rhBMP-7复合rhVEGF-165肌内诱生血管化组织工程化骨瓣的研究
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摘要
研究背景
复合有成骨诱导因子rhBMP-7的牛天然骨矿物BioOss颗粒会在肌肉中异位诱导成骨发生,从而实现可血管化移植的组织工程化骨(肌)瓣的异位预成。临床上成功地应用该技术在患者的背阔肌中预成个体化血管化的组织工程化骨瓣并通过移植该骨瓣修复下颌骨缺损。但该法预成的大块组织工程化骨瓣的成骨水平不高,特别是中心区域的成骨和血管化水平均欠理想,因此提高异位预成大块组织工程化骨瓣的成骨水平和血管化程度具有重要意义。
研究目的
相比单一应用rhBMP-7加载组织工程支架,复合应用rhBMP-7和血管形成诱导因子rhVEGF-165能否提高肌肉内异位预成大块组织工程化骨瓣的骨量、机械强度和血管化。
相比单一以BioOss颗粒作为内支架,复合应用自体松质骨颗粒(AB)和BioOss颗粒作为内支架,是否能提高肌内异位预成大块组织工程化骨的骨量和机械强度。
材料和方法
本研究以8只家猪为实验模型,并构建6组组织工程支架复合体。支架复合体以2.0x2.0x1.0cm~3的微孔钛网盒控制外形,内充填以6组不同的内支架,分别是BioOss/rhBMP-7、BioOss/AB、BioOss/AB/rhBMP-7、BioOss/rhBMP-7/rhVEGF-165、BioOss/AB/rhVEGF-165和BioOss/AB/rhBMP-7/rhVEGF-165,其中rhBMP-7的用量为660μg/支架、rhVEGF-165用量为4μg/支架。
将6组支架复合体植入8只家猪的双侧背阔肌内预成,并以多彩荧光标记各时期的成骨。12周后回收植入物,并制备成硬组织切片和圆柱形标准件。对于硬组织切片,应用微放射摄片技术、荧光显微镜观察、组织学观察等多种手段对预成骨瓣进行定性研究,并应用组织形态测量定量研究预成骨瓣的骨组织分布密度、残留BioOss分布密度、骨结合的BioOss比例和早期骨形成速度。对于圆柱形标准件,通过压缩试验定量分析各组标本的压缩强度。
结果
多彩荧光标记显示,新骨在支架植入2周后即已开始形成,而在第4、5周时最活跃,在第7周时则很微弱。应用rhVEGF-165的各组标本中多彩荧光条带分布较未应用rhVEGF-165者稠密,表明rhVEGF-165促进了早期新骨形成的分布。自体松质骨的应用并未明显提高早期新骨形成的分布。
组织学观察显示,复合应用两种生长因子加载于BioOss者其预成骨瓣的新骨和血管分布更加均匀,新骨板层结构明显。复合应用BioOss和AB者其预成骨瓣较单一应用BioOss者结构上更加成熟,且存在大量脂肪细胞。复合应用rhBMP-7和rhVEGF-165者其骨瓣内残留BioOss颗粒的骨结合较高。未结合骨组织的BioOss可被破骨细胞吸收,但过程较为缓慢。
在以BioOss为内支架的两组中,复合应用两种生长因子者预成骨瓣的骨组织分布密度为31.93%±4.31%,高于单用rhBMP-7者(t=3.567,P=0.023)。在以BioOss/AB为内支架的四组中,复合应用生长因子者骨组织分布密度为32.66%±4.55%,高于其它组(F=3.341,P=0.041)。在复合应用生长因子的两组中,未显示应用AB颗粒能提高骨组织分布密度。
复合应用生长因子rhBMP-7和rhVEGF-165者残留BioOss颗粒的骨结合程度为67.12%±15.29%,较单一应用rhBMP-7者高(t=2.866,P=0.045),而内支架中加用AB颗粒未提高BioOss颗粒的骨结合程度。
复合应用生长因子者其早期成骨速度与单一应用rhBMP-7者无明显差异,而进一步复合AB则会明显提高(t=2.630,P=0.046)。
压缩试验显示,复合应用生长因子加载BioOss者,其预成骨瓣的压缩强度为4.71±1.42MPa,高于单用rhBMP-7者(t=2.991,P=0.040),而应用自体松质骨颗粒又进一步提高预成骨瓣的压缩强度的趋势(5.84±1.60MPa),尽管尚未达到统计学意义(P=0.057)。
结论
复合应用成骨诱导因子rhBMP-7和血管形成诱导因子rhVEGF-165促进肌内预成的大块组织工程化骨瓣的早期成骨。
复合应用rhBMP-7和rhVEGF-165促进了肌内预成的大块组织工程化骨瓣的成骨和血管化,提高了BioOss的骨结合程度。
复合应用rhBMP-7和rhVEGF-165提高了肌内预成的大块组织工程骨瓣的压缩强度。
应用AB不能提高生长因子异位诱生的大块组织工程骨瓣的成骨分布密度。
应用AB提高了生长因子异位诱生的大块组织工程骨瓣的骨组织成熟度。
应用AB可能提高生长因子异位诱生的大块组织工程骨瓣的压缩强度。
复合应用成骨诱导因子rhBMP-7和血管形成诱导因子rhVEGF-165在肌内诱生大块血管化组织工程化骨瓣中起协同效应。
本研究为临床上复合应用两种生长因子异位诱生血管化的个体化大型组织工程骨瓣以修复骨缺损奠定了研究基础。
Backgrounds
rhBMP-7,a kind of osteoinductive factor,can induce heterotopic bone formation in muscles,when being carried on BioOss which is a kind of bovine bone minerals.In this way,a vascularized tissue engineered bone graft can be prefabricated in muscles for further transplantation.This technique was applied clinically to prefabricate a large-size tissue engineered bone graft in latissmus dorsi muscle,with which a mandibular defect was successfully repaired.However,the rhBMP-7-induced bone formation as well as vessel density is still low in the central area of the implanted scaffold,especially when the scaffold is large.Therefore,it is necessary and scientifically meaningful to improve bone formation and vascularization of the heterotopic-engineered bone graft.
