多孔钛合金支撑棒对早期距骨骨坏死骨修复的影响
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摘要
背景
距骨骨坏死是临床上能够导致踝关节严重疼痛和功能障碍的慢性疾病之一，目前对其治疗存在诸多争议。从当前的文献可以了解到其发病原因以创伤后所致者为多，由某些系统性疾病、激素、酗酒等引起者相对较少。
创伤性距骨骨坏死一般都有明确的外伤史，如距骨骨折、脱位、血管损伤等经过相应的辅助检查均可查清，因而手术治疗上针对性较强，对血运保存尚好的病例可采取复位、螺钉内固定治疗，对血运保存一般或创伤严重、预期难以骨愈合者则可早期采取关节融合术。而非创伤性距骨骨坏死由于其病程的进展呈潜行性、渐进性发展，治疗上尤其是手术治疗存在诸多疑难，比如在何时介入手术治疗、采用何种手术方式治疗等都是困扰临床工作者的问题。引起这些困扰的主要原因是目前临床虽已存在多种手术方案，其中有简单的、有复杂的，但并非复杂的就一定能取得良好的疗效，因此探索简洁有效的手术方法非常必要且有着积极的临床意义。
在骨坏死疾病中，以股骨头坏死和距骨坏死造成的危害最大，常常导致功能丧失。然而目前的研究主要集中在股骨头坏死方面，距骨坏死的研究并不深入，尤其在新型植入物研发方面明显欠缺。早在2000年，骨小梁金属开始运用于临床，该植入材料通过钽金属支架起到良好的支撑作用、通过将材料设计成多孔小梁状来达到部分髓心减压的效果。本课题组在总结这种多孔钽棒治疗早期股骨头坏死的优缺点时发现其作为治疗骨坏死的一种较新的方法并非完美，虽然它具有弹性模量低、摩擦系数高和能刺激骨修复的优点；但也存在一些缺陷如缺乏生物活性，孔径不利成骨，加工技术缺乏，临床价格昂贵，临床效果不佳等；而且在应力分布研究方面股骨头与距骨在生物力学负重上差别较大，股骨头所受应力不规则且合力方向与身体重心方向成角因而更易导致应力集中，距骨所受合力基本与身体重心方向大致平行、较均匀地分布于距骨顶。受上述研究启发，设计一种新型的多孔钛合金支撑棒植入距骨用来治疗距骨骨坏死或许会带来意想不到的优良结果，因为钛合金材料具有非常优秀的生物相容性而且也便于加工成合适孔径的多孔状结构。截止当前，国内外均未见类似的实验性研究报道。
目的
通过动物体内实验构建距骨骨坏死的大动物模型，并以此模型为基础，植入全新设计制备的多孔钛合金支撑棒，评价该新型植入物对早期距骨骨坏死的影响，并将其疗效与传统髓心减压的治疗方式进行对比以验证其优越性；通过对人尸体踝关节周围解剖分析和距骨内材料埋置实验，探索最佳手术入路和方法。
方法
1.羊距骨骨坏死动物模型的建立：将实验动物随机编号、均分为4个实验组，羊右后腿作为实验侧，用来诱导距骨骨坏死，左侧未作处理的距骨作为对照组，取材时间点为术后2周、4周、12周和24周。采用骨内注射无水酒精的方法诱导距骨骨坏死，手术部位位于距骨头的内侧面中心点。术后各时间点采取的检测方式主要包括：大体观察、X线侧位片、CT扫描以及HE染色的组织学检测。
2.多孔钛合金支撑棒的制备：通过CAD设计棒体的三维模型，将该数据输入EBM S12系统内；然后Ti6Al4V粉末在机器内按CAD模型逐层熔融，制备成型，最后用高压气流吹去残余粉末、清洗消毒即得所需样本。
3.多孔钛合金支撑棒植入治疗距骨骨坏死的动物体内实验：实验动物随机均分为2组。诱导距骨骨坏死1月后，经X线平片和CT检查确认早期骨坏死存在，然后将多孔钛合金支撑棒植入坏死距骨内，并与单纯的髓心减压治疗组进行对比。检测时间点为干预性治疗术后1个月和3个月。检测方式包括大体观察、X线侧位片、CT扫描、Micro-CT和组织学检测。
4.多孔钛合金支撑棒植入法治疗人距骨骨坏死的手术入路探索：通过探索微创手术入路将多孔钛合金支撑棒植入距骨内，术后拍摄正侧位片以观察其置放位置。将距骨的骨密度及生物力学强度进行了相关检测。
结果
1.羊距骨骨坏死动物模型的建立：术后所有实验动物于2周后基本恢复正常行走。有1例出现浅表感染的情况，所有实验动物在全部实验过程中未出现其他并发症。
