严重颅底缺损模型建立及形状记忆合金支架—生物膜的研究
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摘要
研究背景及目的
颅底重建是颅底手术不可缺少的一部分。同时,颅底手术共同的特点是操作空间狭小、组织结构复杂、难度大。颅底手术带来的骨性及膜性的结构缺损会引发脑脊液漏、颅内组织移位,从而继发颅内感染、脑膜脑膨出及相应神经功能障碍等问题。因此,可靠的颅底重建是颅底手术患者康复的有力保障。既要建立可靠持久的颅脑屏障、消除死腔、不影响疾病复查,又要获得理想的美容效果、避免术后并发症的出现,取材方便、操作简单、副损伤小、效果切实。
初始的颅底重建仅以皮瓣密闭硬膜,之后发展到了局部瓣,但脑脊液漏发生率和死亡率高。20世纪70年代出现了区域性肌皮瓣治疗较大缺损,并进行骨性重建的尝试。20世纪80、90年代游离组织瓣以及带血管游离组织瓣的发展使得颅底重建的效果更加可靠。自体组织和异体材料的应用并行,各具优劣点。自体材料已朝建立有效血运的方向发展,异体材料由于具有组织相容性好、取用方便、易于塑形、避免二次创伤等优于自体材料的特点,越来越多地应用于临床。
颅底重建技术在临床诊疗中由简单缝合、堵漏逐步发展到多层重建、恢复原有解剖层次结构,由对不确定修补的摸索发展到并对膜性/软组织性重建与骨性重建并重的不清晰认知。不论是在显微神经外科还是在内镜神经外科,颅底重建技术进步突出。自20世纪90年代开始,有诸多的门类繁多的、据临床医生个性化特点而层出的手段和方式,目前的广泛认识和接受的是利用一种或多种重建材料以三明治式或其各种改良方法进行的多层重建,以此更加确定避免术后脑脊液漏等严重并发症。
与大量、丰富而又各异的临床资料相比,严谨、规范的实验研究却相对稀少。文献中所报导的多数是小范围的、个体化明显的结果,而无普遍代表性价值。
为寻找一种能够应用到临床的、能够应对不同情况颅底缺损的材料与方法,设想将一种形状记忆合金及薄膜材料融合到一起,前者起骨性支撑作用,后者起膜性修补作用,同时又能伸缩、折曲而保持形状不变,就会将骨性重建与膜性重建同步完成,不仅能达到预期的临床效果,还能更加方便手术操作、缩短手术时间、减小手术创伤,从而增加了救治患者的安全系数。
1963年美国海军军械研究室Buehler发现的等原子比的镍钛合金具有形状记忆功能,并以反映其组成成分和初始发现单位的ni-ti-navy-ordnance-laboratory的缩写nitinol为其命名。深入研究发现镍钛合金除了具有良好形状记忆效应外,还有优良的生物相容性、高阻尼效应、高强度、超弹性、抗腐蚀性及抗疲劳性等特点,是一种独特的拟生态材料,现已被广泛应用于生物医学领域。镍钛合金在神经外科的许多应用目前处于发展阶段,相对较少,仅有动脉瘤夹、血管介入治疗材料等。脑膜建是一种生物型人工硬脑膜,具有国内完全自主知识产权,已被较多实验证实并临床用于硬脑膜缺损修补。
本课题拟以形状记忆合金中的镍钛合金和生物型人工硬脑膜脑膜建为材料、设计并制作用于颅底重建中兼顾骨性重建与膜性重建的植入物及其使用器械,从而减轻手术创伤、缩短手术时间,同时又不增加患者费用及医疗单位的运行成本。因近年有文献报导镍钛合金因可能释放镍离子而具有生物毒性,故同时对此做初步研究。
材料与方法
第一章：形状记忆合金支架-薄膜瓣复合体及其相应器械的设计与制作
1.拟定方案：有剪切式、解脱一式和解脱二式三种初始设计方案,均包括形状记忆合金支架-薄膜瓣复合体及其递送器械。详细结构及组成、操作及图示略。
2.材料的选择与制作：按预定设计方案,先生产制作镍钛合金支架；再在生产以猪腱膜提取物为原材料生产生物型人工硬脑膜过程中将镍钛合金支架包裹于其内。同时制作相应器械。
第二章：犬中颅底缺损并脑脊液漏模型的建立及实验治疗
1.实验动物及分组：选择健康杂种犬7只,随机先取2只建模,余下5只随机编号,在建模基础上实施实验治疗,即一期以此前生产制作并无菌化处理的镍钛合金支架-脑膜建复合体行颅底修补重建术。
2.犬颅解剖特点的研究及预实验：确定手术切口及相应手术路径,预见术中可能出现问题、需要使用的特殊器械等。
3.模型制作：腹腔-静脉联合麻醉,经口气管插管,吸氧,心电监测,必要时呼吸机支持,维持静脉通路。侧卧头高位,固定、保护。眼眶后至耳屏前、颧弓上方的手术相邻区域备皮。碘伏消毒。做犬单侧眼眶后水平相邻点与同侧颧弓中点间弧形切口,长约5cm,切开至中颅底外侧骨质。以纵向与横向移行转折处、即骨质垂直面与水平面移行处为标识,于其内侧以微型磨钻于建模区内磨出直径1cm骨窗,放射状切开硬脑膜(蛛网膜一并开放),确认脑组织外露、脑脊液溢出,止血可靠,敷薄层明胶海绵后,分层间断缝合颅外肌层、筋膜,内翻法皮内连续缝合皮肤。术中、术后静脉输入糖盐水1000ml-1500ml,带入青霉素240万单位。及时拔除气管插管。隔离观察、稍加约束、早期进流食、保持切口清洁。3日后解除约束。2周内单独饲养。
4.实验治疗：在建模型成功基础上、相应器械辅助下一期将镍钛合金支架-脑膜建复合体置于犬中颅底缺损区的骨质内板与硬膜间隙(即颅内-硬膜外间隙)。实验治疗动物的其他操作和处置与模型动物一致。
5.观察指标：术后犬的行为活动与生存情况、有无脑脊液漏等；术后3个月行影像学及组织病理学检查。
第三章犬额窦缺损并脑脊液鼻漏模型的建立及实验治疗
1.实验动物及分组：具体同第二章。
2.犬颅解剖特点的研究及预实验：原则上同第二章。
3.模型制作：一般处理同第二章。术中取侧卧头高位,收下颌并颈侧屈,使额部居中、居高。做犬单侧额窦后外侧缘与中线夹角处之三角钩形切口,成角600左右,每边长约2cm,基底侧朝向同侧前外之眶部。切开至骨质,剥离肌皮瓣翻向前外侧,显露额窦上壁额顶部骨质；于其最凸出处以微钻磨出直径12mm骨窗,显露并切开额窦粘膜；于额窦下壁中部近中线侧、稍平坦区,以微钻磨出直径1cm骨窗,显露并放射状切开硬膜(蛛网膜下腔一并开放)。其外敷明胶海绵并涂EC耳脑胶。切口皮瓣随呼吸而龛动,予以加压包扎。
4.实验治疗：在建模成功基础上、在相应器械辅助下一期将镍钛合金支架-脑膜建复合体置于犬额窦下壁缺损区的骨质内板与硬膜间隙(即颅内-硬膜外间隙)。实验治疗动物的其他操作和处置与模型动物完全一致。
5.观察指标：同第二章。
第四章镍钛合金支架抗腐蚀性和镍渗透性研究
1.标本收集与配对分组：收集两种动物模型实验治疗组动物治疗前后的血液标本、局部组织标本,以电感耦合等离子体质谱法检测其中的镍含量。收集两种动物模型实验治疗组动物使用前后的镍钛合金支架以扫描电子显微镜检测支架表面的钛、镍原子比含量。
2.统计学处理：数据采用配对t检验法,经SPSS17.0统计分析软件处理,变量以均数±标准差表示。分别比较两种模型实验治疗前后动物血液标本及局部组织标本中的镍含量、镍钛合金支架使用前与实验治疗后3个月后钛镍原子比含量的比值。P<0.05为差别有统计学意义。
