Nano-HA/BCP/Cs复合rhBMP-2兔脊柱融合的初步研究
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摘要
目的：
使用经纳米羟基磷灰石修饰的双相磷酸钙陶瓷与壳聚糖复合得到复合材料A(Nano-HA/BCP/Cs),并将其作为rhBMP-2的载体得到复合材料B(Nano-HA/BCP/Cs/rhBMP-2)。将A、B两种复合材料分别植入兔腰椎后外侧横突间行植骨融合,观察两种复合材料在兔脊柱融合中的骨替代特点并探讨其成骨机理,为进一步完善及优化材料提供动物试验依据。
方法：
48只骨骼发育成熟日本耳大白兔(年龄,1-1.5岁；体重,2.5-3.5 kg)随机分为3组,每组16只,行腰5、6横突间植骨融合,植入复合材料或自体髂骨。A组植入纳米羟基磷灰石／双相磷酸钙／壳聚糖(Nano-HA/BCP/Cs)复合材料；B组植入纳米羟基磷灰石／双相磷酸钙／壳聚糖/rhBMP-2(Nano-HA/β-TCP/Cs/rhBMP-2)复合材料；C组植入自体髂骨(AIBG)。分别于术后4周、8周行X线摄片、CT扫描；术后8周影像学检查后空气栓塞处死行大体观察、手触检测及组织学观察。
结果：
1.实验动物术后一般情况良好,当日动物清醒,开始饮水,次日开始进食；术后切口I／甲愈合,切口无明显出血、红肿、渗出及感染、化脓等并发症,未见神经系统并发症、植入物排异反应及过敏反应。
2.根据Curylo等制定的放射学评分标准,术后4周X线检查三组总体坚固融合百分比的差异有统计学意义(P<0.05),C组融合率较A组和B组高；但A组与B组比较差异无统计学意义(P>0.05)。术后8周三组总体坚固融合百分比的差异有统计学意义(P<0.05),C组融合率较A组和B组高；A组与B组比较差异有统计学意义(P<0.05),B组融合率较A组高。
3.术后4周时CT检查A组均不融合,B组只有1例评定为融合,C组有12例融合,总体比较P<0.05,差异有统计学意义；A组和B组比较P＞0.05,差异无统计学意义；B组和C组比较P<0.05,差异有统计学意义；A组和C组比较P<0.05,差异有统计学意义。术后8周时CT检查A组的标本均无融合,B组未融合的标本较多(11例),坚固融合的比率低,C组大部分标本(15例)获得坚固融合。总体比较P<0.05,差异有统计学意义；A组和B组比较P<0.05,差异有统计学意义；B组和C组比较P<0.05,差异有统计学意义；A组和C组比较P<0.05,差异有统计学意义。影像学检查见A、B两组复合材料内部均有大量高密度材料残留。
4.术后8周取材大体观察A组材料与周围肌肉组织结合紧密,未见纤维囊包裹及囊腔形成；复合材料周围组织未见感染、坏死、化脓、积液等,双侧上下横突间仍为材料,有部分降解,表面孔径增大,孔内有较多组织长入；B组材料周围组织无感染、坏死、积液等,材料与周围肌肉组织结合紧密,无纤维囊包裹及囊腔形成,4例可见明显融合,其余标本上下横突间仍为材料,表面孔内大量组织长入；C组移植髂骨与周围组织结合紧密,15例可见自体骨与上下横突交界处有大量骨痂形成,为骨性结合,上下横突间植骨块较硬。
5.术后8周取材手触检测A组标本均未融合；B组只有4例获得坚固融合,坚固融合的比率较低；C组大部分标本(15例)获得坚固融合。总体比较P<0.05,差异有统计学意义；A组和B组比较P<0.05,差异有统计学意义；B组和C组比较P<0.05,差异有统计学意义；A组和C组比较P＜0.05,差异有统计学意义。
6.术后8周取材组织学观察A组材料有部分降解,表面有大量毛细血管形成并长入内部,材料与周围组织之间无纤维囊形成,材料内部少量类骨质形成,具有良好的生物相容性及一定的骨传导性。B组材料部分降解,材料内部及表面无炎性反应,与周围组织相容性较好,材料与横突交界处可见骨性连接,内部有新生编织骨形成,但未见骨髓等成熟骨组织出现,具有一定的骨诱导能力。C组可见大量新骨形成,有骨髓等成熟骨组织出现,具有优良的骨传导性、骨诱导性及骨形成能力。
结论：
1.使用经纳米HA修饰的BCP与Cs复合作为rhBMP-2的载体用于兔腰椎后外侧横突间融合；负载较低剂量的rhBMP-2(30 u g／侧)诱导形成一定量的新骨。
2. Nano-HA/BCP/Cs/rhBMP-2复合材料具有良好的生物相容性、一定的骨传导性及骨诱导性,植入后能诱导新骨形成,其成骨效果优于单独Nano-HA/BCP/Cs复合材料,但与自体骨相比尚存在一定差距。材料成为良好的骨移植替代材料尚需进一步改进。
3. Nano-HA/BCP/Cs复合材料植入体内能被机体降解吸收,降解过程中材料本身及其降解产物不会对试验动物产生不良影响,内部大量毛细血管及少量类骨质形成,具有良好的生物相容性及一定的骨传导性。
4.两种复合材料植入后8周见仍有部分材料残留,说明新骨形成与材料降解速率不匹配；残留高密度HA影响影像学对骨融合的评估,需对材料进行进一步优化。
Objective:
