脱细胞羊膜在兔股骨近端诱导成骨的实验研究
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摘要
目的:
初步探讨人完全脱细胞羊膜(human acellular amniotic membrane,HAAM)的在兔股骨近端的成骨诱导能力,为羊膜作为骨组织工程自然衍发基质提供实验依据,进而为骨缺损和骨融合的治疗提供新的治疗思路。
方法:
使用本课题组研发的羊膜无酸碱脱细胞专利技术制取HAAM,约2.0cm×2.0cm大小,做成约为0.5cm×0.4cm×0.3cm大小卷团状。27只成年大耳白兔,随机分为羊膜组、PLGA组和空白对照组,每组进而分为1周、2周、4周三小组,每小组3只。空白对照组在兔股骨背侧近端(大转子下)单纯制作直径约0.6cm的骨缺损,而羊膜组在兔股骨近端骨缺损处植入HAAM,PLGA组则植入PLGA(约0.5cm×0.4cm×0.3cm大小)。分别在1、2、4周时处死兔子,截取标记的骨缺损部位。甲醛固定后常规石蜡定向包埋,切片,分别对其行HE染色,光学显微镜组织学观察和免疫组织化学染色,对比观察各组骨缺损处的成骨能力。
结果:
组织学观察:术后1周时,羊膜组中血管长入层状排列的羊膜基质之间,大量的间充质细胞随血管一起侵入羊膜基质间隙。细胞附着于羊膜表面,并沿羊膜基质纤维方向成极性生长。在羊膜与髓腔交界处向植入物内部延伸。未见炎性攻击和液化现象;PLGA组血细胞侵入PLGA间隙,细胞同PLGA表面未粘附。未见免疫攻击及炎性反应。空白组骨缺损处血肿形成,可见大量红细胞、间充质细胞、脂肪滴及毛细血管。术后2周时,羊膜组中HAAM被进一步吸收,血管生成减少,紧贴HAAM基质边缘,间充质细胞分化为软骨细胞,软骨细胞后方跟随着一层较厚的较成熟软骨组织。细胞在材料表面黏附良好,且在羊膜空隙中相互之间有突起连接,形成网状结构。PLGA组中PLGA开始软化降解,PLGA间隙形成肉芽组织,未见软骨细胞。空白组骨缺损处演变转化为肉芽组织,血管生成活跃。术后4周时,羊膜组中羊膜组织基本消失,血管生成减少,肥大的软骨细胞增多,骨缺损处逐渐填充以软骨组织。PLGA组中PLGA降解残余部分可见细胞附着,肉芽组织中血管丰富,但未见软骨细胞及成骨现象。空白组中骨缺损处填充肉芽组织,血管生成仍然活跃,未见向软骨及骨组织转化的迹象。VEGF染色观察:术后1周时,羊膜组在HAAM表面及间隙呈阳性表达,PLGA组PLGA膜间隙中有散在的着色,空白组很少表达。术后2周时,羊膜组新生血管周围呈较强阳性表达,PLGA组表达稍弱,空白组散在表达阳性。4周时,羊膜组软骨组织内幼稚的软骨细胞VEGF表达阴性,成熟和肥大的软骨细胞较强阳性表达,在与原始骨小梁相连处的肥大软骨细胞亦呈较强阳性表达。此时,PLGA组随血管的长入表达开始增强。空白组因为肉芽组织中毛细血管丰富表达活跃。BMPs染色观察:术后1周时,各组的血管附近均呈较强阳性表达。术后2周时,羊膜组新生血管周围呈较强阳性表达,PLGA组表达减弱,空白组散在表达阳性。4周时,羊膜组软骨细胞表达阴性,成熟和肥大的软骨细胞阳性表达稍强。PLGA组随血管的长入表达开始增强。空白组阳性表达转强。
结论:
相比于PLGA和空白对照,HAAM在兔股骨近端骨缺损区具有更好的成骨诱导作用,可以作为骨组织工程自然衍发基质材料候选物,为骨缺损和骨融合的治疗提供新的治疗思路。
Objectives:
To explore the osteoinductive capability of the human acellular amniotic membrane(HAAM)in proximal femur of adult rabbits,to provides the basis of HAAM as the bone tissue engineering natural occurring matrix,and provides a new treatment idea for the treatment of bone defects and for bone fusion.