Objectives
A main objective of this study was to investigate the possibility of improving bone quantity,vascularization and the compression resistance of the in-muscle engineered bone graft by combination of rhBMP-7 and rhVEGF-165,an intense angiogenic factor.
The other objective was to investigate the potential advantages of combination of autogenous sponge bone granules(AB) and BioOss over BioOss alone as the scaffold in the heterotopic prefabrication of large engineered bone graft in muscles.
Methods
Eight house pigs were applied as the experimental model in the present study.Six various groups of scaffold were fabricated.These scaffolds were composed of the external scaffold that was a micro-mesh titanium box of 2.0×2.0×1.0cm~3 in size and the internal scaffold which was filled in the titanium box and varied between different groups of scaffold.The various internal scaffolds were:(1) 660μg rhBMP-7-carrying BioOss granules,(2) BioOss granules and AB granules,(3) 660μg rhBMP-7-carrying BioOss granules and AB granules,(4) 660μg rhBMP-7 and 4μg rhVEGF 165-carrying BioOss granules,(5) 4μg rhVEGF165-carrying BioOss granules and AB granules,and (6) 660μg rhBMP-7 and 4μg rhVEGF165-carrying BioOss granules and AB granules.
The six groups of scaffold were implanted into the bilateral lattissmus dorsi muscles in all pigs to prefabricate tissue-engineered bone grafts.Polychrome fluorescence labeling was performed sequently.After 12 weeks the implanted constructs were retrieved and used to make undecalcified sections and standard cylinders. Microradiography,fluorescence microscopy and histological microscopy were performed based on the sections to qualitatively investigate the implanted constructs. Further,histomorphometry was done to examine bone distribution density(BD), residual BioOss density(RBOB),percentage of osteointegrated BioOss(POB) and the early-stage mineral apposition rate(MAR).The cylinders were used to test the compressive strength(CS).
Results
Bone formation began at week 2,was active at week 4 and 5 but rare at week 7,as was indicated by polychrome fluorescence labeling.Application of rhVEGF-165,along with rhBMP-7,led to rich and evenly distributed multiple color bands,indicating that rhVEGF-165 propelled early-stage bone formation which was induced by rhBMP-7.
However,the application of AB failed to benefit early bone formation.
Histologically,the combination of osteogenic and angiogenic factors,as well as the application of AB,led to evenly distributed and mature bone and vessels within the scaffolds.Moreover,the application of AB led to more adipocytes and increased the maturity of the bone structure.The combination of osteogenic and angiogenic factors enhanced osteointegration of the BioOss granules,whatever AB/BioOss or BioOss alone as the internal scaffold.The nonintegrated BioOss granules were degraded by osteoclasts in a very slow rate.
