骨形态蛋白-2对兔腰椎脊柱功能单位的运动范围的影响
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摘要
第一部分可重复性、缓慢演变的兔椎间盘退变模型的诱导
目的:证实经腹膜外椎间盘侧前方手术穿刺途径是一种简单易行,且能够成功诱导兔的可重复、缓慢演变的椎间盘退变动物模型。
方法:实验预算使用新西兰大白兔共24只,实际使用了26只(有2只由于意外情况放弃作为实验组的观察)。实验开始3只大白兔被立即宰杀,其椎间盘的影像学及组织学资料被收集与穿刺手术后的大白兔的相关资料做对比。全身麻醉后,通过经腹膜外侧前方对剩余的21只骨骼发育成熟的雌性新西兰大白兔L2-L3,L3-L4和L4-L5椎间盘运用16号皮下穿刺针进行深达5mm的穿刺手术。在术后3、6、12、24周几个时间点对其穿刺节段椎间盘(L2-3、L3-4、L4-5)和完整椎间盘(L1-2和L5-6)进行连续的MRI扫描,且在这几个时间点分别任意选择3只实验大白兔行X线照片和组织学分析(其余9只作为第二部分实验备用),并且和手术前的作比较。
结果:X线照片发现穿刺手术后6周在穿刺椎间盘相邻节段出现了早期的骨赘形成,24周出现了广泛的骨赘,且有骨桥的形成。在手术后3-24周,穿刺椎间盘的MRI指数(T2加权像正中矢状位上髓核区域和信号强度产生)出现进行性的下降(平均MRI指数3周时为术前的82%,24周为术前的31%),且没有证据显示有自然转归的趋势。组织学分析显示髓核内的脊索细胞进行性的减少,取而代之的是纤维软骨细胞,纤维环也发生了结构的紊乱。
结论:运用16号皮下穿刺针对兔侧前方椎间盘进行5mm深度穿刺诱导的可重复性、缓慢演变的兔椎间盘退变的动物模型,发现在手术后24周椎间盘发生的组织学、X线照片和MRI扫描改变与人类椎间盘退变的变化相似。这种椎间盘退变动物模式适合作为椎间盘退变的病源学和病理生理学动物模型研究,还可以为进一步的发现先进的、安全有效的治疗方法提供实验载体。
第二部分骨形态蛋白-2对兔腰椎脊柱功能单位的运动范围的影响
目的:证实骨形态蛋白-2椎间盘注射治疗能够延缓或阻止兔椎间盘的退变,且能引起椎间盘生物力学的改变,进而为临床上开创一种新型的治疗椎间盘退行性疾病的方法提供实验依据。
方法:在兔椎间盘穿刺后3周,自由选取9只实验大白兔同法在穿刺椎间盘的对侧穿刺注入BMP-2,在6、12、24几个时间点观察MRI、组织学及基因表达的改变,同时测量这几个时间点的L3-4的FSU的ROM,并且将正常组、穿刺组和BMP-2治疗组进行比较。
结果:在穿刺术后6、12、24几个时间点椎间盘的MRI、组织学及基因表达均有退变样改变,但是比穿刺组发展的程度低。6周时经BMP-2治疗兔L3-4的FSU的ROM和正常组比较已经发生了改变,但相对于穿刺组还没有发生变化,在12周和24周与正常组比较仍然存在统计学差异,但是已明显向正常的方向转变,且出现了与穿刺组有明显统计学意义上的差距。
结论:BMP-2对兔椎间盘局部注射不仅能够在影像学、组织学、基因表达方面显示出延缓椎间盘的退变,而且通过L3-4的FSU的ROM测试发现在注射后9周至21周(穿刺后12至24周)出现了ROM向正常方向的改变。BMP-2椎间盘局部注射治疗或许是将来治疗椎间盘退行性疾病的一种新型治疗方法。
Objectives: To prove anterolateral extraperitoneal anular stab is not only a simple and practicable but also a successful way to constructn a slowly progressive, reproducible rabbit model of intervertebral disc degeneration.
