摘要
脊柱疾患在临床很常见，多发于中老年人及某些特殊职业；腰椎以及颈椎病变居多，发病率高于胸、骶椎疾病；二者的发病率在中老年人中可占百分之八十以上，严重妨碍了人们正常工作并降低了生活质量。一般来说，采用各种非手术疗法后仍无缓解的脊柱疾病患者有必要采取手术治疗。作为一种治疗脊柱疾病与创伤的外科手术，椎间融合术被人们应用至今有接近百年的经验积淀。椎间融合术因其术后良好的治疗效果被看做是脊柱外科史的里程碑之一。作为手术金标准的自体髂骨移植具有较高的融合率，然而，随之而来的并发症是一个较难避免的问题，文献报告自体髂骨植骨融合术后并发症发生率约为百分之二十五，而且自体髂骨常因强度较弱而塌陷，继而出现椎间高度下降，导致椎管内空间变小，或降低减压效果。虽然椎间融合器获得了较好的效果，但长期积累随访的数据资料显示，目前椎间融合器仍存在一些缺陷，无论材料上或设计上，均有较大的进一步改进空间。
椎间融合器按其材料是否可在体内生物降解分为可吸收型和非吸收型两类。最先设计研制的cage材料是非吸收类材料。金属是最早被使用的非吸收型椎间融合器材料，主要为不锈钢、钛合金椎间融合器。然而，众所周知，金属类较人体骨骼强度高许多，制出的融合器刚度太大；而且金属类材料与人体组织相容性差，另外，金属不被X线穿透难以观察融合情况及影响术后MRI检查而被逐渐淘汰。其他较多的非吸收型融合器有碳纤维椎间融合器、聚醚醚酮（PEEK）及新近开发研制的纳米羟基磷灰石/聚酰胺66（n-HA/PA66）融合器，弹性模量均较金属类更接近于正常成人骨骼，而成为目前手术台上的主流融合器。大量研究证明，适宜的压应力刺激可以促进骨折愈合，加速植骨融合。虽然PEEK等材料制作的融合器在植入早期应力遮挡效应不明显，但后期随着其内部植骨逐渐吸收降解，而作为非吸收型融合器，其并没有随内部的植骨相应的吸收下降，导致椎体植骨融合界面之间的压应力下降，出现显著的应力遮挡效应，产生了不利于椎间植骨融合的生物力学环境，由此而影响了融合速度及效果。异体骨虽然可吸收，没有应力遮挡效应，但由于来源有限以及疾病传播风险，另外还存在和自体植骨块同样的后期塌陷问题限制了其
广泛应用。当前，许多学者已开始转向研究开发可能更适宜人体的生物可吸收型融合器。其中，研究较多的融合器材料是多聚乳酸（Polylactideacid，PLA）。理论上，采用聚乳酸制成的可吸收椎间融合器能克服可吸收类融合器因其内早期植骨降解后产生的应力遮挡效应。然而聚乳酸椎间融合器也存在自身的不足之处，主要包括力学强度欠佳、聚乳酸在体内的降解速度过快，因此导致在椎间融合前聚乳酸类融合器的强度往往已经不能达到胸腰椎脊柱载荷所需了。聚乳酸类融合器在脊柱轴向载荷的作用下极易发生塌陷椎间高度丢失进而出现脊柱不稳等现象；另外其组织相容性也不太理想，降解产生的乳酸局部堆积可出现无菌性炎症及溶骨等不良反应。因上述原因，聚乳酸类以及类似的多聚乙醇酸类可吸收椎间融合器尚未在临床上推广普及使用。
鉴于上述可吸收型及非吸收型椎间融合器存在的一些问题，我们提出了早期主动增加压应力刺激，加速椎间与植骨的融合，后期防止椎间融合器塌陷的新型设计理念。具体实施方法是组合可吸收型材料和非吸收型材料制作新型椎间融合器。新型可吸收材料采用新开发的多聚氨基酸/硫酸钙；非吸收型材料采用临床上已使用多年的cage材料n-HA/PA66。将两种材料组合，以期实施上述理念，达到早期增加对椎间融合器内植骨的压应力刺激，提高融合速度，后期仍具有足够的强度支撑椎体的预期效果，改善融合效果的目的。
目的：
1.设计部分可吸收椎间融合器（PBIFC），制造出实验样本。
2.采用有限元模型评估部分可吸收融合器的生物力学性能，并与非吸收型椎间融合器比较。
3.评估部分可吸收融合器的体外生物力学性能。
4.在大型动物体内进行腰椎融合实验，评估部分可吸收椎间融合器的融合效果，探讨其作为椎间融合器的可行性，为临床应用提供实验基础。
方法：
1.在目前国内临床上使用多年的纳米羟基磷灰石/聚酰胺66椎间融合器的基础上，设计出部分可吸收椎间融合器，并与公司合作造出样品。
2.选29岁健康男性自愿者进行腰椎CT扫描(重医二院放射科)，通过工作站将扫描获得的图像导入计算机中，建立完整L3/L4腰椎功能节段的有限元模型，并进行验证。在该模型基础上，模拟经前路植入一枚部分可吸收椎间融合器或非吸收型椎间融合器，分别建立了腰椎融合术后即刻和术后4周的模型，包括：部分可吸收椎间融合器植入即刻和纳米羟基磷灰石/聚酰胺66(n-HA/PA66)椎间融合器植入即刻的模型，部分可吸收椎间融合器植入4周和n-HA/PA66椎间融合器植入4周的模型。依次在L3上表面施加400N轴向压缩模拟脊柱轴向压缩运动；400N轴向压缩预载荷和10Nm扭矩模拟脊柱前屈、后伸、旋转和侧屈运动，采集融合器、植骨、L4上终板的应力值及L4上终板应力分布轮廓数据。比较各椎间融合器及植骨在不同运动状态下的应力值和L4上终板的应力分布图。对植入两种cage四周前后进行生物力学评估。模型的建立及运算分析采用有限元软件ANSYS12.10。
3.选健康小牛的新鲜L3-L4腰椎制作成单独的腰椎功能节段，模拟前方入路行椎间融合器植入。部分前纵韧带及纤维环被切去，钳出髓核并尽量清理终板软骨。打磨平部分骨性终板后分别斜向植入一枚PBIFC、一枚n-HA/PA66融合器和自体髂骨块。通过加载扭矩模拟脊柱的各种功能运动状态，测试各cage植入后腰椎节段的活动范围，比较各组数据，评估PBIFC用于腰椎融合的稳定性；然后测试PBIFC的拔出力学性能；最后测评PBIFC的抗压性能。
4.16只本地雌性山羊，随机分为3组：A组，植入载满自体髂骨的部分可吸收椎间融合器；B组，植入载满自体髂骨的n-HA/PA66椎间融合器；以及C组自体髂骨块。在每只动物L2-L5三个椎间隙经前路植入以上两种椎间融合器和一枚自体髂骨块，顺序随机，行腰椎间融合术。成功手术的实验动物在术后即刻以及术后每月拍摄山羊腰椎侧位片，观察植骨融合情况，测量计算融合前后椎间隙高度（DSH）变化。术后24周处死动物行CT扫描，观察植骨融合情况，进行融合度评分；随后取术段标本切片，作Masson、甲苯胺蓝染色后镜下观察，了解植骨与椎体间融合、材料与椎体界面成骨及新骨形成情况，以及材料在体内降解情况。
结果：
1．成功设计出部分可吸收椎间融合器并制造出产品样品。