1)大体观察：建模术后早期各样本外部轮廓正常；12周时出现小范围的软骨变性与缺损；24周时软骨大量变性缺损。坏死部位剖面示：建模术后2周的标本内部出现部分骨组织变性；4周后，距骨头内部大都形成大小约4mm×4mm×3mm的腔隙性缺损；而12周后，腔隙性缺损范围略缩小，但周缘有软组织增生的现象；到术后24周，样本剖面已经形成广泛的坏死性缺损。
2)影像学观察：X线侧位片显示：建模2周后，诱导坏死的距骨头内部出现较小范围的低密度影；4周后，低密度影范围扩大并出现骨小梁纹理断裂；12周后，距骨内部低密度影范围明显扩大；24周时，距骨头出现变形、软骨破坏并形成缺损。将CT数据三维重建并沿坏死中心点进行切割，可获得直观的剖面图，定量分析发现坏死腔的大小随诱导坏死后时间的延续而逐渐进展。
3)组织学分析:建模2周后，在坏死中心部位的骨小梁内出现了很多空泡陷窝。4周后，坏死中心部位骨小梁内的空泡陷窝数量明显增加，而活骨细胞数量则显著减少。12周后，骨小梁内仍存在大量空泡陷窝但小梁周缘可发现较明显的新骨形成和纤维组织增生。24周后，骨小梁数量明显减少，骨内出现大量的纤维组织增生。统计分析显示在相邻的不同时间点的两组样本中，成活骨小梁百分数递减且大多数有统计学意义（p<0.05），除外建模后4周与12周比较(p=0.051)无统计学意义。
2.多孔钛合金支撑棒的制备：所制备样本为直径4mm、长度12mm与直径8mm、长度20mm的2种规格的多孔圆柱状棒体，其孔隙率约为70%而孔径大小约为1mm；
3.多孔钛合金支撑棒植入治疗距骨骨坏死的动物体内实验：术后羊患肢略跛行，1周后伤口愈合，无局部感染、植入物脱落断裂及病理性骨折等并发症。
1)大体观察：外科干预术后1个月，所有距骨样本外观均正常。3个月后，进行过单纯髓心减压的距骨骨面出现了约5mm×6mm的软骨缺损及软骨变性；植入了多孔钛合金支撑棒的距骨外观仍正常。
2)影像学检查： X线片检查发现髓心减压1个月后距骨头部有非常明显的低密度影，到3个月后这些低密度影变浅，但范围明显扩大；多孔钛合金支撑棒植入1个月与3个月后，距骨内部密度较均一。Micro-CT检查定量分析结果提示在两个不同时间点植入材料组感兴趣区内重建的骨小梁在数量和质量上均明显高于髓心减压组。
3)组织学检测：髓心减压一个月时，原骨缺损部位空腔非常明显；三个月后，整个距骨内部骨小梁结构普遍变得极为疏松，小梁形态极不规则，骨小梁内部则为大量的空泡陷窝。多孔钛合金支撑棒植入一个月后，仅有少量骨小梁长入邻近边缘的孔隙内；三个月后，骨小梁大量长入多孔的钛合金材料内部，且结合紧密。统计数据显示在干预术后1个月，两组新生骨小梁无统计学差异(P＞0.05)，而干预3个月后，植入材料组新生骨小梁比髓心减压组高出1.7倍，具有统计学意义(P <0.05)。
4.多孔钛合金支撑棒植入法治疗人距骨骨坏死的手术入路探索：多孔钛合金支撑棒在微创手术下植入人距骨后的正侧位片显示棒体位于距骨体正中，位置良好。距骨样本骨密度检测及相应的生物力学检测数据显示正常距骨在其皮质骨未受损的情况下，采用髓心减压、及髓心减压后植入多孔钛合金支撑棒的处理方式对距骨的最大抗压缩强度影响不大，而原距骨的骨密度值大小与其最大抗压缩强度值基本成正比。
结论
1.通过骨内注射无水酒精的方法可以建立距骨骨坏死从早期到晚期的大动物模型，这一模型可以在一定程度上模拟人类距骨骨坏死的自然病理生理进程，并且在此基础上可以探索诊断治疗距骨骨坏死的新方法。
2.由于实验观测时间点有限，多孔钛合金支撑棒治疗距骨骨坏死的长期效果如何还有待进一步实验的验证。但就目前实验而言，多孔钛合金支撑棒对羊距骨早期骨坏死的疗效值得肯定，这一探索性研究为今后多孔钛金属材料在治疗骨坏死方面应用于临床打下了基础。
3.多孔钛合金支撑棒植入法治疗距骨骨坏死在手术过程上有其可行性，其手术入路完全可在微创下进入，在髓心减压的基础上进行，这一术式非常简洁，在逐步完善相关研究后有应用于临床的良好前景。
Background
ONT (Osteonecrosis of the Talus) is a kind of chronic disease which is able to resultin severe ache and disablity of the ankle joint. The treatment of ONT is still controversialat present.