Methods:
The HAAM was created by the patented technologies of the amniotic cells from non-acid-base system.27 adult rabbits were divided into 3 groups of HAAM,PLGA and the blank control group,and observed in 1,2,4 weeks after implantion.The bone defects were made in dorsal of femur,just below the great trochanter,0.6 cm in diameter.In group HAAM and PLGA,the defects filled with HAAM,PLGA,and the blank control group only sutured.The rabbits were sacrificed by the end of 1,2,4 weeks.Obtain the marked site of bone defect.Fixed with formaldehyde,embedded into paraffin,and sliced in routine.The light microscopy was applied as the pathologic morphology observation.The immunochemistry was applied as the specific expression of VEGF and BMPs for explore the potential ability for bone inductivity.
Results:
Histological morphology observation:After one week,in group HAAM, vasculars and a large number of mesenchymal cells intruded into the space of HAAM. The cells attached to the surface of HAAM,and the cells' mophologic along the amniotic matrix fiber.No inflammatory attacks and liquefaction phenomenon.In group PLGA,the blood cells intruded into the space of PLGA,there was no adhesion between cells and the surface of PLGA.No immune and inflammatory response.In the blank control group,hematoma formed in the bone defects,a large number of red blood cells,mesenchymal cells,fat drops and capillaries can be observed.After two weeks,in group HAAM,the further absorption and reduce angiogenesis can be observed;close to the edge HAAM layers,mesenchymal cells into cartilage cells, cartilage cells following a thick layers of new formed bone matrix.Cell adhered to the surface of HAAM,and the processes connected forming a network structure.In group PLGA,PLGA began to soften and degradation,granulation tissue formed in the space of PLGA,but no cartilage cells.In blank control group,granulation tissue can be observed in bone defects,angiogenesis actively.After four weeks,in group HAAM,the amniotic organizations disappeared,angiogenesis reduce,the hypertrophy cartilage cells increased,bone defects gradually filled with cartilage.In group PLGA,cells adhered to the residual of PLGA,granulation tissue rich in blood vessels,but no cartilage cells and osteoinductive phenomenon.In blank control group, the bone defect filled with granulation tissue,angiogenesis is still active,but no cartilage and bone tissue.
Immunochemistry observation:(1)VEGF:After one week,in group HAAM, the VEGF positive expression at the surface and space of HAAM;in group PLGA, the positive expression scattered in hematoma and;in the control group,the expression rarely.After two weeks,in group HAAM,strong expression can be observed around angiogenesis;in group PLGA,fewer positive expression can be observed;in the control group,positive expression diffused distribution.After four weeks,in group HAAM,the naive cartilage cells' VEGF expression negative, matured and hypertrophy cartilage cells color darked,the hypertrophy cartilage cells in the area of original bone connected to cartilage were more positive.In group PLGA,the expression of VEGF enhance with the intrusion of vascular.In blank control group,the expression highly because of the rich capillaries in granulation tissue.(2)BMPs:After 1 week,in group HAAM and PLGA,positive expression highly can be observed around vessels in every group.After two weeks,in group HAAM,there is a strong positive expression around angiogenesis,in group PLGA, the expression fewer than group HAAM;in the control group,positive expression scattered distribution.After four weeks,in group HAAM,the cartilage cells expressed negative.In group PLGA,the expression highly with the intrusion of vessels.In the control group,the expression increased.
Conclusions:
Compared to PLGA and blank control,HAAM have a better osteoinductive capabilities in rabbit femur,can be used as material candidate of bone tissue engineering natural occurring matrix,provide a new treatment idea for the treatment of bone defects and for bone fusion.
