CN103099689B - 微创手术用盘旋状髓核假体的制备方法及应用 - Google Patents
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Abstract
本发明涉及微创手术用盘旋状髓核假体的制备方法及应用，适用于微创经皮-穿刺手术植入，用于颈椎、腰椎间盘病变的治疗。属于生物医用材料领域。其特征是通过将一定质量比的PVA和去离子水混合，高温高压下形成溶胶，在特定模具中经过数次冷冻-解冻循环、γ射线辐射等方法得到具有良好生物力学性能的仿生盘旋状髓核假体，该髓核假体通过微创经皮-穿刺手术器械植入，通过器械后，恢复盘旋状，形状记忆性好，并可以通过微创经皮-穿刺手术取出，安全性高；该髓核假体生物相容性好，生物力学性能接近人体髓核，满足髓核医学服役要求；溶胀性能满足术后恢复及服役要求。
Description
技术领域
本发明涉及新型医用仿生材料技术领域，具体的说，涉及微创经皮-穿刺手术用仿生盘旋状髓核假体的制备方法及应用。
背景技术
椎间盘病变是一种常见多发病，其中以颈椎、腰椎间盘病变最为常见，严重影响患者的劳动能力和生活质量，受到社会的高度重视。在椎间盘病变中，髓核及纤维环完全破坏后一般需要进行全盘置换，这种手术创伤大且长期效果并不明显。而对一般的髓核退变来说，纤维环是完好的，这时只需进行髓核置换。人工髓核置换由于维持了脊椎正常的生理运动功能，恢复了椎间盘的高度，纠正了椎间盘髓核切除后的应力分部紊乱和结构异常，被公认为是替代传统脊柱融合术和椎间盘髓核摘除术治疗椎间盘病变的有效方法。随着对脊柱生物力学机制认识的加深和材料科学的发展，人工髓核假体已成为当今医学及材料科学研究的热点。
现代仿生髓核假体材料的设计既要考虑到其生物力学模拟功能，还要考虑其生物介质传输功能等，需满足的设计要求为：
1.良好的生物相容性、力学性能和抗疲劳性能。无局部、全身排斥反应，能在正常应力负荷范围内维持椎间盘应有的高度。
2.不需固定装置，假体在摘除的髓核空间中具有良好稳定性、顺从性。假体不易移位，避免接触面的高应力，具有较均匀的应力分散作用，保护终板，能恢复纤维环正常长度和张力，促进纤维环愈合。
3.外形设计尽量的简单，与正常髓核相似，减少纤维环的损伤。
4.人工髓核的刚度应该与正常髓核一致。这样可以防止椎体终板的应力屏蔽、萎缩和重吸收，因为这些因素都可能导致椎体终板的下陷。
5.具有液体泵的作用，为纤维环输送营养，移除代谢物，使纤维环保持其生物力学强度。
人工髓核根据其基本设计思路和发展过程分为3类：预成形人工髓核、原位灌注成形人工髓核和半成形人工髓核。
1)预成形人工髓核是将已定形的假体放入椎间隙，1966年报道的Fernstrom设计的不锈钢球即为此种，由于金属假体接触面应力过大，假体容易发生下沉，已被淘汰。20世纪90年代，美国Charles D. Ray医生与Raymediea公司合作改用了一种叫HYPAN的水凝胶（聚丙烯腈与聚丙烯酰胺的共聚体）为核心，外包聚乙烯纤维外套研制出了PDN人工髓核产品。在美国，它通过了FDA/ISO 10996对其进行的生物安全性、毒性和致瘤性试验及动物体内长期植入试验，均未出现异常。迄今为止，PDN人工髓核假体已经投入了临床应用， 其在欧洲应用的临床成功率为85%。但是，PDN人工髓核是通过开放手术植入的，创伤大，在临床应用时会出现髓核的前后径偏小，假体和终板接触面积小，对终板压力大等问题，增加了髓核突入椎体的危险性。为防止髓核脱出，需要带支具制动，这影响了病人的术后康复，后路植入时对椎管的干扰导致相应的并发症。Zimmer公司研制的NewcLeus假体是由复合碳酸盐—氨基甲酸乙酯弹性体制成，它能吸收相当于自身重量35%的水分，假体通常状态下呈卷曲螺旋状，开放植入后能紧贴纤维环内壁呈层状螺旋排列。由于它呈螺旋状，没有固定的轴，因此在承重时并不限定于某一特定的轴向，即使没有植入最佳位置，仍能发挥抗压作用。但是，这种髓核假体目前正在通过国际多中心研究来观察其远期临床效果。