The main aetiological agent of ONT comes from traumatic damage of the anklejoint, and other causes are relatively less, such as some systemic disease, corticalhormone, and insobriety and so on. To treat the traumatic ONT, reduction and internalfixation are always used for those cases preserved proper blood supply; nevertheless,arthrodesis is the first choice for those cases with severe fracture of the bone and poorblood supply. However, as far as the atraumatic ONT is concerned, there exist manypuzzles in surgical treatment because of the evolution of the disease is subtle andnecrobiotic. Such as when and how to operate are both difficulties which perplex thesurgeons. Presently, there are several surgical methods including simple and complicatedways in treating ONT, and the clinical experiences suggest that complicated ways are farfrom the idea methods for the curative effects are sometimes abjective. Therefore, toexplore a simple and effective operative approach is very necessary and positive in clinic.
Among the diseases of osteonecrosis, ONFH (Osteonecrosis of the Femoral Head)and ONT are especially dangerous for they always lead to functional incapacitation of ankles. However, the present researches mainly focus on the ONFH nowadays. Theresearches on ONT are really superficial particularly in the field of novel implants. Thetrabecular metal (porous tantalum) has been applied in clinic for treating the ONFH sincethe year of2000. This kind of implant possesses well function of internal support andcore decompression for its tantalum metal and porous structure. Our research group havestudied this kind of porous metal and found that it had some advantages such as lowmodulus of elasticity, high friction factor and capability to stimulate the bone repair. Butit was not perfect as an implant to treat the osteonecrosis. The main problem is that thebioactivity was poor, the pore size was too tiny and dense, the process was difficult, veryexpensive and the clinical results were not very well. Moreover, there exist greatdifference between femoral head and talus as far as the biomechanics is concerned. So,on considering these backgrounds, to treat the ONT by designing a novel porous titaniumalloy may bring a surprise result, because the titanium alloy possesses excellentbiocompatibility and easy to molding. To this day, there are none of the reports have evermentioned this treatment.
Objective
To establish the first animal model of ONT through experiments in vivo, andimplant a newly designed porous titanium alloy rod to treat the early-stage ONT based onthis animal model and the curative effect will be tested and verified by comparing to thetreatment of core decompression. To explore the concise and valid operative approach byimplant this kind of porous titanium alloy rod into the human cadaveric talus.
Methods
1. Animal model of ONT: After number the animals randomly; they were dividedinto4groups evenly. The right tali of the sheep were used as experimental group toinduce the osteonecrosis and the untreated left tali were treated as control group. Allsamples were harvested2,4,12and24weeks after operation. The ONT was induced byintraosseous injection of pure ethanol, and the surgical site was located in the central ofthe medial talar heads. The assessment methods included macro observation, lateral filmof the X-ray, CT scan, and histological examination and so on.
2. The preparation of the porous titanium alloy rods: Firstly, design the threedimensional model of the rod by CAD and input the data into EBM S12system; Secondly, the Ti6Al4V powder are melt layer-by-layer in the machine according to theCAD model and the sample of the rod prepared; Last, blow away the residual powderwith high pressure draft and disinfect the rod.
3. To treat the ONT by implanting the porous titanium alloy rods into the tali ofsheep in vivo: The animals were evenly divided into experimental and control groupsrandomly. A month after animal model of ONT were induced and the osteonecrosis wereconfirmed by X-ray and CT scan, the porous titanium alloy rods of the experimentalgroup were implanted into the tali, and the curative effect was compared to the controlgroup which treated by core decompression. The samples were harvested one and threemonths after intervention. The assessment methods included macro observation, theX-ray, CT scan, Micro-CT, histological examination and so on.
4. The exploration of operative approach by implanting the porous titanium alloyrods into the human cadaveric tali: Implanting the porous titanium alloy rods into thehuman cadaveric tali by minimally invasive surgery, and to observe the location byanterioposterior and lateral film of X-ray postoperatively. The BMD and thebiomechanical compression strength of the talus were detected.
Results
1. Animal model of ONT: All of the animals recovered to normal physicalconditions two weeks postoperatively. A case of superficial infection occurred andrecovered two weeks later after careful debridement. No other complications occurredduring the whole experimentation.
1) Macro observation： The samples of early-stage (2weeks and4weekspostoperatively) kept normal contour. However, the cartilage degeneration and colobomaof small area on the talar surface appeared12weeks after the surgery, and thisphenomenon get worse at the time of24weeks postoperatively. The section view of thenecrotic parts showed that parts of the trabeculae inside the tali degenerated2weeks aftersurgery. After4weeks, lacunar defect of about4mm×4mm×3mm formed in most talarheads. By the end of week12, the lacunar defect slightly decreased but there were somesoft tissue proliferated around the defect. Until the end of week24, the comprehensive necrotic defect had formed inside all of the samples.
