VK、钙剂防治骨质疏松动物骨骼的骨密度,动物血液血磷、血钙、咸性磷酸酶指标,以扫描电镜观察动物骨组织显微结构,以图像分析系统观察,骨小梁周长、骨小梁相对体积,骨小梁平均厚度,骨小梁的两侧平均距离。对各种治疗方法动物骨骼的拉伸,压缩、弯曲、扭转、剪切、冲击力学性能和拉伸应力松驰、蠕变粘弹性(流变)性质未见报道。
鉴于相关研究和临床需要,作者设计了一组实验,将180只大鼠随机分成6组,分别设为正常对照组织30只,模型组30只,中药治疗组30只,西药治疗(阿伦膦酸纳)组30只、VK治疗组30只、钙剂治疗组30只,各组动物饲养15周周末在腹主动脉采血用于血钙、血磷、碱性磷酸酶测定,之后以腹主动脉放血法处死大鼠,取各组大鼠股骨、胫骨各8个试样,在骨中央切开测量骨密度。取各组大鼠胫骨各10个试样进行组织学观察,取各组大鼠骨进行拉伸、压缩、弯曲、扭转、剪切、冲击实验,并对各组大鼠骨进行拉伸应力松驰、蠕变实验。
得出了各组大鼠骨拉伸、压缩、弯曲、扭转、剪切、冲击力学性能指标;得出了各组大鼠应力松驰,蠕变数据和曲线,得出了各组大鼠骨应力松弛方程和蠕变方程。得出了各组大鼠骨的骨密度;得出了各组大鼠血清中血钙、血磷、碱性磷酸酶生化指标;得出了各组大鼠骨小梁周长、骨小梁相对体积、骨小梁平均厚度等指标,以期为骨质疏松的研究和临床提供理论基础。
Osteoporosis is a common disease in postmenopausal women and the elderly. It is characterized by reduction in bone mass, damage on micro-structure of bone tissue, the increasing of brittleness and bone fracture. At present, osteoporosis has been paid more attention for its dangerous and common chronic property, and serious impact on older people's life quality and living conditions. Over the past 30 years, with the further study on the ultrastructure of osteoporosis epidemiology, its etiology and pathogenesis has been much clear, and has confirmed that women are the main victims of this disease. The osteoporosis of senile is one of the three major diseases, which mostly occurred in postmenopausal women, as time increases after menopause, the incident of osteoporosis increased significantly, indicating that estrogen of ovarian has much infect on the osteoporosis and its development.
Many researches have been carried out about osteoporosis with bone mechanics methods at home and abroad. However, few experimental researches have been performed on the osteoporosis with new Chinese medicine treatment, animal bone tensile, compression, bending, torsion, impact, stress relaxation, creep, histology analysis, blood biochemistry, and bone mineral density as well.
In view of the actual clinical needs, a lot of experiments and systematic studies have been carried out to evaluate the postmenopausal osteoporosis systematically and objectively. The experiments are: the Chinese medicine, bisphosphonate, VK, and calcium dose are used in three models respectively, which are osteoporosis of ovariectomized rat model, normal rat model and osteoporosis of rat model, the aim is to investigate on the blood biochemistry, bone biomechanics, bone mineral density and bone tissue microstructure systematically. It is hoped to provide a theoretical basis of clinical practice.
In order to have a systematically study on biomechanical mechanism of the ovariectomized osteoporosis, osteoporosis of ovariectomized rat models were made to carry out the research. 180 rats are randomly divided into six groups, the experimental groups of rats were ovariectomized at 0 week, thereafter, the experimental groups were treated with Chinese medicine, bisphosphonate, VK, and calcium dose respectively. After 18 weeks feeding, the rats were killed with abdominal aortic blood method, the blood was centrifuged and the serum was preserved in the refrigerator, the rats were anatomized to extract the left and right femur, tibia and humerus. The extracted ones were wrapped with 0.9% saline gauze, the bone mineral density of lateral condyle, femoral intertrochanteric, and tibial plateau were measured respectively. Then, the femur, tibia, humerus were fixed in the mould with denture acrylic, thus the examples were made.