初步探讨人完全脱细胞羊膜(human acellular amniotic membrane,HAAM)的在兔股骨近端的成骨诱导能力,为羊膜作为骨组织工程自然衍发基质提供实验依据,进而为骨缺损和骨融合的治疗提供新的治疗思路。
方法:
使用本课题组研发的羊膜无酸碱脱细胞专利技术制取HAAM,约2.0cm×2.0cm大小,做成约为0.5cm×0.4cm×0.3cm大小卷团状。27只成年大耳白兔,随机分为羊膜组、PLGA组和空白对照组,每组进而分为1周、2周、4周三小组,每小组3只。空白对照组在兔股骨背侧近端(大转子下)单纯制作直径约0.6cm的骨缺损,而羊膜组在兔股骨近端骨缺损处植入HAAM,PLGA组则植入PLGA(约0.5cm×0.4cm×0.3cm大小)。分别在1、2、4周时处死兔子,截取标记的骨缺损部位。甲醛固定后常规石蜡定向包埋,切片,分别对其行HE染色,光学显微镜组织学观察和免疫组织化学染色,对比观察各组骨缺损处的成骨能力。
结果:
组织学观察:术后1周时,羊膜组中血管长入层状排列的羊膜基质之间,大量的间充质细胞随血管一起侵入羊膜基质间隙。细胞附着于羊膜表面,并沿羊膜基质纤维方向成极性生长。在羊膜与髓腔交界处向植入物内部延伸。未见炎性攻击和液化现象;PLGA组血细胞侵入PLGA间隙,细胞同PLGA表面未粘附。未见免疫攻击及炎性反应。空白组骨缺损处血肿形成,可见大量红细胞、间充质细胞、脂肪滴及毛细血管。术后2周时,羊膜组中HAAM被进一步吸收,血管生成减少,紧贴HAAM基质边缘,间充质细胞分化为软骨细胞,软骨细胞后方跟随着一层较厚的较成熟软骨组织。细胞在材料表面黏附良好,且在羊膜空隙中相互之间有突起连接,形成网状结构。PLGA组中PLGA开始软化降解,PLGA间隙形成肉芽组织,未见软骨细胞。空白组骨缺损处演变转化为肉芽组织,血管生成活跃。术后4周时,羊膜组中羊膜组织基本消失,血管生成减少,肥大的软骨细胞增多,骨缺损处逐渐填充以软骨组织。PLGA组中PLGA降解残余部分可见细胞附着,肉芽组织中血管丰富,但未见软骨细胞及成骨现象。空白组中骨缺损处填充肉芽组织,血管生成仍然活跃,未见向软骨及骨组织转化的迹象。VEGF染色观察:术后1周时,羊膜组在HAAM表面及间隙呈阳性表达,PLGA组PLGA膜间隙中有散在的着色,空白组很少表达。术后2周时,羊膜组新生血管周围呈较强阳性表达,PLGA组表达稍弱,空白组散在表达阳性。4周时,羊膜组软骨组织内幼稚的软骨细胞VEGF表达阴性,成熟和肥大的软骨细胞较强阳性表达,在与原始骨小梁相连处的肥大软骨细胞亦呈较强阳性表达。此时,PLGA组随血管的长入表达开始增强。空白组因为肉芽组织中毛细血管丰富表达活跃。BMPs染色观察:术后1周时,各组的血管附近均呈较强阳性表达。术后2周时,羊膜组新生血管周围呈较强阳性表达,PLGA组表达减弱,空白组散在表达阳性。4周时,羊膜组软骨细胞表达阴性,成熟和肥大的软骨细胞阳性表达稍强。PLGA组随血管的长入表达开始增强。空白组阳性表达转强。
结论:
相比于PLGA和空白对照,HAAM在兔股骨近端骨缺损区具有更好的成骨诱导作用,可以作为骨组织工程自然衍发基质材料候选物,为骨缺损和骨融合的治疗提供新的治疗思路。
Objectives:
To explore the osteoinductive capability of the human acellular amniotic membrane(HAAM)in proximal femur of adult rabbits,to provides the basis of HAAM as the bone tissue engineering natural occurring matrix,and provides a new treatment idea for the treatment of bone defects and for bone fusion.
Methods:
The HAAM was created by the patented technologies of the amniotic cells from non-acid-base system.27 adult rabbits were divided into 3 groups of HAAM,PLGA and the blank control group,and observed in 1,2,4 weeks after implantion.The bone defects were made in dorsal of femur,just below the great trochanter,0.6 cm in diameter.In group HAAM and PLGA,the defects filled with HAAM,PLGA,and the blank control group only sutured.The rabbits were sacrificed by the end of 1,2,4 weeks.Obtain the marked site of bone defect.Fixed with formaldehyde,embedded into paraffin,and sliced in routine.The light microscopy was applied as the pathologic morphology observation.The immunochemistry was applied as the specific expression of VEGF and BMPs for explore the potential ability for bone inductivity.
Results:
Histological morphology observation:After one week,in group HAAM, vasculars and a large number of mesenchymal cells intruded into the space of HAAM. The cells attached to the surface of HAAM,and the cells' mophologic along the amniotic matrix fiber.No inflammatory attacks and liquefaction phenomenon.In group PLGA,the blood cells intruded into the space of PLGA,there was no adhesion between cells and the surface of PLGA.No immune and inflammatory response.In the blank control group,hematoma formed in the bone defects,a large number of red blood cells,mesenchymal cells,fat drops and capillaries can be observed.After two weeks,in group HAAM,the further absorption and reduce angiogenesis can be observed;close to the edge HAAM layers,mesenchymal cells into cartilage cells, cartilage cells following a thick layers of new formed bone matrix.Cell adhered to the surface of HAAM,and the processes connected forming a network structure.In group PLGA,PLGA began to soften and degradation,granulation tissue formed in the space of PLGA,but no cartilage cells.In blank control group,granulation tissue can be observed in bone defects,angiogenesis actively.After four weeks,in group HAAM,the amniotic organizations disappeared,angiogenesis reduce,the hypertrophy cartilage cells increased,bone defects gradually filled with cartilage.In group PLGA,cells adhered to the residual of PLGA,granulation tissue rich in blood vessels,but no cartilage cells and osteoinductive phenomenon.In blank control group, the bone defect filled with granulation tissue,angiogenesis is still active,but no cartilage and bone tissue.