结果
第一章：形状记忆合金支架-薄膜瓣复合体及其相应器械的设计与制作
1.方案一中的镍钛合金支架-脑膜建复合体之二、方案二和方案三中的镍钛合金支架-脑膜建复合体结构基本一致,按预定方案制作成功,其中,镍钛合金支架暂做四条支臂。已生产出的镍钛合金支架-脑膜建复合体均行灭菌处理,达到植入生物体内的要求,可备作动物模型的治疗实验用。
2.方案一中的器械制作成功。金属材质为医用不锈钢,激光焊接工艺,手柄部材质为工程塑料,将器械主体的手柄和前端设计并生产制作成为更利于操作的钝角形,可经高温高压、低温等离子等方法灭菌后使用。方案二和方案三中的器械未能制作成功。
3.将方案一中的镍钛合金支架-脑膜建复合体之二和相应器械配合使用,需要借助丝线牵拉,操作相对方便。注：在此后的动物模型治疗实验中据此而实际应用。
4.将前述方案做了修改,设计并制作出方案四。未再在此基础上加工生产镍钛合金支架-脑膜建复合体。试用中操作便捷性优于前者,且能达到抓持、固定、释放、取回等效果。
第二章：犬中颅底缺损并脑脊液漏模型的建立及治疗实验
1.按原定计划,单纯建模2例,实验治疗5例；模型可靠,手术顺利,单纯重建动作均在1分钟内完成。
2.2例单纯建模动物术中平稳,术后全部存活,切口愈合良好,无脑脊液漏,无神经功能障碍。5例实验治疗动物全部存活。术后情况同2例模型动物。
3.头颅侧位和斜位X光片显示单纯建模动物中颅底外侧骨性缺损区边缘清晰,缺损在10mm左右,未见其他异常表现,而实验治疗动物同时可见镍钛合金支架结构清晰,无伪影,无移位,四条支臂无弯曲变形。64排螺旋CT扫描并容积重建及最大密度投影进一步证实上述结果。1.5TMRI扫描可见手术区域脑挫伤表现,实验治疗动物对应位置未见支架影像,无干扰信号。
4.单纯建模动物肉眼观察术区及组织切片HE染色光镜下见局部、轻微炎性反应,肉芽组织瘢痕样生长。实验治疗动物尚见未全吸收脑膜建组织、镍钛合金支架包埋于其中,稳固,其表面小部分有少量瘢痕组织附着,其他大部分表面光滑完整。
第三章犬额窦缺损并脑脊液鼻漏模型的建立及实验治疗
1.单纯建模动物1例,因其出现脑脊液鼻漏未愈且可预见性死亡,在证实模型可靠性后,原拟定第2例单纯建模动物于术后半小时后即改行实验治疗。实际实施实验治疗6例。单纯重建操作在1分钟内完成。
2.术中经过平稳。第1例单纯建模动物术后持续脑脊液鼻漏,未能行走,复苏后意识逐渐清醒,术后4小时嗜睡、术后1天昏睡、术后3天昏迷,术后5天死亡。6例实验治疗者生存良好。术后过程与第二章描述基本一致。
3.实验治疗组动物头颅上下位X光片显示镍钛合金支架结构清晰,无伪影,四条支臂无弯曲变形,与额窦骨质缺损区的相对位置良好。64排螺旋CT检查结果证实上述结果。1.5TMRI检查仅见手术区域软组织损伤及轻微脑挫伤表现,未明确支架影像,无干扰信号。单纯建模死亡动物未行上述检查。
4.单纯建模动物尸检证实手术区局部和颅内组织广泛重度炎症。实验治疗动物犬颅底缺损区表面有薄层粘膜组织生长,其下有层状瘢痕组织形成,并与未全吸收脑膜建组织交错,镍钛合金支架包埋于其中,稳固。切片结果与第二章基本一致。
第四章镍钛合金支架抗腐蚀性和镍渗透性研究
1.犬中颅底缺损并脑脊液漏实验治疗前血清及局部组织中的镍含量分别为0.4180±0.09706、9.6680±2.93828,实验治疗后分别为0.4440±0.08173、9.0320±3.45773,实验治疗前后均无显著性差异(P值分别为0.240和0.581,均大于0.05)。犬额窦缺损并脑脊液鼻漏实验治疗前血清及局部组织中的镍含量分别为0.4420±0.06979、11.0600±2.68480,实验治疗后分别为0.4360±0.08204、10.7780±2.45873,实验治疗前后的结果均无显著性差异(P值分别为0.772和0.531,均大于0.05)。
2.犬中颅底缺损并脑脊液漏实验治疗组动物治疗所用镍钛合金支架使用前后钛、镍原子比含量比值分别为0.9847±0.00350、0.9832±0.00583,使用前后无显著性差异(P值为0.617,大于0.05)。犬额窦缺损并脑脊液鼻漏实验治疗组动物治疗所用镍钛合金支架使用前后钛、镍原子比含量比值分别为0.9864±0.00365,使用前后无显著性差异(P值为0.819,大于0.05)。
结论
1.镍钛合金支架-脑膜建复合体设计与制作成功,应用简便。
2.成功建立犬中颅底外侧缺损并脑脊液漏和犬额窦缺损并脑脊液鼻漏两种模型,稳定、可靠；前者可发生自愈,后者脑脊液漏致命。
3.镍钛合金支架-脑膜建复合体在两种动物模型中成功进行颅底重建,使用简便、安全,没有镍毒性反应的相关证据。
Background and Objection:
Skull base reconstruction is necessary portion of skull base surgery, which is so difficult because space is narrow and the organizational structure is complex. Bony and membrane structure defect caused by skull base surgery could bring up a lot of complication such as cerebrospinal fluid leakage, intracranial organization shift, and secondary intracranial infection, encephalomeningocele and corresponding disorders of nervous functions. Therefore, reliable reconstruction powerfully guarantees skull base surgery patients to recovery. We should establish a reliable lasting brain barrier, eliminate the dead space, do not affect the disease rechecked, obtain ideal beauty effect and avoid the appearance of the postoperative complications based on the convenient, simple operation, little injury, and true effect.