Methods: In the experiment, we anticipated 24 New Zealand rabbits would be used. Actually, 26 rabbits were used in the experiment because 2 rabbits had to quit because of unforeseen situation. Three rabbits were killed promptly to provide intact disc specimens and collected radioloty and histology data for comparison with the preoperative state of discs. After general anesthesia, the L2-L3, L3-L4, and L4-L5 lumbar intervertebral discs of remaining 21 skeletally mature female New Zealand White rabbits were stabbed by 16-gauge hypodermic needle to a depth of 5 mm in the left anterolateral annulus fibrosus. All experimental rabbits were performed serial magnetic resonance imaging scan in the stabbed discs and intact L1-L2 and L5-L6 control discs at 3, 6, 12, and 24 weeks post surgery. Three rabbits were chosen randomly each time supplemental radiograph and histologic analyses (Remain 9 rabbits were used in the secondary stage experiment) . At the same time, whole results were compared with preoperative observation results.
Results: Radiograph findings included early osteophyte formation in adjacent intervertebral by 6 weeks post stab and extensive, bridging osteophytes by 24 weeks. The stabbed discs exhibited a progressive decrease in "magnetic resonance imaging index" (the product of nucleus pulposus area and signal intensity from T2-weighted midsagittal plane images) starting at 3 weeks post stab and continuing through 24 weeks (mean MRI index was 82% of preoperative MRI index by week 3, decreasing to 31% by week 24.) , with no evidence of spontaneous recovery or reversal of magnetic resonance imaging changes. Histologic analysis revealed progressive loss of notochordal cells from the nucleus pulposus, filling of the nucleus pulposus space with fibrocartilage, and derangement of anulus fibrosus.
Conclusion: Stabbing the anterolateral anulus fibrosus of adult rabbit lumbar discs with a 16-gauge hypodermic needle to a limited (5-mm) depth results in a number of slowly progressive and reproducible magnetic resonance imaging, radiograph, and histologic changes over 24 weeks that show a similarity to changes seen in human intervertebral disc degeneration. This model would appear suitable for studying pathogenesis and pathophysiology of intervertebral disc degeneration and testing safety and efficacy of novel treatments of intervertebral disc degeneration.
Part II. To Evaluate Bone Morphogenetic Protein -2 Effects in Range of Motion of Functional Spinal Unit Of Rabbit's Lumbar Spine
Objectives: To determine the efficacy of Bone Morphogenetic Protein-2 injection in degenerated intervertebral rabbit disc in preventing or delaying the progression of disc degeneration, it also can change the biomechanics of intervertebral disc and provide the experiments evidences for initiate a new therapy in intervertebral disc degeneration disease.
Methods: Optional choosing 9 experiment rabbit were injected BMP-2 in stabbed intervertebral disc with Contralateral track in 3 weeks postoperation. At the time point of 6, 12 and 24 weeks postoperation, treatment intervertebral discs were analyzed the changes in MRI, histology and gene expression. At the same time, the ROM testing of FSU of L3-4 were completed and compared the difference in intact, stabbed and BMP-2 therapy three groups.
Results: The treatment interverbral discs were found some degenerative changes by MRI, histology and gene expression at 6, 12, 24 weeks postoperation but had low level degeneration. The ROM testing of FSU of L3-4 in BMP-2 therapy group had some differences with intact group but had no changes with stabbed group at 6 weeks. At 12 and 24 weeks time points, treatment group still had variance with intact group in ROM testing but the results showed they were developing to normal and had obvious statistically significant differences with stabbed group.
Conclusion: BMP-2 Partially injected in rabbit intervertebral disc not only shows delaying disc degeneration evidences by imagelogy, histology and gene expression but also finds the gene therapy discs are developing to normal by ROM testing of FUS of L3-4 during 9 to 21 weeks after BMP-2 injection(during 12 to 24weeks postoperation). We can hypothesis that the way of BMP-2 injected directly in intervertebral disc may be an effective new treatment to degeneration disc disease in the future.