When loaded on BioOss granules,the combination of osteogenic and angiogenic factors led to higher BD(31.93%±4.31%) than the application of rhBMP-7 alone (t=3.567,P=0.023).Among the four groups with AB/BioOss as the internal scaffold,the combined application of osteogenic and angiogenic factors reached the highest BD (32.66%±4.55%)(F=3.341,P=0.041).However,the combination of AB and BioOss failed to show any advantage over BioOss alone in BD.
When the BioOss granules were loaded with both rhBMP-7 and rhVEGF-165, POB was 67.12%±15.29%and higher than those loaded with rhBMP-7 alone(t=2.866, P=0.045).The application of AB granules failed to enhance POB.
The combination of rhBMP-7 and rhVEGF-165 failed to show any advantage over rhBMP-7 alone of improving early-stage mineral apposition rate.However,the rate became higher when AB granules were applied along with rhBMP-7 and rhVEGF-165 (t=2.630,P=0.046).
CS was 4.71±1.42MPa when BioOss granules were loaded with both rhBMP-7 and rhVEGF-165,and was higher than when with rhBMP-7 alone(t=2.991,P=0.040). The further application of AB,with CS of 5.84±1.60MPa,seemed to enhance compressive strength,although still not enough to reach statistical significance (P=0.057).
Conclusions The combination of rhBMP-7 and rhVEGF-165 benefits the early-stage bone formation in muscles.
The combination of rhBMP-7 and rhVEGF-165 enhances mineralization, vascularization and BioOss osteointegration of the heterotopic induced bone graft in muscles.
The combination of rhBMP-7 and rhVEGF-165 improves compressive strength of the heterotopic tissue engineered bone graft in muscles.
The application of autogenous spongy bone(AB) granules fails to improve bone quantity of the growth factor(s)-induced bone graft in muscles.
The application of AB granules improves the maturity of the growth factor(s)-induced bone graft in muscles.
The application of AB granules might enhance the compressive strength of the growth factor(s)-induced bone graft in muscles.
The osteogenic factor rhBMP-7 and the angiogenic factor rhVEGF-165 are synergic in inducing large-size bone graft in muscles.
The present study proves the potentiality of prefabricating a highly mineralized and vascularized tissue-engineered bone graft in heterotopic sites(muscles) by the combination of osteogenic and angiogenic factors,which can be transplanted to repair bone defect.
复合有成骨诱导因子rhBMP-7的牛天然骨矿物BioOss颗粒会在肌肉中异位诱导成骨发生,从而实现可血管化移植的组织工程化骨(肌)瓣的异位预成。临床上成功地应用该技术在患者的背阔肌中预成个体化血管化的组织工程化骨瓣并通过移植该骨瓣修复下颌骨缺损。但该法预成的大块组织工程化骨瓣的成骨水平不高,特别是中心区域的成骨和血管化水平均欠理想,因此提高异位预成大块组织工程化骨瓣的成骨水平和血管化程度具有重要意义。
研究目的
相比单一应用rhBMP-7加载组织工程支架,复合应用rhBMP-7和血管形成诱导因子rhVEGF-165能否提高肌肉内异位预成大块组织工程化骨瓣的骨量、机械强度和血管化。
相比单一以BioOss颗粒作为内支架,复合应用自体松质骨颗粒(AB)和BioOss颗粒作为内支架,是否能提高肌内异位预成大块组织工程化骨的骨量和机械强度。
材料和方法