2) Image examination: The lateral film of X-ray showed a small scale of lowdensity image inside the talar heads after2weeks of the animal model were induced. Thelow density image extended and the image of trabeculae ruptured after4weekspostoperatively. The low density image enlarged obviously by the end of week12, alsodegeneration and cartilage damage appeared on the talar heads by the end of week24.The three-dimensional reconstruction of the CT data showed the visualized sections andthe quantitative analysis suggested that the necrosis of the talar heads progressed withtime.
3) Histological examination: Many lacunas appeared inside the trabeculae of thenecrotic parts after2weeks of the animal model were induced. The quantity of thelacunas increased obviously and the living osteocytes remarkably decreased inside thetrabeculae after4weeks. By the end of week12, there were still huge number of lacunasexisted but a small scale of new bone and fibrosis proliferated around the trabeculae. Bythe end of week24, the quantity of the trabeculae obviously decreased and a great deal offibrosis infiltrated into the talar heads. The statistic analysis showed that the percentageof the living trabeculae decrease progressively with time between every twoneighbouring group and mostly statistical significance, except for week4vs week12(p=0.051).
2. The preparation of the porous titanium alloy rods: Two standard porous titaniumalloy rods were prepared. One was4mm in diameter and12mm in length, the other was8mm in diameter and20mm in length. Their porosity was about70%and the pore sizewas about1mm.
3. To treat the ONT by implanting the porous titanium alloy rods into the tali ofsheep in vivo: All of the experiment sheep got a little lameness after surgery and thewound healed a week later. There were no complications such as infection, implants falloff and breakage or pathologic fracture appeared during the whole study.
1) Macro observation：All talar samples showed ordinary appearance a month aftersurgical intervention. The samples which simply carried out surgery of core decompression appeared cartilage degeneration with defect about5mm×6mm on thepulley of the talar heads. Whereas, the samples which implanted with porous titaniumalloy rods still kept normal contour.
2) Image examination: The lateral film of X-ray showed very clear low densityimage of the talar heads a month after core decompression, and the low density imagebecame thin but enlarged in scale2months later. For the samples implanted with poroustitanium alloy rods, the density of talar heads kept uniform at each time. The quantitativeanalysis of micro-CT scan suggested that the reconstructed trabeculae of the experimentgroup were obviously prior to the control group at each time point both in quantity andquality.
3) Histological examination: The cavities of the defective parts were very clear amonth after core decompression. Two months later, the trabeculae inside the taligenerally became very loosen and the structure of the trabeculae presented very irregular,what’s more, a great deal of lacunas were found in the trabeculae. As far as the samplesof implanting the porous titanium alloy rods were concerned, there were also littlereconstructed trabeculae founded a month after implantation, but a large number oftrabeculae grew into the porous titanium alloy scaffolds3months after implantation andthe trabeculae were tightly combined with the scaffolds. The statistic analysis showedthat the percentage of the reconstructed trabeculae had no significance (P＞0.05) a monthafter intervention, however, the reconstructed trabeculae of experiment group were1.7times more than the control group3months after intervention and the difference wasstatistical significance (p<0.051).
4. The exploration of operative approach by implanting the porous titanium alloyrods into the human cadaveric tali: By using the minimally invasive surgery, the poroustitanium alloy rods were implanted into the human cadaveric tali and the anterioposteriorand lateral film postoperatively showed that the location of the rods were fine. The dataof BMD and the biomechanical compressive strength of all samples suggested thatmaximum compressive strength was not seriously influenced by the surgery ofimplantation or core decompression if the tali were normal, and the maximum compressive strength was generally direct proportional to the BMD of the tali.
Conclusion:
1. It's feasible to induce the animal model of ONT by intraosseous injecting thepure ethanol and this method could induce the animal model from early stage to laterstage. This animal model is able to imitate the natural pathophysiological progress ofhuman ONT to some extent and people could explore novel diagnosis and treatmentsbased on this animal model.
2. Limited by the observation time point, it's very regret that our study has not gotthe long-term data about the treatment effect of porous titanium alloy rods on theearly-stage of ONT, and this experimental is awaiting our research group to makearduous efforts. Whereas, the porous titanium alloy rods were absolutely effective to treatthe early-stage ONT in short time based on present studies, and this exploratory work haslaid the foundation for the porous titanium alloy implant treating osteonecrosis in clinic.
3. By implanting the porous titanium alloy rod into the talus to treat the ONT ispracticable, and the operative approach was completely under minimally invasive surgerybased on core decompression. This is a very concise surgery and has a very broadprospect in clinic after the correlational research has completed.
