重组人骨形态形成蛋白-2缓释体预防人工关节无菌性松动实验研究
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摘要
第一部分微米级磨损微粒刺激溶骨性细胞因子表达的实验研究
目的建立大鼠人工关节无菌性松动air pouch模型,观察钛合金和超高分子量聚乙烯两种微米级磨损微粒在模型体内的生物反应,比较其对溶骨性细胞因子表达的影响。方法大鼠背部皮下注射过滤后的空气3ml,每2天1次,共6次。1周后,囊腔内分别注射微粒悬液(A组为钛合金,B组为超高分子量聚乙烯)和生理盐水(C组)。1周后取囊腔组织称重,进行肉眼及光镜下观察,测定血清AKP含量,免疫组化法检测IL-6及TNF-α的表达,实时定量(real-time)PCR法检测细胞外基质金属蛋白酶诱导因子(EMMPRIN)的mRNA含量。结果肉眼观察囊腔组织位于皮下,有明显的境界,约蚕豆大小。表面可以见到增生的小血管,部分区域可见纤维状组织,类似于无菌性松动假体周围的界膜组织。B组囊腔组织重量明显高于C组(P<0.05)。光镜下,实验组可见大量吞噬细胞,而对照组未见明显组织细胞反应。实验组血清AKP含量均明显高于对照组(P<0.05)。实验组IL-6的表达均高于对照组,且B组高于A组。实验组EMMPRIN的mRNA含量均高于对照组。结论大鼠air pouch模型能够代表人工关节无菌性松动的组织学和生物学特性,是人工关节无菌性松动机制研究中较为理想的动物模型。钛合金和超高分子量聚乙烯微粒均能引起组织学反应,刺激溶骨性细胞因子的产生及活性升高,诱导溶骨反应,形成人工关节无菌性松动。
第二部分RhBMP-2缓释体在大鼠air pouch中生物学反应实验研究
目的观察rhBMP-2缓释体在大鼠皮下air pouch中的生物学反应,探讨rhBMP-2促进成骨及抑制骨溶解的生物活性的可能机制。方法于鼠背部皮下注射过滤后的空气3ml,每2天1次,共6次。1周后,分别于囊腔内注射rhBMP-2缓释体悬液(A组)和生理盐水(B组)。分别于1和2周后取囊腔组织称重,进行肉眼及光镜下观察,测定血清AKP含量,免疫组化法检测IL-6及TNF-α的表达,real-time PCR法检测EMMPRIN的mRNA含量,以及Western blotting法测定EMMPRIN的蛋白表达。结果肉眼观察囊腔组织表面可以见到增生的小血管,部分区域可见纤维状组织,类似于无菌性松动假体周围的界膜组织。其中A组囊腔组织增厚,内含韧性较大的小结节,是骨组织形成。A组第2周囊腔组织的重量与A组第1周及B组相比,差别具有显著意义(P<0.05)。光镜下,A组与B组均未见明显组织细胞反应。A组第1周血清AKP含量与A组第2周及B组相比,差别具有显著意义(P<0.05),A组第2周较B组略低。A组IL-6的表达低于B组。A组EMMPRIN的mRNA含量明显低于B组,而且第2周含量小于第1周。A组EMMPRIN的蛋白表达明显低于B组,而且第2周含量小于第1周。结论RhBMP-2缓释体一方面可能刺激成骨/成骨样细胞的趋化性,调节整合素的表达,加速细胞增殖速度,使成骨细胞整合到ECM成分,从而促进新骨的形成;另一方面抑制了溶骨性细胞因子的产生及活性,从而抑制溶骨反应。实验结果为rhBMP-2用于人工关节松动的早期预防提供了可能。
第三部分RhBMP-2缓释体预防人工关节无菌性松动的可行性研究
目的用rhBMP-2缓释体早期干预大鼠人工关节无菌性松动模型,研究rhBMP-2促进成骨,抑制微米级磨损微粒介导的溶骨性细胞因子表达,从而抑制骨溶解的生物活性,探讨其早期应用预防人工关节无菌性松动的可行性。方法于鼠背部皮下注射过滤后的空气3ml,每2天1次,共6次。1周后,分别于注射了钛合金和超高分子量聚乙烯微粒的囊腔内注射RhBMP-2缓释体悬液和生理盐水。分别于1和2周后取囊腔组织称重,进行肉眼及光镜下观察,测定血清AKP含量,免疫组化法检测IL-6及TNF-α的表达,real-time PCR法检测EMMPRIN的mRNA含量,以及Western blotting法测定EMMPRIN的蛋白表达。结果肉眼观察囊腔组织有明显的境界,约蚕豆大小。实验组A、C组囊腔组织增厚,内含韧性较大的小结节,是骨组织形成。各组第2周囊腔组织的重量与第1周对比差异具有显著意义(P<0.05)。光镜下,A组与C组均未见明显组织细胞反应,对照组B、D组可见大量吞噬细胞。A组血清AKP含量与B组,C组血清AKP含量与D组不同时间段相比,差异均具有显著意义(P<0.05)。A组IL-6的表达低于B组,C组IL-6的表达低于D组。A组EMMPRIN的mRNA含量明显低于B组,C组明显低于D组,而且第2周含量小于第1周。A组EMMPRIN的蛋白表达明显低于B组,C组明显低于D组,而且第2周含量小于第1周。结论RhBMP-2缓释体一方面促进新骨的形成,另一方面抑制微米级磨损微粒介导的溶骨性细胞因子表达,早期应用RhBMP-2预防人工关节无菌性松动是可行的。