The initial skull base reconstruction was only closing dura mater with skip flap, followed by development of the local flap but with high incidence of CSF leakage and mortality. In1970s, regional myocutaneous flap was used to cure large defect, and osseous reconstruction was attemptted. In the80s and90s with the development of free tissue flap and free tissue flap with blood vessels, the effect of skull base reconstruction is more reliable. Autologous and foreign materials with respective good and bad points were applied parallelly. The autologous materials have been developed toward establishing effective blood, and foreign materials were more and more applied clinically because of good biocompitability, convenience, easily moulding and avoiding second trauma better than the characteristics of autologous material. The techniques of skull base reconstruction in clinical diagnosis and treatment have been developed from simple suturing, leak stopping to multilayer reconstruction and original anatomical structure recovery, from the uncertainty of the repair to unclear cognition of simultaneous the membrane/soft organization reconstruction and osseous reconstruction.
Whether in the microscopic neurosurgery or in endoscopic neurosurgery, skull base reconstruction technique make great progress. Since the1990s, many various kinds of means and ways have appeared, according to clinical doctors personalized characteristic. Multilayer reconstruction is widely known and accepted, which used one or several material with sandwich type or any of the improved methods so as to ascertain all the more to avoid postoperative severe complications such as cerebrospinal fluid leakage.
Compared with large, abundant and different clinical data, precise and normative experiment research was but relatively low. Most reports in the literature of werere localized, obvious individual results, and had no common representative value.
To find a kind of material and method which can be applied to clinical work and deal with different situation of the skull base defect, imagine a kind of complex of shape memory alloy and membrane materials, the former acting as support and the latter acting as the membranous repair function, at the same time which can keep the same shape after stretched out-drawn back and flexed, to synchronously finish osseous and membranous reconstruction. Not only it can reach the clinical effect and more convenient operation and shorten the operative time and trauma, but increase safety coefficient of the treatment.
In1963, Buehler, working at the United States naval ordnance laboratory, found that nickel-titanium alloy with equal atom ratio has the shape memory function, and named it after Nitinol which were the abbreviations reflecting the composition and initial found units of ni-ti-navy-ordnance-laboratory.
In further study, it was found that Nitinol was a kind of unique to ecological material, which still has excellent biocompatibility, high damping effect, high strength, corrosion resistance, the flexibility, and fatigue resistance, and other features in addition to good shape memory effect. Therefore, Nitinol has been widely used in biomedical fields.
Nitinol application in neurosurgery is less and developing at present, only including manufacturing aneurysm clamp, vascular interventional material for treatment, and so on. NormalGEN is a kind of biological artificial dural with completely independent intellectual property rights, has been verified at many experiments and used clinically for repairing dural defects.
At this topic, Nitinol and NormalGEN were treated as materials which was designed and manufactured as implants for skull base reconstruction both as osseous reconstruction and membranous reconstruction, corresponding instrument designed in the meantime, which would decrease operative trauma and shorten operative time while not increase patients and medical units operating costs. At the same time, biological toxicity of Nitinol was detected in that it has been reported in recent years that Nitinol may release the nickel ions which has ambiguous biological toxicity.
Methods and materials:
Chapter1:Design and production of complex of shape memory alloy-membrane flap and its corresponding instrument
1. Predetermined schemes:there were three schemes of shearing type, disengaging type1and2, each including shape memory alloy brace and delivering instrument. Detailed structure, composition, operation and chart were not listed.
2. Manufacture:According to the predetermined scheme, firstly produce Nitinol brace; secondly produce biological artificial dural with pig tendinous film as material packing Nitinol brace inside. At the same time, make the corresponding instrument.
Chapter2:Establishment and experimental treatment of dogs model with middle skull base defect and cerebrospinal fluid leakage
1. Experimental animals and grouped:2were randomly chosen to model in7healthy hybrid dogs, and the remaining5randomly numbered and experimentally treated based on modeling, namely Skull base reconstruction followed up modeling with sterilized complex of Nitinol brace-NormalGEN.
2. Studied the anatomic characteristics of dog cranial and performed preliminary experiment so as to ensure surgical incision and corresponding surgical approach, foresee possible intraoperative problem, prepare special equipment, and so on.
3. Model making:The animals were anesthetized by abdominal-venous composite anesthesia. Breathe by tracheal intubation. Supply continuously hypoflow oxygen. Monitored by ECG, and, when necessary, supported by the ventilator, maintained venous circuit. Fixed and protected at the side position with head high. The adjacent area was skin prepared from eye socket backward to antilobium up zygomatic arch and sterilized with iodophors. The arc incision was about5cm long between the cross point of rear margin of unilateral eye socket with level line and midpoint of zygomatic arch. Cut open skin to lateral bone area of middle skull base. It is mark where Vertical and horizontal bone texture transmigrate, namely, bone transit from horizon to vertical plane for identification. Inside the mark, drill a. bone window about1cm in diameter with high-speed miniature grinding drilling. Radially cut dural open together with arachnoid, confirm brain tissue exposed and cerebrospinal fluid overflow. Stop bleeding reliably and pave the thin layer gelatin sponge on dural. Interrupted and layered suture muscle and fascia. Continuously and intracutaneously suture skin with introversion method. During operation, intravenously inject2.4million units of penicillin within1000ml to1500ml physiological saline containing glucose. Remove tracheal intubation in time. Nursed lonely, bound slightly, eat early liquid diets and keep clean incision. Remove constraint after3days. Keep separately for2weeks.
4. Experimental therapy:The sterilized complex of Nitinol brace-Normal GEN was implanted into epidural gap (namely intracranial-epidural space) in defect area of middle skull base, based on successful modeling and aided by the corresponding instrument. Other disposal of experimental-treated animals was consistent with model animals.
5. Observe indexes:Dog's postoperative activity, the survival condition and whether or not cerebrospinal fluid leakage occurs, etc.; imaging and histopathological examination3months after operation.
Chapter3:Establishment and experimental treatment of dogs model with frontal sinus defect and cerebrospinal fluid rhinorrhea
1. Experimental animals and grouped:Same as Chapter2definitely.
2. Studied the anatomic characteristics of dog cranial and performed preliminary experiment same as Chapter2in principle.
3. Model making:Fixed and protected at the side position with head high, mandible adducted and neck lateral flexion so as to frontal region mediate and higher. Triangle hook incision was with two edges, each about2cm long, which angle was about60degree and base toward anterolateral orbital part. One edge was posterolateral margin of unilateral frontal sinus, another was midline. Cut open skin to bone, dissect myocutaneous flap to anterolateral base, expose ipsolateral frontoparietal bone area, drill a bone window about12mm in diameter on prominent place with high-speed miniature grinding drilling, expose and cut open mucous membrane of frontal sinus. Drill a bone window about10mm in diameter on a little even place on inferior wall of frontal sinus close to midline with high-speed miniature grinding drilling, expose and radially cut open dural together with arachnoid, confirm brain tissue exposed and cerebrospinal fluid overflow. Stop bleeding reliably and pave the thin layer gelatin sponge with EC glue on dural. Compress for incision flap moving with breathing. General management was identified with Chapter2.