距骨骨坏死是临床上能够导致踝关节严重疼痛和功能障碍的慢性疾病之一，目前对其治疗存在诸多争议。从当前的文献可以了解到其发病原因以创伤后所致者为多，由某些系统性疾病、激素、酗酒等引起者相对较少。
创伤性距骨骨坏死一般都有明确的外伤史，如距骨骨折、脱位、血管损伤等经过相应的辅助检查均可查清，因而手术治疗上针对性较强，对血运保存尚好的病例可采取复位、螺钉内固定治疗，对血运保存一般或创伤严重、预期难以骨愈合者则可早期采取关节融合术。而非创伤性距骨骨坏死由于其病程的进展呈潜行性、渐进性发展，治疗上尤其是手术治疗存在诸多疑难，比如在何时介入手术治疗、采用何种手术方式治疗等都是困扰临床工作者的问题。引起这些困扰的主要原因是目前临床虽已存在多种手术方案，其中有简单的、有复杂的，但并非复杂的就一定能取得良好的疗效，因此探索简洁有效的手术方法非常必要且有着积极的临床意义。
在骨坏死疾病中，以股骨头坏死和距骨坏死造成的危害最大，常常导致功能丧失。然而目前的研究主要集中在股骨头坏死方面，距骨坏死的研究并不深入，尤其在新型植入物研发方面明显欠缺。早在2000年，骨小梁金属开始运用于临床，该植入材料通过钽金属支架起到良好的支撑作用、通过将材料设计成多孔小梁状来达到部分髓心减压的效果。本课题组在总结这种多孔钽棒治疗早期股骨头坏死的优缺点时发现其作为治疗骨坏死的一种较新的方法并非完美，虽然它具有弹性模量低、摩擦系数高和能刺激骨修复的优点；但也存在一些缺陷如缺乏生物活性，孔径不利成骨，加工技术缺乏，临床价格昂贵，临床效果不佳等；而且在应力分布研究方面股骨头与距骨在生物力学负重上差别较大，股骨头所受应力不规则且合力方向与身体重心方向成角因而更易导致应力集中，距骨所受合力基本与身体重心方向大致平行、较均匀地分布于距骨顶。受上述研究启发，设计一种新型的多孔钛合金支撑棒植入距骨用来治疗距骨骨坏死或许会带来意想不到的优良结果，因为钛合金材料具有非常优秀的生物相容性而且也便于加工成合适孔径的多孔状结构。截止当前，国内外均未见类似的实验性研究报道。
目的
通过动物体内实验构建距骨骨坏死的大动物模型，并以此模型为基础，植入全新设计制备的多孔钛合金支撑棒，评价该新型植入物对早期距骨骨坏死的影响，并将其疗效与传统髓心减压的治疗方式进行对比以验证其优越性；通过对人尸体踝关节周围解剖分析和距骨内材料埋置实验，探索最佳手术入路和方法。
方法
1.羊距骨骨坏死动物模型的建立：将实验动物随机编号、均分为4个实验组，羊右后腿作为实验侧，用来诱导距骨骨坏死，左侧未作处理的距骨作为对照组，取材时间点为术后2周、4周、12周和24周。采用骨内注射无水酒精的方法诱导距骨骨坏死，手术部位位于距骨头的内侧面中心点。术后各时间点采取的检测方式主要包括：大体观察、X线侧位片、CT扫描以及HE染色的组织学检测。
2.多孔钛合金支撑棒的制备：通过CAD设计棒体的三维模型，将该数据输入EBM S12系统内；然后Ti6Al4V粉末在机器内按CAD模型逐层熔融，制备成型，最后用高压气流吹去残余粉末、清洗消毒即得所需样本。
3.多孔钛合金支撑棒植入治疗距骨骨坏死的动物体内实验：实验动物随机均分为2组。诱导距骨骨坏死1月后，经X线平片和CT检查确认早期骨坏死存在，然后将多孔钛合金支撑棒植入坏死距骨内，并与单纯的髓心减压治疗组进行对比。检测时间点为干预性治疗术后1个月和3个月。检测方式包括大体观察、X线侧位片、CT扫描、Micro-CT和组织学检测。
4.多孔钛合金支撑棒植入法治疗人距骨骨坏死的手术入路探索：通过探索微创手术入路将多孔钛合金支撑棒植入距骨内，术后拍摄正侧位片以观察其置放位置。将距骨的骨密度及生物力学强度进行了相关检测。
结果
1.羊距骨骨坏死动物模型的建立：术后所有实验动物于2周后基本恢复正常行走。有1例出现浅表感染的情况，所有实验动物在全部实验过程中未出现其他并发症。
1)大体观察：建模术后早期各样本外部轮廓正常；12周时出现小范围的软骨变性与缺损；24周时软骨大量变性缺损。坏死部位剖面示：建模术后2周的标本内部出现部分骨组织变性；4周后，距骨头内部大都形成大小约4mm×4mm×3mm的腔隙性缺损；而12周后，腔隙性缺损范围略缩小，但周缘有软组织增生的现象；到术后24周，样本剖面已经形成广泛的坏死性缺损。