PART ONE An experimental study of the expression of osteolytic cytokines stimulated by micrometer-diameter wear particles
Objective: To investigate the biological reaction of micrometer-diameter wear particles ( Ti-6Al-4V and UHMWPE ) in vivo in a rat subcutaneous air pouch model of aseptic loosening, and evaluate the influence of the expression of osteolytic cytokines induced by the two wear particles. Methods: Filtration air was injected subcutaneously into rats’back 6 times ( 3ml qod ). Air pouch tissue treated with wear debris was obtained from rats killed after day 14. Tissue was also taken from physiological saline treated pouches ( control group ) at day 14. Pouch tissues were weighted, wax embedded and stained with hematoxylin and eosin, observed under microscope. AKP of serium, IL-6 and TNF-a expression with immunohistochemical method, and mRNA expression of EMMPRIN with real time PCR method were measured. Results: Air pouch tissues situated in subcutaneous tissues, with distinct border, horsebean-size, small proliferous blood vessels in the surface, and fibroid tissues in some fields, similar to limiting membrane of periprothesis tissue in the cases of aseptic loosening. As to pouch tissue weight, there was a significant increase in group B than in group C (p<0.05). Microscopy illustrated a large amount of phagocytes in group A and B, compared with no tissular and cellular reaction in group C. Evaluating AKP of serium, there was a significant increase in group A、B than in group C (p<0.05). With immunohistochemical method, there was a significant increase with IL-6 expression in group A、B than in group C. With real time PCR method, there was a significant increase with mRNA expression of EMMPRIN in group A、B than in group C. Conclusions: The rat air pouch model was an optical animal model studying aseptic loosening , which reflected the tissular and biological properties of aseptic loosening.The two wear particles both can cause tissular reactions, modulate the production and expression of osteolytic cytokines, induce osteolytic reactions, lead to aseptic loosening.