本研究以8只家猪为实验模型,并构建6组组织工程支架复合体。支架复合体以2.0x2.0x1.0cm~3的微孔钛网盒控制外形,内充填以6组不同的内支架,分别是BioOss/rhBMP-7、BioOss/AB、BioOss/AB/rhBMP-7、BioOss/rhBMP-7/rhVEGF-165、BioOss/AB/rhVEGF-165和BioOss/AB/rhBMP-7/rhVEGF-165,其中rhBMP-7的用量为660μg/支架、rhVEGF-165用量为4μg/支架。
将6组支架复合体植入8只家猪的双侧背阔肌内预成,并以多彩荧光标记各时期的成骨。12周后回收植入物,并制备成硬组织切片和圆柱形标准件。对于硬组织切片,应用微放射摄片技术、荧光显微镜观察、组织学观察等多种手段对预成骨瓣进行定性研究,并应用组织形态测量定量研究预成骨瓣的骨组织分布密度、残留BioOss分布密度、骨结合的BioOss比例和早期骨形成速度。对于圆柱形标准件,通过压缩试验定量分析各组标本的压缩强度。
结果
多彩荧光标记显示,新骨在支架植入2周后即已开始形成,而在第4、5周时最活跃,在第7周时则很微弱。应用rhVEGF-165的各组标本中多彩荧光条带分布较未应用rhVEGF-165者稠密,表明rhVEGF-165促进了早期新骨形成的分布。自体松质骨的应用并未明显提高早期新骨形成的分布。
组织学观察显示,复合应用两种生长因子加载于BioOss者其预成骨瓣的新骨和血管分布更加均匀,新骨板层结构明显。复合应用BioOss和AB者其预成骨瓣较单一应用BioOss者结构上更加成熟,且存在大量脂肪细胞。复合应用rhBMP-7和rhVEGF-165者其骨瓣内残留BioOss颗粒的骨结合较高。未结合骨组织的BioOss可被破骨细胞吸收,但过程较为缓慢。
在以BioOss为内支架的两组中,复合应用两种生长因子者预成骨瓣的骨组织分布密度为31.93%±4.31%,高于单用rhBMP-7者(t=3.567,P=0.023)。在以BioOss/AB为内支架的四组中,复合应用生长因子者骨组织分布密度为32.66%±4.55%,高于其它组(F=3.341,P=0.041)。在复合应用生长因子的两组中,未显示应用AB颗粒能提高骨组织分布密度。
复合应用生长因子rhBMP-7和rhVEGF-165者残留BioOss颗粒的骨结合程度为67.12%±15.29%,较单一应用rhBMP-7者高(t=2.866,P=0.045),而内支架中加用AB颗粒未提高BioOss颗粒的骨结合程度。
复合应用生长因子者其早期成骨速度与单一应用rhBMP-7者无明显差异,而进一步复合AB则会明显提高(t=2.630,P=0.046)。
压缩试验显示,复合应用生长因子加载BioOss者,其预成骨瓣的压缩强度为4.71±1.42MPa,高于单用rhBMP-7者(t=2.991,P=0.040),而应用自体松质骨颗粒又进一步提高预成骨瓣的压缩强度的趋势(5.84±1.60MPa),尽管尚未达到统计学意义(P=0.057)。
结论
复合应用成骨诱导因子rhBMP-7和血管形成诱导因子rhVEGF-165促进肌内预成的大块组织工程化骨瓣的早期成骨。
复合应用rhBMP-7和rhVEGF-165促进了肌内预成的大块组织工程化骨瓣的成骨和血管化,提高了BioOss的骨结合程度。
复合应用rhBMP-7和rhVEGF-165提高了肌内预成的大块组织工程骨瓣的压缩强度。
应用AB不能提高生长因子异位诱生的大块组织工程骨瓣的成骨分布密度。
应用AB提高了生长因子异位诱生的大块组织工程骨瓣的骨组织成熟度。
应用AB可能提高生长因子异位诱生的大块组织工程骨瓣的压缩强度。
复合应用成骨诱导因子rhBMP-7和血管形成诱导因子rhVEGF-165在肌内诱生大块血管化组织工程化骨瓣中起协同效应。
本研究为临床上复合应用两种生长因子异位诱生血管化的个体化大型组织工程骨瓣以修复骨缺损奠定了研究基础。
Backgrounds
rhBMP-7,a kind of osteoinductive factor,can induce heterotopic bone formation in muscles,when being carried on BioOss which is a kind of bovine bone minerals.In this way,a vascularized tissue engineered bone graft can be prefabricated in muscles for further transplantation.This technique was applied clinically to prefabricate a large-size tissue engineered bone graft in latissmus dorsi muscle,with which a mandibular defect was successfully repaired.However,the rhBMP-7-induced bone formation as well as vessel density is still low in the central area of the implanted scaffold,especially when the scaffold is large.Therefore,it is necessary and scientifically meaningful to improve bone formation and vascularization of the heterotopic-engineered bone graft.
Objectives
A main objective of this study was to investigate the possibility of improving bone quantity,vascularization and the compression resistance of the in-muscle engineered bone graft by combination of rhBMP-7 and rhVEGF-165,an intense angiogenic factor.
The other objective was to investigate the potential advantages of combination of autogenous sponge bone granules(AB) and BioOss over BioOss alone as the scaffold in the heterotopic prefabrication of large engineered bone graft in muscles.