2．建立出完整L3/L4脊柱功能节段有限元模型。各工况结果显示，在融合器植入即刻，部分可吸收椎间融合器内植骨的应力值高于n-HA/PA66椎间融合器；部分可吸收椎间融合器自身以及L4上终板的应力值均低于n-HA/PA66椎间融合器；两组融合器在L4上终板的应力轮廓未见明显区别。各融合器植入4周，两组模型的应力差值较植入即刻时更大；部分可吸收椎间融合器在L4上终板的应力轮廓较n-HA/PA66椎间融合器大。
3．体外力学测试结果显示，部分可吸收椎间融合器具有和n-HA/PA66椎间融合器相近的抗压、抗扭及抗拔脱性能，结果无显著性差异；各指标均高于作为椎间融合术金标准的自体髂骨块，具显著性差异。
4．在部分可吸收腰椎间融合器的动物体内融合实验中，术前及术后即刻三组间DSH无显著性差异；术后4周至24周，nHA/PA66组与PBIFC组及髂骨组DSH差异显著（P<0.05），其中部分可吸收椎间融合器组及髂骨组的DSH降低更显著；术后4周至16周，部分可吸收椎间融合器组同髂骨组间DSH无显著性差异，但术后20周和24周髂骨组DSH较PBIFC组显著降低（P<0.05）。影像学检查，术后24周X检查显示部分可吸收椎间融合器组的融合度与自体髂骨相比已无显著统计学差异，但较nHA/PA66组融合度高。24周时，三组CT层面融合度评分，髂骨组的融合度评分高于部分可吸收椎间融合器组，但无统计学差异；PBIFC组的融合度评分高于nHA/PA66组，具统计学意义。术后24周行组织切片：PBIFC组可见作为cage盖的多聚氨基酸/硫酸钙材料已降解完全；在上下椎体界面的植骨区可见到较多成熟骨小梁，材料上下表面与终板骨组织已经相互嵌合，融合器与终板界面可见大量新生骨组织及纤维骨痂形成。
结论：
1.部分可吸收椎间融合器外形规格等设计符合目前主流，并将设计理念成功融入；部分可吸收融合器强度合适，空间足够，结合紧密，适应腰椎的生理结构；各部分材料与人体骨骼弹性模量接近。
2.有限元结果说明：部分可吸收融合器能长时间维持其内植骨的压应力；相应的融合器自身对终板压应力更小。
3.PBIFC用于腰椎融合将具备足够的抗压及抗滑脱、抗扭转力学性能。
4.PBIFC应用于山羊椎间融合，能够维持腰椎间隙高度，在观测时间内实现融合，效果优于同样外形结构的非吸收椎间融合器。
Spinal disease is very common. Cervical and lumbar diseases have the highest incidence, which account for60%-80%of morbidity rate in adults. For patients with spinal disease in which non-surgical therapies are ineffective, surgery is often needed. Intervertebral fusion, as a therapy for spinal disease and injury, has been used for a few decades; it is a milestone in the history of spinal surgery. The autologous iliac bone graft implant as the gold standard has high healing rate, though the complications are the major problem which cannot be neglected. It is reported that the incidence of complications associated with autologous iliac bone graft implant is25.3%. Moreover, autologous iliac bone graft is likely to subside due to insufficient strength, resulting in the loss of intervertebral height. The capacity of vertebral column and pressure-reducing effect will be directly affected. Bagby was the first to implant BAK cage system into human body in1988, which successfully achieved the desired purposes of maintaining intervertebral space height, increasing the stability of lumbar interbody fusion surgery and reducing the pressure on a nerve root. However, intervertebral cage still has some defects with respect to material and design, and therefore requires further modification.