Rabbit lumbar posterolateral intertransverse process fusion was established using the composite material A, which compound with the nano-hydroxyapatite(Nano-HA) modified biphasic calcium phosphate ceramics and chitosan(Cs), and composite material B, which loaded recombinant human bone morphogenetic protein-2 (rhBMP-2) on composite A, as spinal fusion bone graft substitutes. The two kinds of composite A and B were implanted to rabbit posterolateral intertransverse process separately. The purpose was to observe the characteristics of bone substitute and expore the mechanism of bone formation of the composite materials. It will provide an animal experimental basis for the further improvement and optimization of the bone graft substitutes.
Methods:
Forty eight skeletally maturated Japanese white rabbits (age,1～1.5 years-old; weight,3.5～4.5 kg) were randomly divided into three groups depending on the materials implanted to the intertransverse process. The nano-hydroxyapatite/biphasic calcium phosphate ceramics/chitosan composite was implanted to group A, and the nano-hydroxyapatite/biphasic calcium phosphate ceramics/chitosan/recombinant human bone morphogenetic protein-2 to group B and autogenous iliac bone graft to group C. For each group there were sixteen rabbites. Each rabbit underwent surgery for a single level bilateral posterolateral intertransverse process fusion at L5-L6.X-ray and CT scan was done to obersve the bone healing separately at 4 and 8 weeks after surgery. After radiographic examination at 8 weeks postoperation, all the experimental animals were killed to observe the posterolateral fusion mass by general observation, manual palpation and histologic examination.
Results:
1. Experimental animals were generally in good condition after surgery. The day after operation, all animales sobered and started drinking water, started eating the next day. The wound was I/A healing without evidence of bleeding, swelling, skin effusion and purulent infection complications. There were also no neurological complications, implant rejection, and allergic reactions.
2. According to the radiographic evaluation criteria established by Curylo, four weeks after operation X-ray showed that the overall solid fusion rate of the three groups was statistically significant difference (P＜0.05). The fusion rate of group C was higher than that of group A and group B, but the difference between group A and group B was not statistically significance (P＞0.05). Eight weeks postoperation the overall solid fusion rate between the three groups was statistically significant difference (P＜0.05).The fusion rate of group C was higher than that of group A and group B; There was significant difference between group A and B(P＜0.05). The fusion rate of group B was higher than that of group A.
