转子下内翻截骨术对兔Perthes病股骨头血管化及软骨内成骨的影响
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摘要
目的
儿童Perthes病经历了100多年的历史,仍然是一个疑难疾病,治疗的选择仍很困难。回顾大量文献发现转子下内翻截骨术对儿童Perthes病的治疗有很好的疗效,本研究通过建立兔Perthes病模型并探讨转子下内翻截骨术对兔Perthes病股骨头VEGF表达的影响,评价转子下内翻截骨术能否促进股骨头骺软骨的血管长入和软骨内成骨。
方法
2个月～2个半月龄新西兰大白兔34只,体重1.8～2.0kg。以每只兔右侧股骨头进行制作兔Perthes病模型,手术切断右侧圆韧带及股骨头支持带血供,建立兔Perthes病模型;造模2周后随机抽取2只兔处死,进行股骨头组织病理学观察证实造模成功。将32只兔随机分成A、B两组,A组16只兔,B组16只兔,B组行右侧股骨转子下内翻截骨术;于截骨术后2、4、6、8周每组分别随机抽取4只兔,行X线、腹主动脉造影、处死后肉眼观察双侧股骨头、病理组织学观察:(普通HE染色、VEGF免疫组织化学染色);将A、B两组兔左侧股骨头随机抽取16个作为空白组,B组右侧股骨头为实验组、A组右侧股骨头为对照组;所有数据均是运用SPSS17.0进行统计学分析的。
结果
兔perthes病模型制备成功,无1例死亡。
大体观察:截骨术后各个时间点A、B两组兔左侧股骨头大体观察均处于兔perthes病股骨头大体观察分级的0级; A组兔右侧股骨头术后2周(1级水平2例、2级水平2例),术后4周(1级水平1例,2级水平1例、3级水平2例),术后6周(1级水平1例、3级水平3例),术后8周(2级水平2例、3级水平2例);术后2、4、6周B组兔右侧股骨头均(1级水平2例、2级水平2例),术后8周为(1级水平2例、2级水平1例、3级水平1例)。
X线片观察:A、B两组左侧髋关节试验期间各个时间点均未发生明显变化,都处于兔perthes病X线分级的Ⅰ级水平。截骨术后2周A、B两组右侧股骨头分别有(Ⅰ级水平2例、Ⅱ级水平2例);术后4周A组右侧股骨头(Ⅱ级水平4例),术后6周(Ⅱ级水平2例、Ⅲ级水平2例),术后8周(Ⅱ级水平1例、Ⅲ级水平2例、Ⅳ级水平1例);术后4、6、8周B组兔右侧股骨头均处于Ⅱ级水平。动脉造影:X线摄片检查显示A组右侧股深浅动脉的分支较左侧未见明显的差别,B组右侧股深浅动脉的分支较左侧明显的增加,股骨近端手术区的血管数量明显增加。
HE染色观察:造模后2周处死的2只兔右侧股骨头骺软骨内可见软骨陷窝,但软骨陷窝多空虚,骨髓腔由无定形的碎屑填充,骨小梁碎裂成片状或压缩成块,但无修复现象,证明造模成功。空白组股骨头各时间点未见股骨头坏死及骨修复现象。转子下内翻截骨术后2、4、6、8周各时间点A、B两组兔右侧股骨头坏死区的边缘可见新生血管的形成;并可见到新生的肉芽组织,侵入坏死区,吸收坏死骨;新生的肉芽组织由微血管、炎性细胞和成纤维细胞组成。但是B组兔在截骨术后第4周就出现了明显的骨修复,有新骨形成;对照组在第6周才出现明显的骨修复,新骨形成。免疫组织化学:空白组股骨头骺软骨的肥大区在各时间点均表现出较高的VEGF免疫反应性(VEGF immunoreactivity,VEGF-IR),但是其增殖区却表现较低;实验组和对照组的各个时间点股骨头骺软骨的肥大区的VEGF阳性细胞率比较有统计学意义(p<0.001),但在截骨术后2、4、6周的各个时间点均低于空白组,直到第8周才和空白组达到相当水平。空白组股骨头骺软骨增殖区各时间点VEGF阳性细胞率较低,远远低于实验组和对照组,实验组、对照组和空白组两两比较均有统计学意义(p<0.001);实验组的VEGF阳性细胞率高于对照组,数值并随时间延长而增加。
结论
1、VEGF在股骨头骺软骨坏死后促进其血管发生、骺软骨骨化中心的修复重建方面起着至关重要的调节作用。
2、股骨转子下内翻截骨术可以促进截骨术区的血管长入。
3、股骨转子下内翻截骨术可以增强VEGF的表达,从而促进坏死股骨头修复和缩短儿童Perthes病病程。
Objective
Perthes’disease is still an enigmatic disease after it was described 100 years,and the ideal treatment of it is difficult to get.Lookaround reviews of the literature,the treatment of Perthes’disease with subtrochanteric varus osteotomy has good results.The aim of this study was to explore the change and their significance of VEGF expression in the femoral head after subtrochanteric varus osteotomy in a rabbit model,and to appraise wheather subtrochanteric varus osteotomy can promote new vascular invasion and cartilaginous ossification in the femoral head epiphysial cartilage.