Depending on the used material, intervertebral cage is divided into non-absorbable cage and absorbable cage. Metal cage is the first applied non-absorbable lumbar cage. It is mainly made of stainless steel or titanium alloy, which has high stiffness and poor histocompatibility. Metal cage was then phased out as it affected post-operative MRI scan. Carbon fiber cage, PEEK cage and nHA/PA66cage are also made of non-absorbable materials, having modulus of elasticity similar to that of normal adult skeleton. But as the bone graft is degraded and absorbed, the fusion cage is not being accordingly absorbedand degraded. As a result, the compressive stress of interface between the vertebra and the bone graft will decrease. The stress shielding effect thus produced will affect the fusion speed and effect.
Extensive studies have demonstrated that appropriate compressive stress will stimulate fracture recovery and accelerate bone graft fusion. Allograft bone is absorbable but it has restricted application due to its limited source, subsidence risk and disease dissemination in later stage. Intervertebral fusion cage made of bioabsorbable materials is being intensively studied both in China and internationally. Polylactic acid (PLA) is one of the most important candidate materials. Absorbable cage made of PLA overcomes the defect of stress shielding effect caused by the degradation of bone graft. Polylactic acid cage is not free from the following defects:①Poor mechanical strength;②Rapid degradation of polylactic acid in human bodies, which often results in mechanical strength insufficient for the load on thoracolumbar spine before fusion finish. PLA cage tends to subside under the axial load of spinal column, and such phenomena as loss of intervertebral height and spinal instability are possible occurrences;③Poor histocompatibility. The accumulation of lactic acid may also lead to sterile inflammation and osteolysis. For all these reasons, polylactic acid fusion cage has found not extensive application.
In view of the disadvantages of both absorbable and non-absorbable cages, we propose a new design in which the compressive stress is high at early stage in order to stimulate the fusion of bone graft, and cage subsidence is prevented at later stage by combining absorbable and non-absorbable materials. The new-type case combines n-HA/PA66with calcium sulfate/multi-(amino acid) copolymer composite to achieve these goals.
Objective:
To develop partially bioabsorbable interbody fusion cage (PBIFC), whose biomechanical performance was assessed by finite element analysis and in vitro mechanical test. The fusion effect of PBIFC was also assessed by lumbar interbody fusion experiment in large animals, in order to investigate the feasibility of such PBIFC to be applied as lumbar interbody fusion cage and to provide experimental basis for clinical application.
Method:
1. The new PBIFC was designed based on nHA/PA66cage which has been clinically applied for many years, and was jointly manufactured with a company.