4. Experimental therapy:The sterilized complex of Nitinol brace-NormalGEN was implanted into epidural gap (namely intracranial-epidural space) in defect area of inferior wall of frontal sinus, based on successful modeling and aided by the corresponding instrument. Other disposal of experimental-treated animals was consistent with model animals.
5. Observe indexes:Same as Chapter2.
Chapter4:Research on Corrosion resistance and nickel permeability Of Nitinol brace
1. Specimen collection and matching group:With inductively coupled plasma mass spectrum, test nickel content in blood specimens and local tissue specimens of two kinds of model animals before and3months after receiving experimental treatment. With scanning electron microscope, detect atomic ratio contents of nickel and titanium on the surface of Nitinol brace before and3months after receiving experiment treatment.
2. Statistical treatment:Data were treated with statistical analysis software SPSS17.0using matching t test. The variances were represented by a mean±standard deviation. Compare nickel contents in blood specimens and local tissue specimens of two kinds of model animals before and3months after receiving experimental treatment. Compare ratios of atomic ratio content of titanium and nickel on the surface of Nitinol brace before and3months after experimental treatment. P<0.05indicated difference with a statistical significance.
Results:
Chapter1:
1. The complex2of Nitinol and NormalGEN in scheme1was almost same as the complex of Nitinol and NormalGEN in scheme2and3, which was manufactured successfully according to predetermined scheme. Nitinol brace had four arms. The producted complexes of Nitinol and NormalGEN were sterilized so that it was safe to implant into body. The complexes could be prepared for experimental treatment of the model animals.
2. The instrument in scheme1was produced successfully. Metal material was medical stainless steel with laser welding technology. Material of the instrumental handle was engineering plastic material. It was obtuse angle formed by the handle and the front so that it was more advantageous to use the instrument which could be sterilized by high temperature-high pressure and low temperature plasma sterilization method. But, the instrument in scheme2and3failed to make.
3. Use of the complex and instrument need drag with the help of the silk thread, relatively easily operated. Note:The type of complex and instrument were in practical application during subsequent experimental treatment of model animals accordingly.
4. The scheme4was designed and determined by modifying the3scheme above. The trial operation convenience was superior to the former, and we could achieve effect of grasping, fixing, releasing and retrieving. But, the new complex has not been produced.
Chapter2:
1. As originally planned,2cases were simple modeling,5cases experimental treatmented. Model was reliable and operation smooth. The action of simple reconstruction was completed within1minute.
2. The two simple modeling animals were stable during the process of operation and postoperative survived with incision healed well, no cerebrospinal fluid leakage, no nervous dysfunction. Five cases of experimental treatmented animals all survived. Postoperative situation was same as the two model animals.
3. Head lateral and oblique X-rays films showed clear edge of middle skull base lateral bone defects about10mm in diameter of simple modeling animals without other abnormalities, and showed that Nitinol brace was clear without artifact or shift and four support arm without bending deformation in experimental treatment animals.64-slice spiral CT scanning followed by volume reconstruction and maximum intensity projection further confirmed these results.1.5TMRI scanning showed that brain contusion performance in the surgical field, while no brace images and interfering signals at corresponding to the location of experimental treatment animals.
4. Local and mild inflammatory response with granulation tissue growing scar-like could be seen in the operative area of simple modeling animal by naked eye and on its tissue sections by HE staining under the light microscope. In addition, we could see that NormalGEN were not all absorbed in the operative area of experimental treatment animals, and that Nitinol brace was embedded steadily. A small amount of scar tissue attached to a small part of brace surface, but most of the other surface is smooth and complete.
Chapter3:
1. The first case of simple modeling animal died predictably from CSF rhinorrhea. which confirmed reliable model. The second predetermined simple modeling animal was diverted into experimental treatment after half an hour. Therefore,6cases received experimental treatment. The action of simple reconstruction was completed within1minute.
2. All animals were stable during the process of operation. The first case of simple modeling animal appeared persistent postoperative cerebrospinal fluid rhinorrhea, unable to walk, transient conscious after resuscitation, drowsy after four hours, lethargy after one day, coma after three days and death after five days. Six cases of experimental treatment animals survived well. The postoperative course was same as described in Chapter2.
3. head up-down positional X-ray film showed that Nitinol brace was clear without artifact or shift, four support arm without bending deformation and ideally position relative to the frontal sinus bone defect in experimental treatment animals.64-slice spiral CT scanning followed by volume reconstruction and maximum intensity projection further confirmed these results.1.5TMRI scanning showed that brain contusion performance in the surgical field, while no brace images and interfering signals at corresponding to the location of experimental treatment animals. Dead simple modeling animal had not been checked.
4. Autopsy of simple modeling animal confirmed the operative region and intracranial organizations widely severe inflammation. The thin layer of mucous membrane tissue grew on skull base defect surface of animals receiving experimental treatment with layered scar tissue forming below, and not fully absorbed meningeal built organizations staggered nitinol stents embedded in a solid. Slice results are basically same as Chapter2.
Chapter4:
1. Nickel contents in blood specimens and local tissue specimens of animals modeling with middle skull base defect and cerebrospinal fluid leakage before and3months after receiving experimental treatment was respectively0.4180±0.09706,9.6680±2.93828,0.4440±0.08173,9.0320±3.45773, had no significant difference (P values were respectively0.240and0.581, both greater than0.05). Nickel contents in blood specimens and local tissue specimens of animals modeling with frontal sinus defect and cerebrospinal fluid rhinorrhea before and3months after receiving experimental treatment was respectively0.4420±0.06979,11.0600±2.68480,0.4360±0.08204and10.7780±2.45873, had no significant difference (P values were respectively0.772and0.531, both greater than0.05).
2. Ratios of atomic ratio content of titanium and nickel on the surface of Nitinol brace before and3months after experimental treatment of reconstructing middle skull base defect and cerebrospinal fluid leakage was respectively0.9847±0.00350and0.9832±0.00583without significant difference (P=0.617, greater than0.05). Ratios of atomic ratio content of titanium and nickel on the surface of Nitinol brace before and3months after experimental treatment of reconstructing frontal sinus defect and cerebrospinal fluid rhinorrhea was respectively0.9864±0.00365without significant difference (P=0.819, greater than0.05).
Conclusion
1. Complex of Nitinol brace and NormalGEN was successfully designed and manufactured, easy to use.
2. Successfully established two kinds of animal models including middle skull base defect with cerebrospinal fluid leakage and frontal sinus defect and cerebrospinal fluid rhinorrhea, both stable and reliable; the former can happen self-healing, the latter has deadly cerebrospinal fluid leakage
3. Complex of Nitinol brace and NormalGEN was successfully applied to reconstruct the two kinds of model animals, easy and safe to use. There was no evidence on nickel toxicity.