PART TWO An experimental study of the biological reactions induced by rhBMP-2 slow release formulation in the rat air pouch tissue
Objective: To investigate the subcutaneous biological reaction of rhBMP-2 slow release formulation in the rat air pouch model, analysis the possible mechanism of new bone ingrowth and the inhibition of osteolysis indueced by rhBMP-2. Methods: Filtration air was injected subcutaneously into rats’back 6 times(3ml qod).Air pouch tissue treated with rhBMP-2 slow release formulation was obtained from rats killed after day 7,day 14. Tissue was also taken from physiological saline treated pouches (control group) at day 7,day 14. Pouch tissues were weighted,wax embedded and stained with hematoxylin and eosin,observed under microscope. AKP of serium,IL-6 and TNF-a expression with immunohistochemical method, mRNA expression of EMMPRIN with real time PCR method and protein expression of EMMPRIN with westrern blotting method were measured. Results: Air pouch tissues situated in subcutaneous tissues, with distinct border, horsebean-size, small proliferous blood vessels in the surface, and fibroid tissues in some fields, similar to limiting membrane of periprothesis tissue in the cases of aseptic loosening. Air pouch tissues were incrassate in group A, it contained a small flexible nodule, which indicated the new bone ingrowth. As to pouch tissue weight,there was a significant difference between group A(day 14) and group A(day 7),group B(p<0.05). Microscopy illustrated no tissular and cellular reaction in both group A and group B.Evaluating of AKP of serium, there was a significant difference between group A(day 7) and group A(day 14),group B(p<0.05). With immunohistochemical method, there was a significant decrease with IL-6 expression in group A than in group B. With real time PCR method,there was a significant decrease with mRNA expression of EMMPRIN in group A than in group B,and in group A(day 14) than in group A(day 7). With western blotting method,there was a significant decrease with protein expression of EMMPRIN in group A than in group B,and in group A(day 14) than in group A(day 7). Conclusions: In one hand, rhBMP-2 slow release formulation stimulated the chemotaxis of osteoblasts/osteoblastlike cells, modulated expression of integrin, increased the speed of cell proliferation, so as to integrate osteoblasts into extracellular matrix, lead to new bone ingrowth;In the other hand, rhBMP-2 slow release formulation inhibited the production and activities of osteolytic cytokines, so as to inhibit osteolytic reaction.It afforded the possibility of using rhBMP-2 in the early prevetion of aseptic loosening.
PART THREE The experimental study of the feasibility of using rhBMP-2 slow release formulation to prevent prothetic aseptic loosening
Objective: To investigate the subcutaneous biological reaction interfered with rhBMP-2 slow release formulation in vivo in the rat air pouch model of aseptic loosening, analysis the biological activities of using rhBMP-2 to improve new bone ingrowth and inhibit the production and activities of osteolytic cytokines, so as to inhibit osteolytic reaction, evaluate the feasibility of early using rhBMP-2 in prevetion of aseptic loosening. Methods: Filtration air was injected subcutaneously into rats’back 6 times(3ml qod).Air pouch tissue treated with wear debris and interfered with rhBMP-2 slow release formulation was obtained from rats killed after day 7,day 14. Tissue was also taken from wear debris and physiological saline treated pouches (control group) at day 7,day 14. Pouch tissues were weighted,wax embedded and stained with hematoxylin and eosin,observed under microscope. AKP of serium,IL-6 and TNF-a expression with immunohistochemical method, mRNA expression of EMMPRIN with real time PCR method and protein expression of EMMPRIN with western blotting method were measured. Results: Air pouch tissues situated in subcutaneous tissues, with distinct border, horsebean-size. Air pouch tissues were incrassate in group A and group C, it contained a small flexible nodule, which indicated the new bone ingrowth.As to pouch tissue weight,there was a significant decrease in day 14 than in day 7 in each group(p<0.05). Microscopy illustrated a large amount of phagocytes in group B and D, compared with no tissular and cellular reaction in group A and group C.Evaluating AKP of serium, there was a significant difference in group A than in group B,in group C than in group D(p<0.05) in different stage of time. With immunohistochemical method, there was a significant decrease with IL-6 expression in group A than in group B,in group C than in group D. With real time PCR method,there was a significant decrease with mRNA expression of EMMPRIN in group A than in group B, in group C than in group D,and decrease in day 14 than in day 7. With western blotting method,there was a significant decrease with protein expression of EMMPRIN in group A than in group B, in group C than in group D,and decrease in day 14 than in day 7.Conclusions: RhBMP-2 slow release formulation improved new bone ingrowth, inhibited the expression of osteolytic cytokines mediated by wear particles. It indicated that early using rhBMP-2 to prevent prothetic aseptic loosening was feasible.