Materials and methods
Thirty-four 2～2.5-month-old New Zealand rabbits were used(weighing 1.8～2.0Kg). A rabbit model of Perthes’disease was made by excision of right ligamentum teres and retinacular blood supplies of femoral head. At 2 weeks,2 rabbits were selected randomly, histological observations of the femoral head proved that the model of Perthes’disease was made successfully.Thirty-two New Zealand rabbits were divided into groups A and B randomly.Group B were operated with subtrochanteric varus osteotomy at 2 weeks after Perthes’disease model. 4 rabbites in each experimental goup were selected randomly and killed at 2,4,6,8 weeks.The gross appearance,X-ray film, abdominal aortography and histological observations (HE、VEGF) were carried out at 2,4,6,8 weeks after operation;16 left femoral heads were selected randomly from group A and B,which was the blank group,the right femoral heads of group A was the control group and the right femoral heads of group B was the test group. All the data were analyzed by the software SPSS 17.0.
Results
The rabbit model of Perthes’disease was made successfully;None of rabbits was dead.
General observation:All the left femoral heads of group A and B were in grade 0 of the femoral head’s general observation grade at all time points after operation.The result of general observation of the right femoral heads of group A at two weeks after operation(2 cases in grade 1,2 cases in grade 2),at four weeks(1 case in grade 1,1 case in grade 2,2 cases in grade 3),at six weeks(1 case in grade1,3 cases in grade 3),at eight weeks(2 cases in grade 2,2 cases in grade 2); The result of general observation of the right femoral heads of group B at two,four,six weeks after operation(2 cases in grade 1,2 cases in grade 2),at eight weeks(2 cases in grade 1,1case in grade 2,1 case in grade 3).
The results of X-ray: All the left femoral heads of group A and B were in gradeⅠof the femoral head’s X-ray grade,which were normal. The respective result of X-ray of the right femoral heads of group A and B at two weeks after operation(2 cases in gradeⅠ,2 cases in gradeⅡ); The result of X-ray of the right femoral heads of group A at four weeks after operation(4 cases in gradeⅡ),at six weeks(2 cases in gradeⅡ,2 cases in gradeⅢ),at eight weeks(1 case in gradeⅡ,2 cases in gradeⅢ,1 case in gradeⅣ); At four,six and eight weeks,all the right femoral heads of group B were in gradeⅡof the femoral head’s X-ray grade.
Abdominal aortography data: Visually,There was no difference in both right superficial and profunda femoral arteries by radiographic examinations,and their branches of group A as compared with the left. There were increased number in both right superficial and profunda femoral arteries by radiographic examinations,and their branches of group B as compared with the left.There were increased vascularity in the region of the operated proximal femur.