2)影像学观察：X线侧位片显示：建模2周后，诱导坏死的距骨头内部出现较小范围的低密度影；4周后，低密度影范围扩大并出现骨小梁纹理断裂；12周后，距骨内部低密度影范围明显扩大；24周时，距骨头出现变形、软骨破坏并形成缺损。将CT数据三维重建并沿坏死中心点进行切割，可获得直观的剖面图，定量分析发现坏死腔的大小随诱导坏死后时间的延续而逐渐进展。
3)组织学分析:建模2周后，在坏死中心部位的骨小梁内出现了很多空泡陷窝。4周后，坏死中心部位骨小梁内的空泡陷窝数量明显增加，而活骨细胞数量则显著减少。12周后，骨小梁内仍存在大量空泡陷窝但小梁周缘可发现较明显的新骨形成和纤维组织增生。24周后，骨小梁数量明显减少，骨内出现大量的纤维组织增生。统计分析显示在相邻的不同时间点的两组样本中，成活骨小梁百分数递减且大多数有统计学意义（p<0.05），除外建模后4周与12周比较(p=0.051)无统计学意义。
2.多孔钛合金支撑棒的制备：所制备样本为直径4mm、长度12mm与直径8mm、长度20mm的2种规格的多孔圆柱状棒体，其孔隙率约为70%而孔径大小约为1mm；
3.多孔钛合金支撑棒植入治疗距骨骨坏死的动物体内实验：术后羊患肢略跛行，1周后伤口愈合，无局部感染、植入物脱落断裂及病理性骨折等并发症。
1)大体观察：外科干预术后1个月，所有距骨样本外观均正常。3个月后，进行过单纯髓心减压的距骨骨面出现了约5mm×6mm的软骨缺损及软骨变性；植入了多孔钛合金支撑棒的距骨外观仍正常。
2)影像学检查： X线片检查发现髓心减压1个月后距骨头部有非常明显的低密度影，到3个月后这些低密度影变浅，但范围明显扩大；多孔钛合金支撑棒植入1个月与3个月后，距骨内部密度较均一。Micro-CT检查定量分析结果提示在两个不同时间点植入材料组感兴趣区内重建的骨小梁在数量和质量上均明显高于髓心减压组。
3)组织学检测：髓心减压一个月时，原骨缺损部位空腔非常明显；三个月后，整个距骨内部骨小梁结构普遍变得极为疏松，小梁形态极不规则，骨小梁内部则为大量的空泡陷窝。多孔钛合金支撑棒植入一个月后，仅有少量骨小梁长入邻近边缘的孔隙内；三个月后，骨小梁大量长入多孔的钛合金材料内部，且结合紧密。统计数据显示在干预术后1个月，两组新生骨小梁无统计学差异(P＞0.05)，而干预3个月后，植入材料组新生骨小梁比髓心减压组高出1.7倍，具有统计学意义(P <0.05)。
4.多孔钛合金支撑棒植入法治疗人距骨骨坏死的手术入路探索：多孔钛合金支撑棒在微创手术下植入人距骨后的正侧位片显示棒体位于距骨体正中，位置良好。距骨样本骨密度检测及相应的生物力学检测数据显示正常距骨在其皮质骨未受损的情况下，采用髓心减压、及髓心减压后植入多孔钛合金支撑棒的处理方式对距骨的最大抗压缩强度影响不大，而原距骨的骨密度值大小与其最大抗压缩强度值基本成正比。
结论
1.通过骨内注射无水酒精的方法可以建立距骨骨坏死从早期到晚期的大动物模型，这一模型可以在一定程度上模拟人类距骨骨坏死的自然病理生理进程，并且在此基础上可以探索诊断治疗距骨骨坏死的新方法。
2.由于实验观测时间点有限，多孔钛合金支撑棒治疗距骨骨坏死的长期效果如何还有待进一步实验的验证。但就目前实验而言，多孔钛合金支撑棒对羊距骨早期骨坏死的疗效值得肯定，这一探索性研究为今后多孔钛金属材料在治疗骨坏死方面应用于临床打下了基础。
3.多孔钛合金支撑棒植入法治疗距骨骨坏死在手术过程上有其可行性，其手术入路完全可在微创下进入，在髓心减压的基础上进行，这一术式非常简洁，在逐步完善相关研究后有应用于临床的良好前景。
Background
ONT (Osteonecrosis of the Talus) is a kind of chronic disease which is able to resultin severe ache and disablity of the ankle joint. The treatment of ONT is still controversialat present.