3. Four weeks postoperation CT scan revealed that there was no fusion in group A and only one case was assessed as solid fusion in group B and twelve in group C. The overall solid fusion rate between the three groups was statistically significant difference (P＜0.05). But there was no statistically significant difference between group A and group B (P＞0.05). The difference between group B and group C was statistically significance (P＜0.05), and so it is between group A and group C(P＜0.05). Eight weeks after operation CT scan showed that there was no fusion case in group A and much of the group B did not get solid fusion (11 cases). The solid fusion rate of group B was much lower. Most specimens of the group C got solid fusion (15 cases). The overall comparison of the three group was statistically significant difference(P＜0.05). There was statistically significant difference between group A and group B (P＜0.05); Group B and group C were statistical difference (P＜0.05); There was statistically significant difference between group A and group C (P＜0.05). There were a large number of high density materials remained within the composite of group A and B.
4. Eight weeks after operation gross observation showed that the composite material of group A combined with the surrounding muscle tissue closely. No fibrous capsule wraping the materials and cavity formation was not found. There was no infection, necrosis, purulent, fluid phenomena around the implant materials. Materials still remained in the intertransverse process. The materials degraded partly and the pore size on the surface increased.There was much tissue that grew into the holes. There was also no infection, necrosis, purulent, fluid phenomena around the implant materials of group B. The materials closely integrated with the surrounding muscle tissue, without fibrous capsule wraping the materials and cavity formation. Four cases showed obvious sign of fusion. Materials still remined between the transverse process in the rest specimens, with plenty of tissue grew into the holes too. The grafted autogenous iliac bone combined with the surrounding tissue closely. Boney connection can be seen between transverse process and the grafted bone, with obvious callus formation. The fusion mass between the transverse process was hard.
5. Eight weeks postoperation manual palpation showed that no one sample got fusion in group A. Only four specimens of group B got solid fusion, with much lower rate of fusion. The majority of group C(15 cases) got solid fusion. The overall solid fusion rate between the three groups was statistically significant difference (P＜0.05). There was significant difference between group A and B (P＜0.05). Group B and group C were statistical difference (P＜0.05). Also, There was statistically significant difference between group A and group C (P＜0.05).
6. Eight weeks after the surgery histologic examination showed that there was part of degradation in the composite of group A. A large number of capillaries formed onto the surface and grew into the inner of the materials of group A. No fiber capsule formed between materials and surface tissue, and a small amount of osteoid formed within the material, which performed good biocompatibility and a certain bone conductivity. There was also part of degradation in the composite of group B. No inflammatory reaction was seen on the surface and inner of group B which showed better compatibility with the surrounding tissue. The junction of the materials and transverse process was connected by bony component. Newly formed woven bone was found inside the composite of group B, but mature bone and bone marrow did not appear. The composite materials of group B have a certain degree of bone induction ability. A large number of newly formed bone was seen in group C. A lot of matured bone and bone marrow appeared. The autogenous bone has much better bone conduction, bone induction and bone formation ability.
Conlusions:
1. Use nano-hydroxyapatite modified biphasic calcium phosphate ceramics compound chitosan as the carrier of rhBMP-2 for lumbar posterolateral intertransverse process fusion in rabbits. Load a much lower dose of rhBMP-2 (30μg/side) to induce a certain degree of new bone formation at the inner of the composite.
2. The Nano-HA/BCP/Cs/rhBMP-2 composite has an excellent biocompatibility, a certain degree of bone conductivity and bone induction that can induce new bone formation within the materials after implantation. Bone formation is better than that of Nano-HA/BCP/Cs group. But compared with the autologous bone, there are still some disadvantages. To be good bone graft substitutes, Nano-HA/BCP/Cs/rhBMP-2 composite requires further improvement.
3. The Nano-HA/BCP/Cs composite can be degraded and absorbed in vivo when implanted into the body. The composite itself and its degradation products do not have adverse effects on test animals. There were plenty of capillaries that grew into the material and a small amount of osteoid formed inside the materials. Therefore the composit materials have much better biocompatibility and some degree of bone conductivity.
4. Eight weeks after implantation of the two groups of composite materials, a majority of residual materials were observed in the fusion mass. New bone formation and material degradation rate does not match better enough. Because of the remained high-density HA, it is much difficult to assess weather it is fusion or not in the fussion mass. The material need to be further optimized.