The HE staining observation:By 2 weeks,many empty lacunae were observed in the right femoral head epiphyseal cartilage of the 2 rabbits which were killed by two weeks after the induction of ischemia.The bone marrow cavity filled by the amorphous debris;Trabecular bone fragmented into a sheet or compressed into blocks,but the repair phenomenon was not observed.So,the rabbit model of Perthes’disease was made successfully.The femoral heads had no necrosis changes in blank group.At 2,4,6,8weeks after subtrochanteric varus osteotomy,neovascularization was observed at the periphery of the infarcted femoral head.Vascular granulation tissue was consisted of capillaries,inflammatory cells and fibroblastic cells. Vascular granulation tissue were seen invading the necrotic marrow space,and the resorption of dead bone.However,there were obviously bone reparation and new bone formation at 4 weeks after subtrochanteric varus osteotomy in group B;There were no bone reparation and new bone formation until the 6th weeks in group A.
Immunohistochemistry staining:In the epiphyseal cartilage of the femoral heads of blank group,an intensive VEGF immunoreactivity(VEGF-IR) was found in the hypertrophic zone , and a low level of VEGF-IR in the proliferative zone at all time points.There were statistically significant differences in the ratios of VEGF+ cells in hypertrophic zone of the femoral heads between test group and control group at all time points(P<0.001),but the ratios of VEGF+ cells in hypertrophic zone of the femoral heads of test group and control group were significantly lower than blank group at 2,4,6 weeks,there were not reached a considerable level until the 8 weeks after subtrochanteric varus osteotomy of the three groups. The ratios of VEGF+ cells in the proliferative zone of the femoral heads of blank group were significantly lower than test group and control group at all time points.There were statistically significant differences in the ratios of VEGF+ cells in proliferative zone of the femoral heads between test group,control group and blank group by pairwise comparison at all time points(P<0.001). The ratios of VEGF+ cells of test group were significantly higher than blank group at all time points,which was increased with time.
Conclusions
1、It is obvious that VEGF act a key regulator that couples angiogenesis,cartilage remodeling,and ossification after ischemic damage to restore endochondral ossification in the epiphyseal cartilage.
2、Subtrochanteric varus osteotomy can promote vascular invasion in the region of the operated proximal femur.
3、Subtrochanteric varus osteotomy can promote VEGF upregulation and the repair of ischemic necrosis of the femoral head,and can shorten the course of Perthes’disease.
儿童Perthes病经历了100多年的历史,仍然是一个疑难疾病,治疗的选择仍很困难。回顾大量文献发现转子下内翻截骨术对儿童Perthes病的治疗有很好的疗效,本研究通过建立兔Perthes病模型并探讨转子下内翻截骨术对兔Perthes病股骨头VEGF表达的影响,评价转子下内翻截骨术能否促进股骨头骺软骨的血管长入和软骨内成骨。
方法