The main aetiological agent of ONT comes from traumatic damage of the anklejoint, and other causes are relatively less, such as some systemic disease, corticalhormone, and insobriety and so on. To treat the traumatic ONT, reduction and internalfixation are always used for those cases preserved proper blood supply; nevertheless,arthrodesis is the first choice for those cases with severe fracture of the bone and poorblood supply. However, as far as the atraumatic ONT is concerned, there exist manypuzzles in surgical treatment because of the evolution of the disease is subtle andnecrobiotic. Such as when and how to operate are both difficulties which perplex thesurgeons. Presently, there are several surgical methods including simple and complicatedways in treating ONT, and the clinical experiences suggest that complicated ways are farfrom the idea methods for the curative effects are sometimes abjective. Therefore, toexplore a simple and effective operative approach is very necessary and positive in clinic.
Among the diseases of osteonecrosis, ONFH (Osteonecrosis of the Femoral Head)and ONT are especially dangerous for they always lead to functional incapacitation of ankles. However, the present researches mainly focus on the ONFH nowadays. Theresearches on ONT are really superficial particularly in the field of novel implants. Thetrabecular metal (porous tantalum) has been applied in clinic for treating the ONFH sincethe year of2000. This kind of implant possesses well function of internal support andcore decompression for its tantalum metal and porous structure. Our research group havestudied this kind of porous metal and found that it had some advantages such as lowmodulus of elasticity, high friction factor and capability to stimulate the bone repair. Butit was not perfect as an implant to treat the osteonecrosis. The main problem is that thebioactivity was poor, the pore size was too tiny and dense, the process was difficult, veryexpensive and the clinical results were not very well. Moreover, there exist greatdifference between femoral head and talus as far as the biomechanics is concerned. So,on considering these backgrounds, to treat the ONT by designing a novel porous titaniumalloy may bring a surprise result, because the titanium alloy possesses excellentbiocompatibility and easy to molding. To this day, there are none of the reports have evermentioned this treatment.
Objective
To establish the first animal model of ONT through experiments in vivo, andimplant a newly designed porous titanium alloy rod to treat the early-stage ONT based onthis animal model and the curative effect will be tested and verified by comparing to thetreatment of core decompression. To explore the concise and valid operative approach byimplant this kind of porous titanium alloy rod into the human cadaveric talus.
Methods
1. Animal model of ONT: After number the animals randomly; they were dividedinto4groups evenly. The right tali of the sheep were used as experimental group toinduce the osteonecrosis and the untreated left tali were treated as control group. Allsamples were harvested2,4,12and24weeks after operation. The ONT was induced byintraosseous injection of pure ethanol, and the surgical site was located in the central ofthe medial talar heads. The assessment methods included macro observation, lateral filmof the X-ray, CT scan, and histological examination and so on.
2. The preparation of the porous titanium alloy rods: Firstly, design the threedimensional model of the rod by CAD and input the data into EBM S12system; Secondly, the Ti6Al4V powder are melt layer-by-layer in the machine according to theCAD model and the sample of the rod prepared; Last, blow away the residual powderwith high pressure draft and disinfect the rod.
3. To treat the ONT by implanting the porous titanium alloy rods into the tali ofsheep in vivo: The animals were evenly divided into experimental and control groupsrandomly. A month after animal model of ONT were induced and the osteonecrosis wereconfirmed by X-ray and CT scan, the porous titanium alloy rods of the experimentalgroup were implanted into the tali, and the curative effect was compared to the controlgroup which treated by core decompression. The samples were harvested one and threemonths after intervention. The assessment methods included macro observation, theX-ray, CT scan, Micro-CT, histological examination and so on.
4. The exploration of operative approach by implanting the porous titanium alloyrods into the human cadaveric tali: Implanting the porous titanium alloy rods into thehuman cadaveric tali by minimally invasive surgery, and to observe the location byanterioposterior and lateral film of X-ray postoperatively. The BMD and thebiomechanical compression strength of the talus were detected.
Results
1. Animal model of ONT: All of the animals recovered to normal physicalconditions two weeks postoperatively. A case of superficial infection occurred andrecovered two weeks later after careful debridement. No other complications occurredduring the whole experimentation.
1) Macro observation： The samples of early-stage (2weeks and4weekspostoperatively) kept normal contour. However, the cartilage degeneration and colobomaof small area on the talar surface appeared12weeks after the surgery, and thisphenomenon get worse at the time of24weeks postoperatively. The section view of thenecrotic parts showed that parts of the trabeculae inside the tali degenerated2weeks aftersurgery. After4weeks, lacunar defect of about4mm×4mm×3mm formed in most talarheads. By the end of week12, the lacunar defect slightly decreased but there were somesoft tissue proliferated around the defect. Until the end of week24, the comprehensive necrotic defect had formed inside all of the samples.