颅底重建是颅底手术不可缺少的一部分。同时,颅底手术共同的特点是操作空间狭小、组织结构复杂、难度大。颅底手术带来的骨性及膜性的结构缺损会引发脑脊液漏、颅内组织移位,从而继发颅内感染、脑膜脑膨出及相应神经功能障碍等问题。因此,可靠的颅底重建是颅底手术患者康复的有力保障。既要建立可靠持久的颅脑屏障、消除死腔、不影响疾病复查,又要获得理想的美容效果、避免术后并发症的出现,取材方便、操作简单、副损伤小、效果切实。
初始的颅底重建仅以皮瓣密闭硬膜,之后发展到了局部瓣,但脑脊液漏发生率和死亡率高。20世纪70年代出现了区域性肌皮瓣治疗较大缺损,并进行骨性重建的尝试。20世纪80、90年代游离组织瓣以及带血管游离组织瓣的发展使得颅底重建的效果更加可靠。自体组织和异体材料的应用并行,各具优劣点。自体材料已朝建立有效血运的方向发展,异体材料由于具有组织相容性好、取用方便、易于塑形、避免二次创伤等优于自体材料的特点,越来越多地应用于临床。
颅底重建技术在临床诊疗中由简单缝合、堵漏逐步发展到多层重建、恢复原有解剖层次结构,由对不确定修补的摸索发展到并对膜性/软组织性重建与骨性重建并重的不清晰认知。不论是在显微神经外科还是在内镜神经外科,颅底重建技术进步突出。自20世纪90年代开始,有诸多的门类繁多的、据临床医生个性化特点而层出的手段和方式,目前的广泛认识和接受的是利用一种或多种重建材料以三明治式或其各种改良方法进行的多层重建,以此更加确定避免术后脑脊液漏等严重并发症。
与大量、丰富而又各异的临床资料相比,严谨、规范的实验研究却相对稀少。文献中所报导的多数是小范围的、个体化明显的结果,而无普遍代表性价值。
为寻找一种能够应用到临床的、能够应对不同情况颅底缺损的材料与方法,设想将一种形状记忆合金及薄膜材料融合到一起,前者起骨性支撑作用,后者起膜性修补作用,同时又能伸缩、折曲而保持形状不变,就会将骨性重建与膜性重建同步完成,不仅能达到预期的临床效果,还能更加方便手术操作、缩短手术时间、减小手术创伤,从而增加了救治患者的安全系数。
1963年美国海军军械研究室Buehler发现的等原子比的镍钛合金具有形状记忆功能,并以反映其组成成分和初始发现单位的ni-ti-navy-ordnance-laboratory的缩写nitinol为其命名。深入研究发现镍钛合金除了具有良好形状记忆效应外,还有优良的生物相容性、高阻尼效应、高强度、超弹性、抗腐蚀性及抗疲劳性等特点,是一种独特的拟生态材料,现已被广泛应用于生物医学领域。镍钛合金在神经外科的许多应用目前处于发展阶段,相对较少,仅有动脉瘤夹、血管介入治疗材料等。脑膜建是一种生物型人工硬脑膜,具有国内完全自主知识产权,已被较多实验证实并临床用于硬脑膜缺损修补。
本课题拟以形状记忆合金中的镍钛合金和生物型人工硬脑膜脑膜建为材料、设计并制作用于颅底重建中兼顾骨性重建与膜性重建的植入物及其使用器械,从而减轻手术创伤、缩短手术时间,同时又不增加患者费用及医疗单位的运行成本。因近年有文献报导镍钛合金因可能释放镍离子而具有生物毒性,故同时对此做初步研究。
材料与方法
第一章：形状记忆合金支架-薄膜瓣复合体及其相应器械的设计与制作
1.拟定方案：有剪切式、解脱一式和解脱二式三种初始设计方案,均包括形状记忆合金支架-薄膜瓣复合体及其递送器械。详细结构及组成、操作及图示略。
2.材料的选择与制作：按预定设计方案,先生产制作镍钛合金支架；再在生产以猪腱膜提取物为原材料生产生物型人工硬脑膜过程中将镍钛合金支架包裹于其内。同时制作相应器械。
第二章：犬中颅底缺损并脑脊液漏模型的建立及实验治疗
1.实验动物及分组：选择健康杂种犬7只,随机先取2只建模,余下5只随机编号,在建模基础上实施实验治疗,即一期以此前生产制作并无菌化处理的镍钛合金支架-脑膜建复合体行颅底修补重建术。
2.犬颅解剖特点的研究及预实验：确定手术切口及相应手术路径,预见术中可能出现问题、需要使用的特殊器械等。
3.模型制作：腹腔-静脉联合麻醉,经口气管插管,吸氧,心电监测,必要时呼吸机支持,维持静脉通路。侧卧头高位,固定、保护。眼眶后至耳屏前、颧弓上方的手术相邻区域备皮。碘伏消毒。做犬单侧眼眶后水平相邻点与同侧颧弓中点间弧形切口,长约5cm,切开至中颅底外侧骨质。以纵向与横向移行转折处、即骨质垂直面与水平面移行处为标识,于其内侧以微型磨钻于建模区内磨出直径1cm骨窗,放射状切开硬脑膜(蛛网膜一并开放),确认脑组织外露、脑脊液溢出,止血可靠,敷薄层明胶海绵后,分层间断缝合颅外肌层、筋膜,内翻法皮内连续缝合皮肤。术中、术后静脉输入糖盐水1000ml-1500ml,带入青霉素240万单位。及时拔除气管插管。隔离观察、稍加约束、早期进流食、保持切口清洁。3日后解除约束。2周内单独饲养。
4.实验治疗：在建模型成功基础上、相应器械辅助下一期将镍钛合金支架-脑膜建复合体置于犬中颅底缺损区的骨质内板与硬膜间隙(即颅内-硬膜外间隙)。实验治疗动物的其他操作和处置与模型动物一致。
5.观察指标：术后犬的行为活动与生存情况、有无脑脊液漏等；术后3个月行影像学及组织病理学检查。
第三章犬额窦缺损并脑脊液鼻漏模型的建立及实验治疗
1.实验动物及分组：具体同第二章。
2.犬颅解剖特点的研究及预实验：原则上同第二章。
3.模型制作：一般处理同第二章。术中取侧卧头高位,收下颌并颈侧屈,使额部居中、居高。做犬单侧额窦后外侧缘与中线夹角处之三角钩形切口,成角600左右,每边长约2cm,基底侧朝向同侧前外之眶部。切开至骨质,剥离肌皮瓣翻向前外侧,显露额窦上壁额顶部骨质；于其最凸出处以微钻磨出直径12mm骨窗,显露并切开额窦粘膜；于额窦下壁中部近中线侧、稍平坦区,以微钻磨出直径1cm骨窗,显露并放射状切开硬膜(蛛网膜下腔一并开放)。其外敷明胶海绵并涂EC耳脑胶。切口皮瓣随呼吸而龛动,予以加压包扎。
4.实验治疗：在建模成功基础上、在相应器械辅助下一期将镍钛合金支架-脑膜建复合体置于犬额窦下壁缺损区的骨质内板与硬膜间隙(即颅内-硬膜外间隙)。实验治疗动物的其他操作和处置与模型动物完全一致。
5.观察指标：同第二章。
第四章镍钛合金支架抗腐蚀性和镍渗透性研究
1.标本收集与配对分组：收集两种动物模型实验治疗组动物治疗前后的血液标本、局部组织标本,以电感耦合等离子体质谱法检测其中的镍含量。收集两种动物模型实验治疗组动物使用前后的镍钛合金支架以扫描电子显微镜检测支架表面的钛、镍原子比含量。
2.统计学处理：数据采用配对t检验法,经SPSS17.0统计分析软件处理,变量以均数±标准差表示。分别比较两种模型实验治疗前后动物血液标本及局部组织标本中的镍含量、镍钛合金支架使用前与实验治疗后3个月后钛镍原子比含量的比值。P<0.05为差别有统计学意义。