2个月～2个半月龄新西兰大白兔34只,体重1.8～2.0kg。以每只兔右侧股骨头进行制作兔Perthes病模型,手术切断右侧圆韧带及股骨头支持带血供,建立兔Perthes病模型;造模2周后随机抽取2只兔处死,进行股骨头组织病理学观察证实造模成功。将32只兔随机分成A、B两组,A组16只兔,B组16只兔,B组行右侧股骨转子下内翻截骨术;于截骨术后2、4、6、8周每组分别随机抽取4只兔,行X线、腹主动脉造影、处死后肉眼观察双侧股骨头、病理组织学观察:(普通HE染色、VEGF免疫组织化学染色);将A、B两组兔左侧股骨头随机抽取16个作为空白组,B组右侧股骨头为实验组、A组右侧股骨头为对照组;所有数据均是运用SPSS17.0进行统计学分析的。
结果
兔perthes病模型制备成功,无1例死亡。
大体观察:截骨术后各个时间点A、B两组兔左侧股骨头大体观察均处于兔perthes病股骨头大体观察分级的0级; A组兔右侧股骨头术后2周(1级水平2例、2级水平2例),术后4周(1级水平1例,2级水平1例、3级水平2例),术后6周(1级水平1例、3级水平3例),术后8周(2级水平2例、3级水平2例);术后2、4、6周B组兔右侧股骨头均(1级水平2例、2级水平2例),术后8周为(1级水平2例、2级水平1例、3级水平1例)。
X线片观察:A、B两组左侧髋关节试验期间各个时间点均未发生明显变化,都处于兔perthes病X线分级的Ⅰ级水平。截骨术后2周A、B两组右侧股骨头分别有(Ⅰ级水平2例、Ⅱ级水平2例);术后4周A组右侧股骨头(Ⅱ级水平4例),术后6周(Ⅱ级水平2例、Ⅲ级水平2例),术后8周(Ⅱ级水平1例、Ⅲ级水平2例、Ⅳ级水平1例);术后4、6、8周B组兔右侧股骨头均处于Ⅱ级水平。动脉造影:X线摄片检查显示A组右侧股深浅动脉的分支较左侧未见明显的差别,B组右侧股深浅动脉的分支较左侧明显的增加,股骨近端手术区的血管数量明显增加。
HE染色观察:造模后2周处死的2只兔右侧股骨头骺软骨内可见软骨陷窝,但软骨陷窝多空虚,骨髓腔由无定形的碎屑填充,骨小梁碎裂成片状或压缩成块,但无修复现象,证明造模成功。空白组股骨头各时间点未见股骨头坏死及骨修复现象。转子下内翻截骨术后2、4、6、8周各时间点A、B两组兔右侧股骨头坏死区的边缘可见新生血管的形成;并可见到新生的肉芽组织,侵入坏死区,吸收坏死骨;新生的肉芽组织由微血管、炎性细胞和成纤维细胞组成。但是B组兔在截骨术后第4周就出现了明显的骨修复,有新骨形成;对照组在第6周才出现明显的骨修复,新骨形成。免疫组织化学:空白组股骨头骺软骨的肥大区在各时间点均表现出较高的VEGF免疫反应性(VEGF immunoreactivity,VEGF-IR),但是其增殖区却表现较低;实验组和对照组的各个时间点股骨头骺软骨的肥大区的VEGF阳性细胞率比较有统计学意义(p<0.001),但在截骨术后2、4、6周的各个时间点均低于空白组,直到第8周才和空白组达到相当水平。空白组股骨头骺软骨增殖区各时间点VEGF阳性细胞率较低,远远低于实验组和对照组,实验组、对照组和空白组两两比较均有统计学意义(p<0.001);实验组的VEGF阳性细胞率高于对照组,数值并随时间延长而增加。
结论
1、VEGF在股骨头骺软骨坏死后促进其血管发生、骺软骨骨化中心的修复重建方面起着至关重要的调节作用。
2、股骨转子下内翻截骨术可以促进截骨术区的血管长入。
3、股骨转子下内翻截骨术可以增强VEGF的表达,从而促进坏死股骨头修复和缩短儿童Perthes病病程。
Objective
Perthes’disease is still an enigmatic disease after it was described 100 years,and the ideal treatment of it is difficult to get.Lookaround reviews of the literature,the treatment of Perthes’disease with subtrochanteric varus osteotomy has good results.The aim of this study was to explore the change and their significance of VEGF expression in the femoral head after subtrochanteric varus osteotomy in a rabbit model,and to appraise wheather subtrochanteric varus osteotomy can promote new vascular invasion and cartilaginous ossification in the femoral head epiphysial cartilage.
Materials and methods
Thirty-four 2～2.5-month-old New Zealand rabbits were used(weighing 1.8～2.0Kg). A rabbit model of Perthes’disease was made by excision of right ligamentum teres and retinacular blood supplies of femoral head. At 2 weeks,2 rabbits were selected randomly, histological observations of the femoral head proved that the model of Perthes’disease was made successfully.Thirty-two New Zealand rabbits were divided into groups A and B randomly.Group B were operated with subtrochanteric varus osteotomy at 2 weeks after Perthes’disease model. 4 rabbites in each experimental goup were selected randomly and killed at 2,4,6,8 weeks.The gross appearance,X-ray film, abdominal aortography and histological observations (HE、VEGF) were carried out at 2,4,6,8 weeks after operation;16 left femoral heads were selected randomly from group A and B,which was the blank group,the right femoral heads of group A was the control group and the right femoral heads of group B was the test group. All the data were analyzed by the software SPSS 17.0.