The biomechanical researches were performed on the rat bone examples, which include, three-point bending, tensile, compression, torsion, impact and shear mechanical properties. The mechanical characteristics of stress relaxation and creep were also examined. The data such as bone tensile, compression, bending, stress, strain, modulus of elasticity were obtained, the torque, the torsion angle and the torsion shear stress were obtained, and the impact energy and impact toughness as well, the maximum bone shear load, shear stress, and also drew the stress relaxation and creep under 7200S load, hence to establish a three-parameter model of rat bone stress relaxation, creep equation.
All the femoral head cancellous bone were decalcification with 2.5% EDTA for a month, pre-fixed with 2.5% glutaraldehyde, post-fixed with 1% osmium tetroxide, dehydrated with acetaldehyde, embedded with epon 812 epoxy resin, sliced with LKB-Ⅲultra-thin slicing machine, double-stained with uranyl acetate and citric acid, finally observed the morphology by scanning electron microscopy.
Blood biochemical testing results are, serum phosphorus, serum phosphorus, alkaline phosphatase of the normal group and Chinese medicine groups have no significant, the normal group and model group have significant differences (P<0.01), calcium group have significant difference between the normal group, calcium group have little difference with the model group.
As for bone mineral density measurement, the normal group and Chinese medicine group, western medicine group have little differences, calcium group and model group have little difference.
The experiment tensile on bone were performed on Shimadzu AG-10TA Automatic Control Electronics Universal Testing Machine, loaded 20 times repeatedly. The specimen was clamped on to the testing machine, the tensile stress imposed on rat femur at a loading speed of 5mm/min , femur fracture more than the backbone, a small number of faults in the epiphysis. Tensile stress and strain and elastic modulus of normal group were greatly higher than that of model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The majority of each group for the cross-sectional fracture are transverse, a small number of them are oblique.
The three-point bending experiments on femur were performed on the same machine as tensile experiments. The specimens were placed on the supporter of the machine, the supporter span is 20mm, the specimens were imposed with bending moment speed of the 5mm/min. the bending moment, bending stress, damage load, and elastic modulus of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The majority of each group for the tension-sectional fracture are transverse, and the compression section are oblique.
The compression experiments were performed on the same machine as tensile experiments, Automatic Control Electronics Universal Testing Machine. The specimen was clamped on to the testing machine, the tensile stress imposed on rat femur at a loading speed of 5mm/min. The damage load, stress, strain, and elastic modulus of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The damage on most samples are oblique fracture damage, and presents a brittle fracture morphology of the damage.
The torsion experiments were performed on the torsion machine, the samples were clamped to the machine chuck, then drive the machine to impose torque on them. The torque, the torsion angle and the torsion shear stress of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The damage on most samples are oblique fracture damage.
The impact experiments were performed on the impact testing machine, the pendulum was swung up to impact on the sample. The impact energy and impact toughness of the normal group were greatly higher then that of the model group(P﹤0.01). There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group. The damage on most samples are mostly comminuted fracture.
The shear experiments were performed on Automatic Control Electronics Universal Testing Machine. The specimen was clamped on to the testing machine, the shear stress imposed on the specimen at a loading speed of 5mm/min. All the index of the normal group were greatly higher then that of the model group(P﹤0.05). There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group(P﹤0.05).
The stress relaxation experiments on femur were performed on the same machine as tensile experiments. The stress relaxation under 7200S load was greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group.
The creep experiments on femur were performed on the same machine as stress relaxation experiments. The creep under 7200S load was greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group, there no difference between calcium group and model group.
Scanning with electron microscope, the trabecular bone was close arranged in the normal group, and which of the model group disorganized and with pores, the trabecular bone of Chinese medicine group and western medicine group were also close arranged, and with no obvious abnormalities.
The bone tensile, compression, bending, impact and torsion mechanical properties of normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
The blood biochemistry index of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
The bone mineral density of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
The stress relaxation and creep under 7200S of the normal group were greatly higher then that of the model group. There are little differences between the normal group and the Chinese medicine group, and the western medicine group.
引文
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