目的:证实经腹膜外椎间盘侧前方手术穿刺途径是一种简单易行,且能够成功诱导兔的可重复、缓慢演变的椎间盘退变动物模型。
方法:实验预算使用新西兰大白兔共24只,实际使用了26只(有2只由于意外情况放弃作为实验组的观察)。实验开始3只大白兔被立即宰杀,其椎间盘的影像学及组织学资料被收集与穿刺手术后的大白兔的相关资料做对比。全身麻醉后,通过经腹膜外侧前方对剩余的21只骨骼发育成熟的雌性新西兰大白兔L2-L3,L3-L4和L4-L5椎间盘运用16号皮下穿刺针进行深达5mm的穿刺手术。在术后3、6、12、24周几个时间点对其穿刺节段椎间盘(L2-3、L3-4、L4-5)和完整椎间盘(L1-2和L5-6)进行连续的MRI扫描,且在这几个时间点分别任意选择3只实验大白兔行X线照片和组织学分析(其余9只作为第二部分实验备用),并且和手术前的作比较。
结果:X线照片发现穿刺手术后6周在穿刺椎间盘相邻节段出现了早期的骨赘形成,24周出现了广泛的骨赘,且有骨桥的形成。在手术后3-24周,穿刺椎间盘的MRI指数(T2加权像正中矢状位上髓核区域和信号强度产生)出现进行性的下降(平均MRI指数3周时为术前的82%,24周为术前的31%),且没有证据显示有自然转归的趋势。组织学分析显示髓核内的脊索细胞进行性的减少,取而代之的是纤维软骨细胞,纤维环也发生了结构的紊乱。
结论:运用16号皮下穿刺针对兔侧前方椎间盘进行5mm深度穿刺诱导的可重复性、缓慢演变的兔椎间盘退变的动物模型,发现在手术后24周椎间盘发生的组织学、X线照片和MRI扫描改变与人类椎间盘退变的变化相似。这种椎间盘退变动物模式适合作为椎间盘退变的病源学和病理生理学动物模型研究,还可以为进一步的发现先进的、安全有效的治疗方法提供实验载体。
第二部分骨形态蛋白-2对兔腰椎脊柱功能单位的运动范围的影响
目的:证实骨形态蛋白-2椎间盘注射治疗能够延缓或阻止兔椎间盘的退变,且能引起椎间盘生物力学的改变,进而为临床上开创一种新型的治疗椎间盘退行性疾病的方法提供实验依据。
方法:在兔椎间盘穿刺后3周,自由选取9只实验大白兔同法在穿刺椎间盘的对侧穿刺注入BMP-2,在6、12、24几个时间点观察MRI、组织学及基因表达的改变,同时测量这几个时间点的L3-4的FSU的ROM,并且将正常组、穿刺组和BMP-2治疗组进行比较。
结果:在穿刺术后6、12、24几个时间点椎间盘的MRI、组织学及基因表达均有退变样改变,但是比穿刺组发展的程度低。6周时经BMP-2治疗兔L3-4的FSU的ROM和正常组比较已经发生了改变,但相对于穿刺组还没有发生变化,在12周和24周与正常组比较仍然存在统计学差异,但是已明显向正常的方向转变,且出现了与穿刺组有明显统计学意义上的差距。
结论:BMP-2对兔椎间盘局部注射不仅能够在影像学、组织学、基因表达方面显示出延缓椎间盘的退变,而且通过L3-4的FSU的ROM测试发现在注射后9周至21周(穿刺后12至24周)出现了ROM向正常方向的改变。BMP-2椎间盘局部注射治疗或许是将来治疗椎间盘退行性疾病的一种新型治疗方法。
Objectives: To prove anterolateral extraperitoneal anular stab is not only a simple and practicable but also a successful way to constructn a slowly progressive, reproducible rabbit model of intervertebral disc degeneration.