Results
The rabbit model of Perthes’disease was made successfully;None of rabbits was dead.
General observation:All the left femoral heads of group A and B were in grade 0 of the femoral head’s general observation grade at all time points after operation.The result of general observation of the right femoral heads of group A at two weeks after operation(2 cases in grade 1,2 cases in grade 2),at four weeks(1 case in grade 1,1 case in grade 2,2 cases in grade 3),at six weeks(1 case in grade1,3 cases in grade 3),at eight weeks(2 cases in grade 2,2 cases in grade 2); The result of general observation of the right femoral heads of group B at two,four,six weeks after operation(2 cases in grade 1,2 cases in grade 2),at eight weeks(2 cases in grade 1,1case in grade 2,1 case in grade 3).
The results of X-ray: All the left femoral heads of group A and B were in gradeⅠof the femoral head’s X-ray grade,which were normal. The respective result of X-ray of the right femoral heads of group A and B at two weeks after operation(2 cases in gradeⅠ,2 cases in gradeⅡ); The result of X-ray of the right femoral heads of group A at four weeks after operation(4 cases in gradeⅡ),at six weeks(2 cases in gradeⅡ,2 cases in gradeⅢ),at eight weeks(1 case in gradeⅡ,2 cases in gradeⅢ,1 case in gradeⅣ); At four,six and eight weeks,all the right femoral heads of group B were in gradeⅡof the femoral head’s X-ray grade.
Abdominal aortography data: Visually,There was no difference in both right superficial and profunda femoral arteries by radiographic examinations,and their branches of group A as compared with the left. There were increased number in both right superficial and profunda femoral arteries by radiographic examinations,and their branches of group B as compared with the left.There were increased vascularity in the region of the operated proximal femur.
The HE staining observation:By 2 weeks,many empty lacunae were observed in the right femoral head epiphyseal cartilage of the 2 rabbits which were killed by two weeks after the induction of ischemia.The bone marrow cavity filled by the amorphous debris;Trabecular bone fragmented into a sheet or compressed into blocks,but the repair phenomenon was not observed.So,the rabbit model of Perthes’disease was made successfully.The femoral heads had no necrosis changes in blank group.At 2,4,6,8weeks after subtrochanteric varus osteotomy,neovascularization was observed at the periphery of the infarcted femoral head.Vascular granulation tissue was consisted of capillaries,inflammatory cells and fibroblastic cells. Vascular granulation tissue were seen invading the necrotic marrow space,and the resorption of dead bone.However,there were obviously bone reparation and new bone formation at 4 weeks after subtrochanteric varus osteotomy in group B;There were no bone reparation and new bone formation until the 6th weeks in group A.
Immunohistochemistry staining:In the epiphyseal cartilage of the femoral heads of blank group,an intensive VEGF immunoreactivity(VEGF-IR) was found in the hypertrophic zone , and a low level of VEGF-IR in the proliferative zone at all time points.There were statistically significant differences in the ratios of VEGF+ cells in hypertrophic zone of the femoral heads between test group and control group at all time points(P<0.001),but the ratios of VEGF+ cells in hypertrophic zone of the femoral heads of test group and control group were significantly lower than blank group at 2,4,6 weeks,there were not reached a considerable level until the 8 weeks after subtrochanteric varus osteotomy of the three groups. The ratios of VEGF+ cells in the proliferative zone of the femoral heads of blank group were significantly lower than test group and control group at all time points.There were statistically significant differences in the ratios of VEGF+ cells in proliferative zone of the femoral heads between test group,control group and blank group by pairwise comparison at all time points(P<0.001). The ratios of VEGF+ cells of test group were significantly higher than blank group at all time points,which was increased with time.
Conclusions
1、It is obvious that VEGF act a key regulator that couples angiogenesis,cartilage remodeling,and ossification after ischemic damage to restore endochondral ossification in the epiphyseal cartilage.
2、Subtrochanteric varus osteotomy can promote vascular invasion in the region of the operated proximal femur.
3、Subtrochanteric varus osteotomy can promote VEGF upregulation and the repair of ischemic necrosis of the femoral head,and can shorten the course of Perthes’disease.
引文
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