2. The lumbar spine of a29-year old male volunteer was scanned at Radiology Department at the Second Affiliated Hospital of Chongqing Medical University. The scanned images were inputted to the computer via the workstation. The finite element model of the third and fourth lumbar vertebrae was constructed and confirmed. Using this model, the implantation of partially absorbable cage or non-absorbable cage via the anterior approach was simulated; the models immediately and4weeks after lumbar intervertebral fusion surgery were respectively constructed, including the models immediately after the implantation of partially absorbable cage and n-HA/PA66cage and the models4weeks after the implantation of partially absorbable cage and n-HA/PA66cage. ANSYS12.10was used for finite element analysis. Axial load of400N and torque of lONm were applied respectively on L3, in order to simulate the movements of anterior flexion, posterior extension, rotation and lateral flexion. The stress on the intervertebral fusion cage and bone graft in different movements and the stress distribution on L4end plate were obtained.
3. Separate spinal segments were made from lumbar vertebrae of fresh calf. Part of the fibrous ring and nuclecus pulposus were resected by anterior approach. Then the new PBIFCs were respectively implanted (in combination or separately). The implants were divided into different groups depending on the experiment purposes. The mechanical performance of combination-type cage under compressive load was first tested, followed by pull-out test on combination-type cage with or without bone graft. Finally, the stability of combination-type cage was assessed by testing the movement angles under vertically compressive load and torsion respectively.
4. Goats were selected for in vivo lumbar intervertebral fusion experiment.16female goats were randomly divided into three groups:Group A: partially absorbable cage filled with auto logo us bone graft; Group B: n-HA/PA66cage filled with autologous bone graft; and autologous bone graft group, in which autologous cortical iliac bone graft was implanted. Either of the two types of intervertebral fusion cages and one autologous iliac bone graft was implanted in intervertebral spaces at L2-L5in each animal. X-ray examination was performed on the lumbar spine of goats in lateral position immediately after lumbar fusion surgery and every month. The fusion of bone graft as well as the changes in intervertebral space height before and after the surgery was observed. All the goats were sacrificed24weeks after the surgery for CT scan. Lumbar interbody fusion was observed and scored.
Result:
1. Partially absorbable cage was successfully designed and manufactured.
2. Three-dimensional finite element model of L3/L4was constructed. Immediately after surgery, the stress on the bone graft in partially absorbable cage was higher than that in n-HA/PA66cage; the stress on the end plate in partially absorbable cage was lower than that in n-HA/PA66cage. The stress profiles of the end plate in the two models were not significantly different. The stress difference between the two models increased four weeks after surgery, compared with that immediately after the surgery. The stress profile of end plate in partially absorbable cage was greater than that in n-HA/PA66cage.
3. The in vitro mechanical performance test of partially absorbable cage showed that it had similar torsion resistance, pull-out resistance and compression resistance as n-HA/PA66cage; the difference was not significant (P>0.05).
4. In goat lumbar intervertebral fusion experiment, DSH before and immediately after surgery was not significantly different among the three groups; from4weeks to24weeks after surgery, DSH in nHA/PA66cage group was significantly different from that in partially absorbable fusion cage group and iliac bone graft group (P<0.05). DSH in partially absorbable fusion cage group and in iliac bone graft group was significantly decreased. From4weeks to16weeks after surgery, DSH was not significantly different from partially absorbable fusion cage group and iliac bone graft group. But the difference between the two groups was significant at the20st week to the24th week after surgery. DSH in iliac bone graft group decreased even more significantly. The lumbar intervertebral fusion with partially absorbable cage was not significantly different from that using iliac bone graft, as indicated by X-ray examination. However, nHA/PA66had the highest degree of lumbar intervertebral fusion (P<0.05).24weeks after the surgery, the lumbar intervertebral fusion at CT layers was scored in the three groups. The score of iliac bone graft group was higher than that of partially absorbable fusion cage group, but the difference was not significant (P>0.05); the score of PBIFC group was higher than that of nHA/PA66cage group, and the difference was significant (P<0.05).
Conclusion:
1. PBIFC designed and manufactured in this study has the appearance, internal structure and surface processing which match well with lumbar intervertebral structure. The strength and modulus of elasticity of PBIFC correspond to those of human skeleton.
2. The compressive stress on the bone graft in PBIFC group can maintain at a steady level and that on the end plate is even smaller.
3. PBIFC has sufficient compression resistance, pull-out resistance and torsion resistance.
4. When applied in goat lumbar interbody fusion, PBIFC is able to maintain intervertebral space height. Lumbar interbody fusion was observed within the specified period, and the effect of lumbar interbody fusion was better than that of non-absorbable fusion cage with the same external structure.
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