结果
第一章：形状记忆合金支架-薄膜瓣复合体及其相应器械的设计与制作
1.方案一中的镍钛合金支架-脑膜建复合体之二、方案二和方案三中的镍钛合金支架-脑膜建复合体结构基本一致,按预定方案制作成功,其中,镍钛合金支架暂做四条支臂。已生产出的镍钛合金支架-脑膜建复合体均行灭菌处理,达到植入生物体内的要求,可备作动物模型的治疗实验用。
2.方案一中的器械制作成功。金属材质为医用不锈钢,激光焊接工艺,手柄部材质为工程塑料,将器械主体的手柄和前端设计并生产制作成为更利于操作的钝角形,可经高温高压、低温等离子等方法灭菌后使用。方案二和方案三中的器械未能制作成功。
3.将方案一中的镍钛合金支架-脑膜建复合体之二和相应器械配合使用,需要借助丝线牵拉,操作相对方便。注：在此后的动物模型治疗实验中据此而实际应用。
4.将前述方案做了修改,设计并制作出方案四。未再在此基础上加工生产镍钛合金支架-脑膜建复合体。试用中操作便捷性优于前者,且能达到抓持、固定、释放、取回等效果。
第二章：犬中颅底缺损并脑脊液漏模型的建立及治疗实验
1.按原定计划,单纯建模2例,实验治疗5例；模型可靠,手术顺利,单纯重建动作均在1分钟内完成。
2.2例单纯建模动物术中平稳,术后全部存活,切口愈合良好,无脑脊液漏,无神经功能障碍。5例实验治疗动物全部存活。术后情况同2例模型动物。
3.头颅侧位和斜位X光片显示单纯建模动物中颅底外侧骨性缺损区边缘清晰,缺损在10mm左右,未见其他异常表现,而实验治疗动物同时可见镍钛合金支架结构清晰,无伪影,无移位,四条支臂无弯曲变形。64排螺旋CT扫描并容积重建及最大密度投影进一步证实上述结果。1.5TMRI扫描可见手术区域脑挫伤表现,实验治疗动物对应位置未见支架影像,无干扰信号。
4.单纯建模动物肉眼观察术区及组织切片HE染色光镜下见局部、轻微炎性反应,肉芽组织瘢痕样生长。实验治疗动物尚见未全吸收脑膜建组织、镍钛合金支架包埋于其中,稳固,其表面小部分有少量瘢痕组织附着,其他大部分表面光滑完整。
第三章犬额窦缺损并脑脊液鼻漏模型的建立及实验治疗
1.单纯建模动物1例,因其出现脑脊液鼻漏未愈且可预见性死亡,在证实模型可靠性后,原拟定第2例单纯建模动物于术后半小时后即改行实验治疗。实际实施实验治疗6例。单纯重建操作在1分钟内完成。
2.术中经过平稳。第1例单纯建模动物术后持续脑脊液鼻漏,未能行走,复苏后意识逐渐清醒,术后4小时嗜睡、术后1天昏睡、术后3天昏迷,术后5天死亡。6例实验治疗者生存良好。术后过程与第二章描述基本一致。
3.实验治疗组动物头颅上下位X光片显示镍钛合金支架结构清晰,无伪影,四条支臂无弯曲变形,与额窦骨质缺损区的相对位置良好。64排螺旋CT检查结果证实上述结果。1.5TMRI检查仅见手术区域软组织损伤及轻微脑挫伤表现,未明确支架影像,无干扰信号。单纯建模死亡动物未行上述检查。
4.单纯建模动物尸检证实手术区局部和颅内组织广泛重度炎症。实验治疗动物犬颅底缺损区表面有薄层粘膜组织生长,其下有层状瘢痕组织形成,并与未全吸收脑膜建组织交错,镍钛合金支架包埋于其中,稳固。切片结果与第二章基本一致。
第四章镍钛合金支架抗腐蚀性和镍渗透性研究
1.犬中颅底缺损并脑脊液漏实验治疗前血清及局部组织中的镍含量分别为0.4180±0.09706、9.6680±2.93828,实验治疗后分别为0.4440±0.08173、9.0320±3.45773,实验治疗前后均无显著性差异(P值分别为0.240和0.581,均大于0.05)。犬额窦缺损并脑脊液鼻漏实验治疗前血清及局部组织中的镍含量分别为0.4420±0.06979、11.0600±2.68480,实验治疗后分别为0.4360±0.08204、10.7780±2.45873,实验治疗前后的结果均无显著性差异(P值分别为0.772和0.531,均大于0.05)。
2.犬中颅底缺损并脑脊液漏实验治疗组动物治疗所用镍钛合金支架使用前后钛、镍原子比含量比值分别为0.9847±0.00350、0.9832±0.00583,使用前后无显著性差异(P值为0.617,大于0.05)。犬额窦缺损并脑脊液鼻漏实验治疗组动物治疗所用镍钛合金支架使用前后钛、镍原子比含量比值分别为0.9864±0.00365,使用前后无显著性差异(P值为0.819,大于0.05)。
结论
1.镍钛合金支架-脑膜建复合体设计与制作成功,应用简便。
2.成功建立犬中颅底外侧缺损并脑脊液漏和犬额窦缺损并脑脊液鼻漏两种模型,稳定、可靠；前者可发生自愈,后者脑脊液漏致命。
3.镍钛合金支架-脑膜建复合体在两种动物模型中成功进行颅底重建,使用简便、安全,没有镍毒性反应的相关证据。
Background and Objection:
Skull base reconstruction is necessary portion of skull base surgery, which is so difficult because space is narrow and the organizational structure is complex. Bony and membrane structure defect caused by skull base surgery could bring up a lot of complication such as cerebrospinal fluid leakage, intracranial organization shift, and secondary intracranial infection, encephalomeningocele and corresponding disorders of nervous functions. Therefore, reliable reconstruction powerfully guarantees skull base surgery patients to recovery. We should establish a reliable lasting brain barrier, eliminate the dead space, do not affect the disease rechecked, obtain ideal beauty effect and avoid the appearance of the postoperative complications based on the convenient, simple operation, little injury, and true effect.