使用经纳米羟基磷灰石修饰的双相磷酸钙陶瓷与壳聚糖复合得到复合材料A(Nano-HA/BCP/Cs),并将其作为rhBMP-2的载体得到复合材料B(Nano-HA/BCP/Cs/rhBMP-2)。将A、B两种复合材料分别植入兔腰椎后外侧横突间行植骨融合,观察两种复合材料在兔脊柱融合中的骨替代特点并探讨其成骨机理,为进一步完善及优化材料提供动物试验依据。
方法：
48只骨骼发育成熟日本耳大白兔(年龄,1-1.5岁；体重,2.5-3.5 kg)随机分为3组,每组16只,行腰5、6横突间植骨融合,植入复合材料或自体髂骨。A组植入纳米羟基磷灰石／双相磷酸钙／壳聚糖(Nano-HA/BCP/Cs)复合材料；B组植入纳米羟基磷灰石／双相磷酸钙／壳聚糖/rhBMP-2(Nano-HA/β-TCP/Cs/rhBMP-2)复合材料；C组植入自体髂骨(AIBG)。分别于术后4周、8周行X线摄片、CT扫描；术后8周影像学检查后空气栓塞处死行大体观察、手触检测及组织学观察。
结果：
1.实验动物术后一般情况良好,当日动物清醒,开始饮水,次日开始进食；术后切口I／甲愈合,切口无明显出血、红肿、渗出及感染、化脓等并发症,未见神经系统并发症、植入物排异反应及过敏反应。
2.根据Curylo等制定的放射学评分标准,术后4周X线检查三组总体坚固融合百分比的差异有统计学意义(P<0.05),C组融合率较A组和B组高；但A组与B组比较差异无统计学意义(P>0.05)。术后8周三组总体坚固融合百分比的差异有统计学意义(P<0.05),C组融合率较A组和B组高；A组与B组比较差异有统计学意义(P<0.05),B组融合率较A组高。
3.术后4周时CT检查A组均不融合,B组只有1例评定为融合,C组有12例融合,总体比较P<0.05,差异有统计学意义；A组和B组比较P＞0.05,差异无统计学意义；B组和C组比较P<0.05,差异有统计学意义；A组和C组比较P<0.05,差异有统计学意义。术后8周时CT检查A组的标本均无融合,B组未融合的标本较多(11例),坚固融合的比率低,C组大部分标本(15例)获得坚固融合。总体比较P<0.05,差异有统计学意义；A组和B组比较P<0.05,差异有统计学意义；B组和C组比较P<0.05,差异有统计学意义；A组和C组比较P<0.05,差异有统计学意义。影像学检查见A、B两组复合材料内部均有大量高密度材料残留。
4.术后8周取材大体观察A组材料与周围肌肉组织结合紧密,未见纤维囊包裹及囊腔形成；复合材料周围组织未见感染、坏死、化脓、积液等,双侧上下横突间仍为材料,有部分降解,表面孔径增大,孔内有较多组织长入；B组材料周围组织无感染、坏死、积液等,材料与周围肌肉组织结合紧密,无纤维囊包裹及囊腔形成,4例可见明显融合,其余标本上下横突间仍为材料,表面孔内大量组织长入；C组移植髂骨与周围组织结合紧密,15例可见自体骨与上下横突交界处有大量骨痂形成,为骨性结合,上下横突间植骨块较硬。
5.术后8周取材手触检测A组标本均未融合；B组只有4例获得坚固融合,坚固融合的比率较低；C组大部分标本(15例)获得坚固融合。总体比较P<0.05,差异有统计学意义；A组和B组比较P<0.05,差异有统计学意义；B组和C组比较P<0.05,差异有统计学意义；A组和C组比较P＜0.05,差异有统计学意义。
6.术后8周取材组织学观察A组材料有部分降解,表面有大量毛细血管形成并长入内部,材料与周围组织之间无纤维囊形成,材料内部少量类骨质形成,具有良好的生物相容性及一定的骨传导性。B组材料部分降解,材料内部及表面无炎性反应,与周围组织相容性较好,材料与横突交界处可见骨性连接,内部有新生编织骨形成,但未见骨髓等成熟骨组织出现,具有一定的骨诱导能力。C组可见大量新骨形成,有骨髓等成熟骨组织出现,具有优良的骨传导性、骨诱导性及骨形成能力。
结论：
1.使用经纳米HA修饰的BCP与Cs复合作为rhBMP-2的载体用于兔腰椎后外侧横突间融合；负载较低剂量的rhBMP-2(30 u g／侧)诱导形成一定量的新骨。
2. Nano-HA/BCP/Cs/rhBMP-2复合材料具有良好的生物相容性、一定的骨传导性及骨诱导性,植入后能诱导新骨形成,其成骨效果优于单独Nano-HA/BCP/Cs复合材料,但与自体骨相比尚存在一定差距。材料成为良好的骨移植替代材料尚需进一步改进。
3. Nano-HA/BCP/Cs复合材料植入体内能被机体降解吸收,降解过程中材料本身及其降解产物不会对试验动物产生不良影响,内部大量毛细血管及少量类骨质形成,具有良好的生物相容性及一定的骨传导性。
4.两种复合材料植入后8周见仍有部分材料残留,说明新骨形成与材料降解速率不匹配；残留高密度HA影响影像学对骨融合的评估,需对材料进行进一步优化。
Objective:
Rabbit lumbar posterolateral intertransverse process fusion was established using the composite material A, which compound with the nano-hydroxyapatite(Nano-HA) modified biphasic calcium phosphate ceramics and chitosan(Cs), and composite material B, which loaded recombinant human bone morphogenetic protein-2 (rhBMP-2) on composite A, as spinal fusion bone graft substitutes. The two kinds of composite A and B were implanted to rabbit posterolateral intertransverse process separately. The purpose was to observe the characteristics of bone substitute and expore the mechanism of bone formation of the composite materials. It will provide an animal experimental basis for the further improvement and optimization of the bone graft substitutes.