目的建立大鼠人工关节无菌性松动air pouch模型,观察钛合金和超高分子量聚乙烯两种微米级磨损微粒在模型体内的生物反应,比较其对溶骨性细胞因子表达的影响。方法大鼠背部皮下注射过滤后的空气3ml,每2天1次,共6次。1周后,囊腔内分别注射微粒悬液(A组为钛合金,B组为超高分子量聚乙烯)和生理盐水(C组)。1周后取囊腔组织称重,进行肉眼及光镜下观察,测定血清AKP含量,免疫组化法检测IL-6及TNF-α的表达,实时定量(real-time)PCR法检测细胞外基质金属蛋白酶诱导因子(EMMPRIN)的mRNA含量。结果肉眼观察囊腔组织位于皮下,有明显的境界,约蚕豆大小。表面可以见到增生的小血管,部分区域可见纤维状组织,类似于无菌性松动假体周围的界膜组织。B组囊腔组织重量明显高于C组(P<0.05)。光镜下,实验组可见大量吞噬细胞,而对照组未见明显组织细胞反应。实验组血清AKP含量均明显高于对照组(P<0.05)。实验组IL-6的表达均高于对照组,且B组高于A组。实验组EMMPRIN的mRNA含量均高于对照组。结论大鼠air pouch模型能够代表人工关节无菌性松动的组织学和生物学特性,是人工关节无菌性松动机制研究中较为理想的动物模型。钛合金和超高分子量聚乙烯微粒均能引起组织学反应,刺激溶骨性细胞因子的产生及活性升高,诱导溶骨反应,形成人工关节无菌性松动。
第二部分RhBMP-2缓释体在大鼠air pouch中生物学反应实验研究
目的观察rhBMP-2缓释体在大鼠皮下air pouch中的生物学反应,探讨rhBMP-2促进成骨及抑制骨溶解的生物活性的可能机制。方法于鼠背部皮下注射过滤后的空气3ml,每2天1次,共6次。1周后,分别于囊腔内注射rhBMP-2缓释体悬液(A组)和生理盐水(B组)。分别于1和2周后取囊腔组织称重,进行肉眼及光镜下观察,测定血清AKP含量,免疫组化法检测IL-6及TNF-α的表达,real-time PCR法检测EMMPRIN的mRNA含量,以及Western blotting法测定EMMPRIN的蛋白表达。结果肉眼观察囊腔组织表面可以见到增生的小血管,部分区域可见纤维状组织,类似于无菌性松动假体周围的界膜组织。其中A组囊腔组织增厚,内含韧性较大的小结节,是骨组织形成。A组第2周囊腔组织的重量与A组第1周及B组相比,差别具有显著意义(P<0.05)。光镜下,A组与B组均未见明显组织细胞反应。A组第1周血清AKP含量与A组第2周及B组相比,差别具有显著意义(P<0.05),A组第2周较B组略低。A组IL-6的表达低于B组。A组EMMPRIN的mRNA含量明显低于B组,而且第2周含量小于第1周。A组EMMPRIN的蛋白表达明显低于B组,而且第2周含量小于第1周。结论RhBMP-2缓释体一方面可能刺激成骨/成骨样细胞的趋化性,调节整合素的表达,加速细胞增殖速度,使成骨细胞整合到ECM成分,从而促进新骨的形成;另一方面抑制了溶骨性细胞因子的产生及活性,从而抑制溶骨反应。实验结果为rhBMP-2用于人工关节松动的早期预防提供了可能。
第三部分RhBMP-2缓释体预防人工关节无菌性松动的可行性研究
目的用rhBMP-2缓释体早期干预大鼠人工关节无菌性松动模型,研究rhBMP-2促进成骨,抑制微米级磨损微粒介导的溶骨性细胞因子表达,从而抑制骨溶解的生物活性,探讨其早期应用预防人工关节无菌性松动的可行性。方法于鼠背部皮下注射过滤后的空气3ml,每2天1次,共6次。1周后,分别于注射了钛合金和超高分子量聚乙烯微粒的囊腔内注射RhBMP-2缓释体悬液和生理盐水。分别于1和2周后取囊腔组织称重,进行肉眼及光镜下观察,测定血清AKP含量,免疫组化法检测IL-6及TNF-α的表达,real-time PCR法检测EMMPRIN的mRNA含量,以及Western blotting法测定EMMPRIN的蛋白表达。结果肉眼观察囊腔组织有明显的境界,约蚕豆大小。实验组A、C组囊腔组织增厚,内含韧性较大的小结节,是骨组织形成。各组第2周囊腔组织的重量与第1周对比差异具有显著意义(P<0.05)。光镜下,A组与C组均未见明显组织细胞反应,对照组B、D组可见大量吞噬细胞。A组血清AKP含量与B组,C组血清AKP含量与D组不同时间段相比,差异均具有显著意义(P<0.05)。A组IL-6的表达低于B组,C组IL-6的表达低于D组。A组EMMPRIN的mRNA含量明显低于B组,C组明显低于D组,而且第2周含量小于第1周。A组EMMPRIN的蛋白表达明显低于B组,C组明显低于D组,而且第2周含量小于第1周。结论RhBMP-2缓释体一方面促进新骨的形成,另一方面抑制微米级磨损微粒介导的溶骨性细胞因子表达,早期应用RhBMP-2预防人工关节无菌性松动是可行的。