Immunochemistry observation:(1)VEGF:After one week,in group HAAM, the VEGF positive expression at the surface and space of HAAM;in group PLGA, the positive expression scattered in hematoma and;in the control group,the expression rarely.After two weeks,in group HAAM,strong expression can be observed around angiogenesis;in group PLGA,fewer positive expression can be observed;in the control group,positive expression diffused distribution.After four weeks,in group HAAM,the naive cartilage cells' VEGF expression negative, matured and hypertrophy cartilage cells color darked,the hypertrophy cartilage cells in the area of original bone connected to cartilage were more positive.In group PLGA,the expression of VEGF enhance with the intrusion of vascular.In blank control group,the expression highly because of the rich capillaries in granulation tissue.(2)BMPs:After 1 week,in group HAAM and PLGA,positive expression highly can be observed around vessels in every group.After two weeks,in group HAAM,there is a strong positive expression around angiogenesis,in group PLGA, the expression fewer than group HAAM;in the control group,positive expression scattered distribution.After four weeks,in group HAAM,the cartilage cells expressed negative.In group PLGA,the expression highly with the intrusion of vessels.In the control group,the expression increased.
Conclusions:
Compared to PLGA and blank control,HAAM have a better osteoinductive capabilities in rabbit femur,can be used as material candidate of bone tissue engineering natural occurring matrix,provide a new treatment idea for the treatment of bone defects and for bone fusion.
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75.邱彦,芮耀诚.血管内皮生长因子血管通透作用研究进展.药学实践杂志,2002,20(4):228-230
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79.Bussolino F,Mantovani A,Persico G.Molecular mechanisms of blood vessel formation.TIBS,1997,22:251
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81. Feng D, Nagy JA, Hipp J, et al. Vesieulo-vacuola/organelles and the regu lation of venule perm eability to macromolecules by vaseular perm eability factor, histamlne, and serotonin. J Exp Med, 1996, 183: 1981
82. 19 Zhang QX, Magovern CJ, Mack CA, et al. Vascular endothelial growth factor is the major an ogenic factor in omentum : mechanism of the omentum-mediated angiogenesis. J Surg Res, 1997, 67(2): 147-154
83. Midy V, Plouet J. Vasculotropin / vascular endothelialgrowth factor induces differentiation of cultured osteoblasts. Biochem Biophys Res Commun. 1994, 199:380-386
84. Wang S, Miura M, Demura H, et al. Anablic effects of 1 、25-Dihydroxyvitamin D3 on osteoblasts are enhanced by vascular endothelial growth factor Droduced by osteoblasts and factors Droduce by endothelial cells [J]. Endocrinology, 1997, 138: 2953-2962
85. Street J, Bao M, deGuzman L, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover [J]. Proc Natl Acad Sci USA, 2002, 99(15): 9656-61
86. Chang CS, Su CY, Lin TC. Scanning electron microscopy observation of vascularization around hydro xyapatite using vascular corrosion casts [J]. J Biomed Mater Res, 1999, 48(4): 411-416
87. Wu X, Rahkin Aikawa E, Guleserian K J, et al. Tissue-engineered microvessels on three-dimensional biodegradable scaffolds using hu man endothelial progenitor cells[J]. Am J Physiol Heart Circ Physiol, 2004, 287(2): H480-487
88. Murphy W L, Peters M C, Kohn D H, et al. Sustained release of vascular endothelial growth factor from mineralized poly(lactide-co-gly-colide) scaffolds for tissue engineering [J]. Biomaterials, 2000, 21 (24): 2521-27
89. Murphy WL, Simmons CA, KaiglerD, et al. Bone regeneration via a mineral substrate and induced angiogenesis [J]. J Dent Res, 2004, 83(3): 204-210
90.Murphy W L,Peters M C,Kohn D H,et al.Sustained release of vascular endothelial growth factor from mineralized poly(lactide-co-gly-colide)scaffolds for tissue engineering[J].Biomaterials,2000,21(24):2521-27
91.Murphy W L,Simmons C A,Kaigler D,et al.Bone regeneration via a mineral substrate and induced angiogenesis[J].J Dent Res,2004,83(3):204-210
92.李强,何清义.VEGF促进骨组织工程血管化的研究进展.第三军医大学学报,27(16):1704-1707
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