Methods:
Forty eight skeletally maturated Japanese white rabbits (age,1～1.5 years-old; weight,3.5～4.5 kg) were randomly divided into three groups depending on the materials implanted to the intertransverse process. The nano-hydroxyapatite/biphasic calcium phosphate ceramics/chitosan composite was implanted to group A, and the nano-hydroxyapatite/biphasic calcium phosphate ceramics/chitosan/recombinant human bone morphogenetic protein-2 to group B and autogenous iliac bone graft to group C. For each group there were sixteen rabbites. Each rabbit underwent surgery for a single level bilateral posterolateral intertransverse process fusion at L5-L6.X-ray and CT scan was done to obersve the bone healing separately at 4 and 8 weeks after surgery. After radiographic examination at 8 weeks postoperation, all the experimental animals were killed to observe the posterolateral fusion mass by general observation, manual palpation and histologic examination.
Results:
1. Experimental animals were generally in good condition after surgery. The day after operation, all animales sobered and started drinking water, started eating the next day. The wound was I/A healing without evidence of bleeding, swelling, skin effusion and purulent infection complications. There were also no neurological complications, implant rejection, and allergic reactions.
2. According to the radiographic evaluation criteria established by Curylo, four weeks after operation X-ray showed that the overall solid fusion rate of the three groups was statistically significant difference (P＜0.05). The fusion rate of group C was higher than that of group A and group B, but the difference between group A and group B was not statistically significance (P＞0.05). Eight weeks postoperation the overall solid fusion rate between the three groups was statistically significant difference (P＜0.05).The fusion rate of group C was higher than that of group A and group B; There was significant difference between group A and B(P＜0.05). The fusion rate of group B was higher than that of group A.