Methods
Eight house pigs were applied as the experimental model in the present study.Six various groups of scaffold were fabricated.These scaffolds were composed of the external scaffold that was a micro-mesh titanium box of 2.0×2.0×1.0cm~3 in size and the internal scaffold which was filled in the titanium box and varied between different groups of scaffold.The various internal scaffolds were:(1) 660μg rhBMP-7-carrying BioOss granules,(2) BioOss granules and AB granules,(3) 660μg rhBMP-7-carrying BioOss granules and AB granules,(4) 660μg rhBMP-7 and 4μg rhVEGF 165-carrying BioOss granules,(5) 4μg rhVEGF165-carrying BioOss granules and AB granules,and (6) 660μg rhBMP-7 and 4μg rhVEGF165-carrying BioOss granules and AB granules.
The six groups of scaffold were implanted into the bilateral lattissmus dorsi muscles in all pigs to prefabricate tissue-engineered bone grafts.Polychrome fluorescence labeling was performed sequently.After 12 weeks the implanted constructs were retrieved and used to make undecalcified sections and standard cylinders. Microradiography,fluorescence microscopy and histological microscopy were performed based on the sections to qualitatively investigate the implanted constructs. Further,histomorphometry was done to examine bone distribution density(BD), residual BioOss density(RBOB),percentage of osteointegrated BioOss(POB) and the early-stage mineral apposition rate(MAR).The cylinders were used to test the compressive strength(CS).
Results
Bone formation began at week 2,was active at week 4 and 5 but rare at week 7,as was indicated by polychrome fluorescence labeling.Application of rhVEGF-165,along with rhBMP-7,led to rich and evenly distributed multiple color bands,indicating that rhVEGF-165 propelled early-stage bone formation which was induced by rhBMP-7.
However,the application of AB failed to benefit early bone formation.
Histologically,the combination of osteogenic and angiogenic factors,as well as the application of AB,led to evenly distributed and mature bone and vessels within the scaffolds.Moreover,the application of AB led to more adipocytes and increased the maturity of the bone structure.The combination of osteogenic and angiogenic factors enhanced osteointegration of the BioOss granules,whatever AB/BioOss or BioOss alone as the internal scaffold.The nonintegrated BioOss granules were degraded by osteoclasts in a very slow rate.
When loaded on BioOss granules,the combination of osteogenic and angiogenic factors led to higher BD(31.93%±4.31%) than the application of rhBMP-7 alone (t=3.567,P=0.023).Among the four groups with AB/BioOss as the internal scaffold,the combined application of osteogenic and angiogenic factors reached the highest BD (32.66%±4.55%)(F=3.341,P=0.041).However,the combination of AB and BioOss failed to show any advantage over BioOss alone in BD.
When the BioOss granules were loaded with both rhBMP-7 and rhVEGF-165, POB was 67.12%±15.29%and higher than those loaded with rhBMP-7 alone(t=2.866, P=0.045).The application of AB granules failed to enhance POB.
The combination of rhBMP-7 and rhVEGF-165 failed to show any advantage over rhBMP-7 alone of improving early-stage mineral apposition rate.However,the rate became higher when AB granules were applied along with rhBMP-7 and rhVEGF-165 (t=2.630,P=0.046).
CS was 4.71±1.42MPa when BioOss granules were loaded with both rhBMP-7 and rhVEGF-165,and was higher than when with rhBMP-7 alone(t=2.991,P=0.040). The further application of AB,with CS of 5.84±1.60MPa,seemed to enhance compressive strength,although still not enough to reach statistical significance (P=0.057).
Conclusions The combination of rhBMP-7 and rhVEGF-165 benefits the early-stage bone formation in muscles.
The combination of rhBMP-7 and rhVEGF-165 enhances mineralization, vascularization and BioOss osteointegration of the heterotopic induced bone graft in muscles.
The combination of rhBMP-7 and rhVEGF-165 improves compressive strength of the heterotopic tissue engineered bone graft in muscles.
The application of autogenous spongy bone(AB) granules fails to improve bone quantity of the growth factor(s)-induced bone graft in muscles.
The application of AB granules improves the maturity of the growth factor(s)-induced bone graft in muscles.
The application of AB granules might enhance the compressive strength of the growth factor(s)-induced bone graft in muscles.
The osteogenic factor rhBMP-7 and the angiogenic factor rhVEGF-165 are synergic in inducing large-size bone graft in muscles.
The present study proves the potentiality of prefabricating a highly mineralized and vascularized tissue-engineered bone graft in heterotopic sites(muscles) by the combination of osteogenic and angiogenic factors,which can be transplanted to repair bone defect.
引文
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