The initial skull base reconstruction was only closing dura mater with skip flap, followed by development of the local flap but with high incidence of CSF leakage and mortality. In1970s, regional myocutaneous flap was used to cure large defect, and osseous reconstruction was attemptted. In the80s and90s with the development of free tissue flap and free tissue flap with blood vessels, the effect of skull base reconstruction is more reliable. Autologous and foreign materials with respective good and bad points were applied parallelly. The autologous materials have been developed toward establishing effective blood, and foreign materials were more and more applied clinically because of good biocompitability, convenience, easily moulding and avoiding second trauma better than the characteristics of autologous material. The techniques of skull base reconstruction in clinical diagnosis and treatment have been developed from simple suturing, leak stopping to multilayer reconstruction and original anatomical structure recovery, from the uncertainty of the repair to unclear cognition of simultaneous the membrane/soft organization reconstruction and osseous reconstruction.
Whether in the microscopic neurosurgery or in endoscopic neurosurgery, skull base reconstruction technique make great progress. Since the1990s, many various kinds of means and ways have appeared, according to clinical doctors personalized characteristic. Multilayer reconstruction is widely known and accepted, which used one or several material with sandwich type or any of the improved methods so as to ascertain all the more to avoid postoperative severe complications such as cerebrospinal fluid leakage.
Compared with large, abundant and different clinical data, precise and normative experiment research was but relatively low. Most reports in the literature of werere localized, obvious individual results, and had no common representative value.
To find a kind of material and method which can be applied to clinical work and deal with different situation of the skull base defect, imagine a kind of complex of shape memory alloy and membrane materials, the former acting as support and the latter acting as the membranous repair function, at the same time which can keep the same shape after stretched out-drawn back and flexed, to synchronously finish osseous and membranous reconstruction. Not only it can reach the clinical effect and more convenient operation and shorten the operative time and trauma, but increase safety coefficient of the treatment.
In1963, Buehler, working at the United States naval ordnance laboratory, found that nickel-titanium alloy with equal atom ratio has the shape memory function, and named it after Nitinol which were the abbreviations reflecting the composition and initial found units of ni-ti-navy-ordnance-laboratory.
In further study, it was found that Nitinol was a kind of unique to ecological material, which still has excellent biocompatibility, high damping effect, high strength, corrosion resistance, the flexibility, and fatigue resistance, and other features in addition to good shape memory effect. Therefore, Nitinol has been widely used in biomedical fields.
Nitinol application in neurosurgery is less and developing at present, only including manufacturing aneurysm clamp, vascular interventional material for treatment, and so on. NormalGEN is a kind of biological artificial dural with completely independent intellectual property rights, has been verified at many experiments and used clinically for repairing dural defects.
At this topic, Nitinol and NormalGEN were treated as materials which was designed and manufactured as implants for skull base reconstruction both as osseous reconstruction and membranous reconstruction, corresponding instrument designed in the meantime, which would decrease operative trauma and shorten operative time while not increase patients and medical units operating costs. At the same time, biological toxicity of Nitinol was detected in that it has been reported in recent years that Nitinol may release the nickel ions which has ambiguous biological toxicity.
Methods and materials:
Chapter1:Design and production of complex of shape memory alloy-membrane flap and its corresponding instrument
1. Predetermined schemes:there were three schemes of shearing type, disengaging type1and2, each including shape memory alloy brace and delivering instrument. Detailed structure, composition, operation and chart were not listed.
2. Manufacture:According to the predetermined scheme, firstly produce Nitinol brace; secondly produce biological artificial dural with pig tendinous film as material packing Nitinol brace inside. At the same time, make the corresponding instrument.
Chapter2:Establishment and experimental treatment of dogs model with middle skull base defect and cerebrospinal fluid leakage
1. Experimental animals and grouped:2were randomly chosen to model in7healthy hybrid dogs, and the remaining5randomly numbered and experimentally treated based on modeling, namely Skull base reconstruction followed up modeling with sterilized complex of Nitinol brace-NormalGEN.
2. Studied the anatomic characteristics of dog cranial and performed preliminary experiment so as to ensure surgical incision and corresponding surgical approach, foresee possible intraoperative problem, prepare special equipment, and so on.
3. Model making:The animals were anesthetized by abdominal-venous composite anesthesia. Breathe by tracheal intubation. Supply continuously hypoflow oxygen. Monitored by ECG, and, when necessary, supported by the ventilator, maintained venous circuit. Fixed and protected at the side position with head high. The adjacent area was skin prepared from eye socket backward to antilobium up zygomatic arch and sterilized with iodophors. The arc incision was about5cm long between the cross point of rear margin of unilateral eye socket with level line and midpoint of zygomatic arch. Cut open skin to lateral bone area of middle skull base. It is mark where Vertical and horizontal bone texture transmigrate, namely, bone transit from horizon to vertical plane for identification. Inside the mark, drill a. bone window about1cm in diameter with high-speed miniature grinding drilling. Radially cut dural open together with arachnoid, confirm brain tissue exposed and cerebrospinal fluid overflow. Stop bleeding reliably and pave the thin layer gelatin sponge on dural. Interrupted and layered suture muscle and fascia. Continuously and intracutaneously suture skin with introversion method. During operation, intravenously inject2.4million units of penicillin within1000ml to1500ml physiological saline containing glucose. Remove tracheal intubation in time. Nursed lonely, bound slightly, eat early liquid diets and keep clean incision. Remove constraint after3days. Keep separately for2weeks.
4. Experimental therapy:The sterilized complex of Nitinol brace-Normal GEN was implanted into epidural gap (namely intracranial-epidural space) in defect area of middle skull base, based on successful modeling and aided by the corresponding instrument. Other disposal of experimental-treated animals was consistent with model animals.
5. Observe indexes:Dog's postoperative activity, the survival condition and whether or not cerebrospinal fluid leakage occurs, etc.; imaging and histopathological examination3months after operation.
Chapter3:Establishment and experimental treatment of dogs model with frontal sinus defect and cerebrospinal fluid rhinorrhea
1. Experimental animals and grouped:Same as Chapter2definitely.
2. Studied the anatomic characteristics of dog cranial and performed preliminary experiment same as Chapter2in principle.
3. Model making:Fixed and protected at the side position with head high, mandible adducted and neck lateral flexion so as to frontal region mediate and higher. Triangle hook incision was with two edges, each about2cm long, which angle was about60degree and base toward anterolateral orbital part. One edge was posterolateral margin of unilateral frontal sinus, another was midline. Cut open skin to bone, dissect myocutaneous flap to anterolateral base, expose ipsolateral frontoparietal bone area, drill a bone window about12mm in diameter on prominent place with high-speed miniature grinding drilling, expose and cut open mucous membrane of frontal sinus. Drill a bone window about10mm in diameter on a little even place on inferior wall of frontal sinus close to midline with high-speed miniature grinding drilling, expose and radially cut open dural together with arachnoid, confirm brain tissue exposed and cerebrospinal fluid overflow. Stop bleeding reliably and pave the thin layer gelatin sponge with EC glue on dural. Compress for incision flap moving with breathing. General management was identified with Chapter2.