3. Four weeks postoperation CT scan revealed that there was no fusion in group A and only one case was assessed as solid fusion in group B and twelve in group C. The overall solid fusion rate between the three groups was statistically significant difference (P＜0.05). But there was no statistically significant difference between group A and group B (P＞0.05). The difference between group B and group C was statistically significance (P＜0.05), and so it is between group A and group C(P＜0.05). Eight weeks after operation CT scan showed that there was no fusion case in group A and much of the group B did not get solid fusion (11 cases). The solid fusion rate of group B was much lower. Most specimens of the group C got solid fusion (15 cases). The overall comparison of the three group was statistically significant difference(P＜0.05). There was statistically significant difference between group A and group B (P＜0.05); Group B and group C were statistical difference (P＜0.05); There was statistically significant difference between group A and group C (P＜0.05). There were a large number of high density materials remained within the composite of group A and B.
4. Eight weeks after operation gross observation showed that the composite material of group A combined with the surrounding muscle tissue closely. No fibrous capsule wraping the materials and cavity formation was not found. There was no infection, necrosis, purulent, fluid phenomena around the implant materials. Materials still remained in the intertransverse process. The materials degraded partly and the pore size on the surface increased.There was much tissue that grew into the holes. There was also no infection, necrosis, purulent, fluid phenomena around the implant materials of group B. The materials closely integrated with the surrounding muscle tissue, without fibrous capsule wraping the materials and cavity formation. Four cases showed obvious sign of fusion. Materials still remined between the transverse process in the rest specimens, with plenty of tissue grew into the holes too. The grafted autogenous iliac bone combined with the surrounding tissue closely. Boney connection can be seen between transverse process and the grafted bone, with obvious callus formation. The fusion mass between the transverse process was hard.
5. Eight weeks postoperation manual palpation showed that no one sample got fusion in group A. Only four specimens of group B got solid fusion, with much lower rate of fusion. The majority of group C(15 cases) got solid fusion. The overall solid fusion rate between the three groups was statistically significant difference (P＜0.05). There was significant difference between group A and B (P＜0.05). Group B and group C were statistical difference (P＜0.05). Also, There was statistically significant difference between group A and group C (P＜0.05).
6. Eight weeks after the surgery histologic examination showed that there was part of degradation in the composite of group A. A large number of capillaries formed onto the surface and grew into the inner of the materials of group A. No fiber capsule formed between materials and surface tissue, and a small amount of osteoid formed within the material, which performed good biocompatibility and a certain bone conductivity. There was also part of degradation in the composite of group B. No inflammatory reaction was seen on the surface and inner of group B which showed better compatibility with the surrounding tissue. The junction of the materials and transverse process was connected by bony component. Newly formed woven bone was found inside the composite of group B, but mature bone and bone marrow did not appear. The composite materials of group B have a certain degree of bone induction ability. A large number of newly formed bone was seen in group C. A lot of matured bone and bone marrow appeared. The autogenous bone has much better bone conduction, bone induction and bone formation ability.
Conlusions:
1. Use nano-hydroxyapatite modified biphasic calcium phosphate ceramics compound chitosan as the carrier of rhBMP-2 for lumbar posterolateral intertransverse process fusion in rabbits. Load a much lower dose of rhBMP-2 (30μg/side) to induce a certain degree of new bone formation at the inner of the composite.
2. The Nano-HA/BCP/Cs/rhBMP-2 composite has an excellent biocompatibility, a certain degree of bone conductivity and bone induction that can induce new bone formation within the materials after implantation. Bone formation is better than that of Nano-HA/BCP/Cs group. But compared with the autologous bone, there are still some disadvantages. To be good bone graft substitutes, Nano-HA/BCP/Cs/rhBMP-2 composite requires further improvement.
3. The Nano-HA/BCP/Cs composite can be degraded and absorbed in vivo when implanted into the body. The composite itself and its degradation products do not have adverse effects on test animals. There were plenty of capillaries that grew into the material and a small amount of osteoid formed inside the materials. Therefore the composit materials have much better biocompatibility and some degree of bone conductivity.
4. Eight weeks after implantation of the two groups of composite materials, a majority of residual materials were observed in the fusion mass. New bone formation and material degradation rate does not match better enough. Because of the remained high-density HA, it is much difficult to assess weather it is fusion or not in the fussion mass. The material need to be further optimized.
引文
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