2) Image examination: The lateral film of X-ray showed a small scale of lowdensity image inside the talar heads after2weeks of the animal model were induced. Thelow density image extended and the image of trabeculae ruptured after4weekspostoperatively. The low density image enlarged obviously by the end of week12, alsodegeneration and cartilage damage appeared on the talar heads by the end of week24.The three-dimensional reconstruction of the CT data showed the visualized sections andthe quantitative analysis suggested that the necrosis of the talar heads progressed withtime.
3) Histological examination: Many lacunas appeared inside the trabeculae of thenecrotic parts after2weeks of the animal model were induced. The quantity of thelacunas increased obviously and the living osteocytes remarkably decreased inside thetrabeculae after4weeks. By the end of week12, there were still huge number of lacunasexisted but a small scale of new bone and fibrosis proliferated around the trabeculae. Bythe end of week24, the quantity of the trabeculae obviously decreased and a great deal offibrosis infiltrated into the talar heads. The statistic analysis showed that the percentageof the living trabeculae decrease progressively with time between every twoneighbouring group and mostly statistical significance, except for week4vs week12(p=0.051).
2. The preparation of the porous titanium alloy rods: Two standard porous titaniumalloy rods were prepared. One was4mm in diameter and12mm in length, the other was8mm in diameter and20mm in length. Their porosity was about70%and the pore sizewas about1mm.
3. To treat the ONT by implanting the porous titanium alloy rods into the tali ofsheep in vivo: All of the experiment sheep got a little lameness after surgery and thewound healed a week later. There were no complications such as infection, implants falloff and breakage or pathologic fracture appeared during the whole study.
1) Macro observation：All talar samples showed ordinary appearance a month aftersurgical intervention. The samples which simply carried out surgery of core decompression appeared cartilage degeneration with defect about5mm×6mm on thepulley of the talar heads. Whereas, the samples which implanted with porous titaniumalloy rods still kept normal contour.
2) Image examination: The lateral film of X-ray showed very clear low densityimage of the talar heads a month after core decompression, and the low density imagebecame thin but enlarged in scale2months later. For the samples implanted with poroustitanium alloy rods, the density of talar heads kept uniform at each time. The quantitativeanalysis of micro-CT scan suggested that the reconstructed trabeculae of the experimentgroup were obviously prior to the control group at each time point both in quantity andquality.
3) Histological examination: The cavities of the defective parts were very clear amonth after core decompression. Two months later, the trabeculae inside the taligenerally became very loosen and the structure of the trabeculae presented very irregular,what’s more, a great deal of lacunas were found in the trabeculae. As far as the samplesof implanting the porous titanium alloy rods were concerned, there were also littlereconstructed trabeculae founded a month after implantation, but a large number oftrabeculae grew into the porous titanium alloy scaffolds3months after implantation andthe trabeculae were tightly combined with the scaffolds. The statistic analysis showedthat the percentage of the reconstructed trabeculae had no significance (P＞0.05) a monthafter intervention, however, the reconstructed trabeculae of experiment group were1.7times more than the control group3months after intervention and the difference wasstatistical significance (p<0.051).
4. The exploration of operative approach by implanting the porous titanium alloyrods into the human cadaveric tali: By using the minimally invasive surgery, the poroustitanium alloy rods were implanted into the human cadaveric tali and the anterioposteriorand lateral film postoperatively showed that the location of the rods were fine. The dataof BMD and the biomechanical compressive strength of all samples suggested thatmaximum compressive strength was not seriously influenced by the surgery ofimplantation or core decompression if the tali were normal, and the maximum compressive strength was generally direct proportional to the BMD of the tali.
Conclusion:
1. It's feasible to induce the animal model of ONT by intraosseous injecting thepure ethanol and this method could induce the animal model from early stage to laterstage. This animal model is able to imitate the natural pathophysiological progress ofhuman ONT to some extent and people could explore novel diagnosis and treatmentsbased on this animal model.
2. Limited by the observation time point, it's very regret that our study has not gotthe long-term data about the treatment effect of porous titanium alloy rods on theearly-stage of ONT, and this experimental is awaiting our research group to makearduous efforts. Whereas, the porous titanium alloy rods were absolutely effective to treatthe early-stage ONT in short time based on present studies, and this exploratory work haslaid the foundation for the porous titanium alloy implant treating osteonecrosis in clinic.
3. By implanting the porous titanium alloy rod into the talus to treat the ONT ispracticable, and the operative approach was completely under minimally invasive surgerybased on core decompression. This is a very concise surgery and has a very broadprospect in clinic after the correlational research has completed.
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