Methods: In the experiment, we anticipated 24 New Zealand rabbits would be used. Actually, 26 rabbits were used in the experiment because 2 rabbits had to quit because of unforeseen situation. Three rabbits were killed promptly to provide intact disc specimens and collected radioloty and histology data for comparison with the preoperative state of discs. After general anesthesia, the L2-L3, L3-L4, and L4-L5 lumbar intervertebral discs of remaining 21 skeletally mature female New Zealand White rabbits were stabbed by 16-gauge hypodermic needle to a depth of 5 mm in the left anterolateral annulus fibrosus. All experimental rabbits were performed serial magnetic resonance imaging scan in the stabbed discs and intact L1-L2 and L5-L6 control discs at 3, 6, 12, and 24 weeks post surgery. Three rabbits were chosen randomly each time supplemental radiograph and histologic analyses (Remain 9 rabbits were used in the secondary stage experiment) . At the same time, whole results were compared with preoperative observation results.
Results: Radiograph findings included early osteophyte formation in adjacent intervertebral by 6 weeks post stab and extensive, bridging osteophytes by 24 weeks. The stabbed discs exhibited a progressive decrease in "magnetic resonance imaging index" (the product of nucleus pulposus area and signal intensity from T2-weighted midsagittal plane images) starting at 3 weeks post stab and continuing through 24 weeks (mean MRI index was 82% of preoperative MRI index by week 3, decreasing to 31% by week 24.) , with no evidence of spontaneous recovery or reversal of magnetic resonance imaging changes. Histologic analysis revealed progressive loss of notochordal cells from the nucleus pulposus, filling of the nucleus pulposus space with fibrocartilage, and derangement of anulus fibrosus.
Conclusion: Stabbing the anterolateral anulus fibrosus of adult rabbit lumbar discs with a 16-gauge hypodermic needle to a limited (5-mm) depth results in a number of slowly progressive and reproducible magnetic resonance imaging, radiograph, and histologic changes over 24 weeks that show a similarity to changes seen in human intervertebral disc degeneration. This model would appear suitable for studying pathogenesis and pathophysiology of intervertebral disc degeneration and testing safety and efficacy of novel treatments of intervertebral disc degeneration.
Part II. To Evaluate Bone Morphogenetic Protein -2 Effects in Range of Motion of Functional Spinal Unit Of Rabbit's Lumbar Spine
Objectives: To determine the efficacy of Bone Morphogenetic Protein-2 injection in degenerated intervertebral rabbit disc in preventing or delaying the progression of disc degeneration, it also can change the biomechanics of intervertebral disc and provide the experiments evidences for initiate a new therapy in intervertebral disc degeneration disease.
Methods: Optional choosing 9 experiment rabbit were injected BMP-2 in stabbed intervertebral disc with Contralateral track in 3 weeks postoperation. At the time point of 6, 12 and 24 weeks postoperation, treatment intervertebral discs were analyzed the changes in MRI, histology and gene expression. At the same time, the ROM testing of FSU of L3-4 were completed and compared the difference in intact, stabbed and BMP-2 therapy three groups.
Results: The treatment interverbral discs were found some degenerative changes by MRI, histology and gene expression at 6, 12, 24 weeks postoperation but had low level degeneration. The ROM testing of FSU of L3-4 in BMP-2 therapy group had some differences with intact group but had no changes with stabbed group at 6 weeks. At 12 and 24 weeks time points, treatment group still had variance with intact group in ROM testing but the results showed they were developing to normal and had obvious statistically significant differences with stabbed group.
Conclusion: BMP-2 Partially injected in rabbit intervertebral disc not only shows delaying disc degeneration evidences by imagelogy, histology and gene expression but also finds the gene therapy discs are developing to normal by ROM testing of FUS of L3-4 during 9 to 21 weeks after BMP-2 injection(during 12 to 24weeks postoperation). We can hypothesis that the way of BMP-2 injected directly in intervertebral disc may be an effective new treatment to degeneration disc disease in the future.
引文
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[1] Wehling P, Schulitz KP, Robbins PD, Evans CH, Reinecke JA: Transfer of genes to chondrocytic cells of the lumbar spine: Proposal for a treatment strategy of spinal disorders by local gene therapy. Spine 1997;22: 1092-1097.
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[4] Paul R, Haydon RC, Cheng H, et al: Potential use of Sox9 gene therapy for intervertebral degenerative disc disease.Spine 2003;28:755-763.
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