PART ONE An experimental study of the expression of osteolytic cytokines stimulated by micrometer-diameter wear particles
Objective: To investigate the biological reaction of micrometer-diameter wear particles ( Ti-6Al-4V and UHMWPE ) in vivo in a rat subcutaneous air pouch model of aseptic loosening, and evaluate the influence of the expression of osteolytic cytokines induced by the two wear particles. Methods: Filtration air was injected subcutaneously into rats’back 6 times ( 3ml qod ). Air pouch tissue treated with wear debris was obtained from rats killed after day 14. Tissue was also taken from physiological saline treated pouches ( control group ) at day 14. Pouch tissues were weighted, wax embedded and stained with hematoxylin and eosin, observed under microscope. AKP of serium, IL-6 and TNF-a expression with immunohistochemical method, and mRNA expression of EMMPRIN with real time PCR method were measured. Results: Air pouch tissues situated in subcutaneous tissues, with distinct border, horsebean-size, small proliferous blood vessels in the surface, and fibroid tissues in some fields, similar to limiting membrane of periprothesis tissue in the cases of aseptic loosening. As to pouch tissue weight, there was a significant increase in group B than in group C (p<0.05). Microscopy illustrated a large amount of phagocytes in group A and B, compared with no tissular and cellular reaction in group C. Evaluating AKP of serium, there was a significant increase in group A、B than in group C (p<0.05). With immunohistochemical method, there was a significant increase with IL-6 expression in group A、B than in group C. With real time PCR method, there was a significant increase with mRNA expression of EMMPRIN in group A、B than in group C. Conclusions: The rat air pouch model was an optical animal model studying aseptic loosening , which reflected the tissular and biological properties of aseptic loosening.The two wear particles both can cause tissular reactions, modulate the production and expression of osteolytic cytokines, induce osteolytic reactions, lead to aseptic loosening.