4. Experimental therapy:The sterilized complex of Nitinol brace-NormalGEN was implanted into epidural gap (namely intracranial-epidural space) in defect area of inferior wall of frontal sinus, based on successful modeling and aided by the corresponding instrument. Other disposal of experimental-treated animals was consistent with model animals.
5. Observe indexes:Same as Chapter2.
Chapter4:Research on Corrosion resistance and nickel permeability Of Nitinol brace
1. Specimen collection and matching group:With inductively coupled plasma mass spectrum, test nickel content in blood specimens and local tissue specimens of two kinds of model animals before and3months after receiving experimental treatment. With scanning electron microscope, detect atomic ratio contents of nickel and titanium on the surface of Nitinol brace before and3months after receiving experiment treatment.
2. Statistical treatment:Data were treated with statistical analysis software SPSS17.0using matching t test. The variances were represented by a mean±standard deviation. Compare nickel contents in blood specimens and local tissue specimens of two kinds of model animals before and3months after receiving experimental treatment. Compare ratios of atomic ratio content of titanium and nickel on the surface of Nitinol brace before and3months after experimental treatment. P<0.05indicated difference with a statistical significance.
Results:
Chapter1:
1. The complex2of Nitinol and NormalGEN in scheme1was almost same as the complex of Nitinol and NormalGEN in scheme2and3, which was manufactured successfully according to predetermined scheme. Nitinol brace had four arms. The producted complexes of Nitinol and NormalGEN were sterilized so that it was safe to implant into body. The complexes could be prepared for experimental treatment of the model animals.
2. The instrument in scheme1was produced successfully. Metal material was medical stainless steel with laser welding technology. Material of the instrumental handle was engineering plastic material. It was obtuse angle formed by the handle and the front so that it was more advantageous to use the instrument which could be sterilized by high temperature-high pressure and low temperature plasma sterilization method. But, the instrument in scheme2and3failed to make.
3. Use of the complex and instrument need drag with the help of the silk thread, relatively easily operated. Note:The type of complex and instrument were in practical application during subsequent experimental treatment of model animals accordingly.
4. The scheme4was designed and determined by modifying the3scheme above. The trial operation convenience was superior to the former, and we could achieve effect of grasping, fixing, releasing and retrieving. But, the new complex has not been produced.
Chapter2:
1. As originally planned,2cases were simple modeling,5cases experimental treatmented. Model was reliable and operation smooth. The action of simple reconstruction was completed within1minute.
2. The two simple modeling animals were stable during the process of operation and postoperative survived with incision healed well, no cerebrospinal fluid leakage, no nervous dysfunction. Five cases of experimental treatmented animals all survived. Postoperative situation was same as the two model animals.
3. Head lateral and oblique X-rays films showed clear edge of middle skull base lateral bone defects about10mm in diameter of simple modeling animals without other abnormalities, and showed that Nitinol brace was clear without artifact or shift and four support arm without bending deformation in experimental treatment animals.64-slice spiral CT scanning followed by volume reconstruction and maximum intensity projection further confirmed these results.1.5TMRI scanning showed that brain contusion performance in the surgical field, while no brace images and interfering signals at corresponding to the location of experimental treatment animals.
4. Local and mild inflammatory response with granulation tissue growing scar-like could be seen in the operative area of simple modeling animal by naked eye and on its tissue sections by HE staining under the light microscope. In addition, we could see that NormalGEN were not all absorbed in the operative area of experimental treatment animals, and that Nitinol brace was embedded steadily. A small amount of scar tissue attached to a small part of brace surface, but most of the other surface is smooth and complete.
Chapter3:
1. The first case of simple modeling animal died predictably from CSF rhinorrhea. which confirmed reliable model. The second predetermined simple modeling animal was diverted into experimental treatment after half an hour. Therefore,6cases received experimental treatment. The action of simple reconstruction was completed within1minute.
2. All animals were stable during the process of operation. The first case of simple modeling animal appeared persistent postoperative cerebrospinal fluid rhinorrhea, unable to walk, transient conscious after resuscitation, drowsy after four hours, lethargy after one day, coma after three days and death after five days. Six cases of experimental treatment animals survived well. The postoperative course was same as described in Chapter2.
3. head up-down positional X-ray film showed that Nitinol brace was clear without artifact or shift, four support arm without bending deformation and ideally position relative to the frontal sinus bone defect in experimental treatment animals.64-slice spiral CT scanning followed by volume reconstruction and maximum intensity projection further confirmed these results.1.5TMRI scanning showed that brain contusion performance in the surgical field, while no brace images and interfering signals at corresponding to the location of experimental treatment animals. Dead simple modeling animal had not been checked.
4. Autopsy of simple modeling animal confirmed the operative region and intracranial organizations widely severe inflammation. The thin layer of mucous membrane tissue grew on skull base defect surface of animals receiving experimental treatment with layered scar tissue forming below, and not fully absorbed meningeal built organizations staggered nitinol stents embedded in a solid. Slice results are basically same as Chapter2.
Chapter4:
1. Nickel contents in blood specimens and local tissue specimens of animals modeling with middle skull base defect and cerebrospinal fluid leakage before and3months after receiving experimental treatment was respectively0.4180±0.09706,9.6680±2.93828,0.4440±0.08173,9.0320±3.45773, had no significant difference (P values were respectively0.240and0.581, both greater than0.05). Nickel contents in blood specimens and local tissue specimens of animals modeling with frontal sinus defect and cerebrospinal fluid rhinorrhea before and3months after receiving experimental treatment was respectively0.4420±0.06979,11.0600±2.68480,0.4360±0.08204and10.7780±2.45873, had no significant difference (P values were respectively0.772and0.531, both greater than0.05).
2. Ratios of atomic ratio content of titanium and nickel on the surface of Nitinol brace before and3months after experimental treatment of reconstructing middle skull base defect and cerebrospinal fluid leakage was respectively0.9847±0.00350and0.9832±0.00583without significant difference (P=0.617, greater than0.05). Ratios of atomic ratio content of titanium and nickel on the surface of Nitinol brace before and3months after experimental treatment of reconstructing frontal sinus defect and cerebrospinal fluid rhinorrhea was respectively0.9864±0.00365without significant difference (P=0.819, greater than0.05).
Conclusion
1. Complex of Nitinol brace and NormalGEN was successfully designed and manufactured, easy to use.
2. Successfully established two kinds of animal models including middle skull base defect with cerebrospinal fluid leakage and frontal sinus defect and cerebrospinal fluid rhinorrhea, both stable and reliable; the former can happen self-healing, the latter has deadly cerebrospinal fluid leakage
3. Complex of Nitinol brace and NormalGEN was successfully applied to reconstruct the two kinds of model animals, easy and safe to use. There was no evidence on nickel toxicity.
引文
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