PART TWO An experimental study of the biological reactions induced by rhBMP-2 slow release formulation in the rat air pouch tissue
Objective: To investigate the subcutaneous biological reaction of rhBMP-2 slow release formulation in the rat air pouch model, analysis the possible mechanism of new bone ingrowth and the inhibition of osteolysis indueced by rhBMP-2. Methods: Filtration air was injected subcutaneously into rats’back 6 times(3ml qod).Air pouch tissue treated with rhBMP-2 slow release formulation was obtained from rats killed after day 7,day 14. Tissue was also taken from physiological saline treated pouches (control group) at day 7,day 14. Pouch tissues were weighted,wax embedded and stained with hematoxylin and eosin,observed under microscope. AKP of serium,IL-6 and TNF-a expression with immunohistochemical method, mRNA expression of EMMPRIN with real time PCR method and protein expression of EMMPRIN with westrern blotting method were measured. Results: Air pouch tissues situated in subcutaneous tissues, with distinct border, horsebean-size, small proliferous blood vessels in the surface, and fibroid tissues in some fields, similar to limiting membrane of periprothesis tissue in the cases of aseptic loosening. Air pouch tissues were incrassate in group A, it contained a small flexible nodule, which indicated the new bone ingrowth. As to pouch tissue weight,there was a significant difference between group A(day 14) and group A(day 7),group B(p<0.05). Microscopy illustrated no tissular and cellular reaction in both group A and group B.Evaluating of AKP of serium, there was a significant difference between group A(day 7) and group A(day 14),group B(p<0.05). With immunohistochemical method, there was a significant decrease with IL-6 expression in group A than in group B. With real time PCR method,there was a significant decrease with mRNA expression of EMMPRIN in group A than in group B,and in group A(day 14) than in group A(day 7). With western blotting method,there was a significant decrease with protein expression of EMMPRIN in group A than in group B,and in group A(day 14) than in group A(day 7). Conclusions: In one hand, rhBMP-2 slow release formulation stimulated the chemotaxis of osteoblasts/osteoblastlike cells, modulated expression of integrin, increased the speed of cell proliferation, so as to integrate osteoblasts into extracellular matrix, lead to new bone ingrowth;In the other hand, rhBMP-2 slow release formulation inhibited the production and activities of osteolytic cytokines, so as to inhibit osteolytic reaction.It afforded the possibility of using rhBMP-2 in the early prevetion of aseptic loosening.
PART THREE The experimental study of the feasibility of using rhBMP-2 slow release formulation to prevent prothetic aseptic loosening
Objective: To investigate the subcutaneous biological reaction interfered with rhBMP-2 slow release formulation in vivo in the rat air pouch model of aseptic loosening, analysis the biological activities of using rhBMP-2 to improve new bone ingrowth and inhibit the production and activities of osteolytic cytokines, so as to inhibit osteolytic reaction, evaluate the feasibility of early using rhBMP-2 in prevetion of aseptic loosening. Methods: Filtration air was injected subcutaneously into rats’back 6 times(3ml qod).Air pouch tissue treated with wear debris and interfered with rhBMP-2 slow release formulation was obtained from rats killed after day 7,day 14. Tissue was also taken from wear debris and physiological saline treated pouches (control group) at day 7,day 14. Pouch tissues were weighted,wax embedded and stained with hematoxylin and eosin,observed under microscope. AKP of serium,IL-6 and TNF-a expression with immunohistochemical method, mRNA expression of EMMPRIN with real time PCR method and protein expression of EMMPRIN with western blotting method were measured. Results: Air pouch tissues situated in subcutaneous tissues, with distinct border, horsebean-size. Air pouch tissues were incrassate in group A and group C, it contained a small flexible nodule, which indicated the new bone ingrowth.As to pouch tissue weight,there was a significant decrease in day 14 than in day 7 in each group(p<0.05). Microscopy illustrated a large amount of phagocytes in group B and D, compared with no tissular and cellular reaction in group A and group C.Evaluating AKP of serium, there was a significant difference in group A than in group B,in group C than in group D(p<0.05) in different stage of time. With immunohistochemical method, there was a significant decrease with IL-6 expression in group A than in group B,in group C than in group D. With real time PCR method,there was a significant decrease with mRNA expression of EMMPRIN in group A than in group B, in group C than in group D,and decrease in day 14 than in day 7. With western blotting method,there was a significant decrease with protein expression of EMMPRIN in group A than in group B, in group C than in group D,and decrease in day 14 than in day 7.Conclusions: RhBMP-2 slow release formulation improved new bone ingrowth, inhibited the expression of osteolytic cytokines mediated by wear particles. It indicated that early using rhBMP-2 to prevent prothetic aseptic loosening was feasible.
引文
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