2)原位灌注成形人工髓核设计思路是将预反应的聚合物前驱体注入摘除退变髓核后的椎间隙中，可以在原位反应凝固成半固态，聚合塑形。原位成形髓核假体使假体与髓核空腔壁紧密相贴，稳定性、顺应性好，具有较均匀的应力分散作用，能恢复纤维环的正常长度和张力，可以明显减少假体突出率。但是，灌注过程中不能避免预反应的液态单体从纤维环切口和可能存在的纤维环裂隙溢出对周围结构产生损害，甚至有毒性作用，聚合过程伴发的放热反应也会引起周围组织损伤。现今研究阶段的原位灌注成形人工髓核的材料是硅胶和聚氨基甲酸乙酯。硅胶无毒，组织相容性好、无致癌性，但易老化，术后长期观察有椎间隙边缘密度增高和间隙狭窄的报道。聚氨基甲酸乙酯比硅橡胶有更良好的耐压性和缓冲能力，但硅橡胶的抗疲劳和耐磨损能力有限，聚氨基甲酸乙酯控制单体的聚合速度和放热反应较难，而且由于单体的毒性作用，其成份比例需极严格控制，难以满足髓核微创植入的临床要求。
3)鉴于上述两种假体的不足之处，出现了介于两者之间的设计类型即半成形人工髓核。半成形人工髓核假体在放入过程中，其外形或大小可按实际需要改变，放入后保持所需的外形或大小。一种是放入经脱水处理的半成形凝胶假体，放入椎间隙后凝胶水化、膨胀；另外一种是向摘除的髓核腔放入可折叠变形的气囊，再注入可原位凝固成半固态的高分子材料使气囊充分膨胀，进而使塌陷的椎间盘恢复应有的高度。
微创手术是近些年新兴的一种医疗技术，与传统开放手术相比，具有创伤小、疼痛轻、恢复快、出血少等优点。脊柱外科微创经皮-穿刺手术是通过经皮穿刺或者微小穿孔，运用特殊器械和装置来实施的。本发明基于微创经皮-穿刺手术，设计出一种盘旋状物理成形、聚集态人工髓核假体。相对于用于开放手术的PDN人工髓核来说，具有创伤小、不滑脱稳定性好、最大程度和上下终板之间形成“足印”样结合、减小终板的不均衡负荷、手术难度低等优异特征，并由于盘旋结构具有承载时不限定某一固定轴向生物力学的优势。与微创手术的原位聚合注射成形髓核假体相比避免了单体毒性作用、聚合温度高可能导致软骨终板的损伤以及凝固时间较长、液态单体内漏出等问题，并且能够通过微创手术安全顺利取出。因此，本发明制备的仿生盘旋状髓核假体具有很好的仿生髓核假体医学安全服役性能，能够满足微创经皮-穿刺临床手术对髓核假体的要求。
发明内容
本发明提供了一种微创经皮-穿刺手术用仿生盘旋状髓核假体的制备方法及其应用。本发明就是要解决现今腰、颈椎间盘临床医学中急需的能够通过微创手术实现髓核植入的材料制备问题，并且植入的人工髓核具有良好的形状记忆性能、溶胀性能、生物力学性能及安全服役性能。
本发明的技术方案：微创经皮-穿刺手术用仿生盘旋状髓核假体的制备方法具体制备步骤是：
a)将平均聚合度为1750±50的聚乙烯醇颗粒与去离子水按照质量比为15~25:75~85混合，用玻璃棒搅拌均匀，得到混合液；
b)将上述步骤得到的混合液放入高压釜中120℃、0.12~0.16MPa熔融2h，熔融过程中高压釜内进行搅拌确保溶液的均匀性，得到溶胶溶液；
c)将上述步骤得到的凝胶溶液从出料口流入盘旋状模具中成型，使胶液充分填充模具空隙，静止20分钟除去浇注过程中产生的气泡；
d)将填充满胶液的模具自然冷却到室温后放入冰箱冷冻，在温度为-20℃冷冻8h，再升温至0℃缓冷3-4h，然后在室温解冻8h，完成一次冷冻-解冻循环，如此反复完成四个循环后脱模得到盘旋状PVA水凝胶；
e)将盘旋状PVA水凝胶在真空干燥箱内60℃抽真空处理10h后经过40kGy的γ射线辐射交联，得到自然状态下盘旋状的微创经皮-穿刺手术用仿生髓核假体。
本发明还提供另一种微创经皮-穿刺手术用仿生盘旋状髓核假体的制备方法具体制备步骤是：
a)将平均聚合度为1750±50的聚乙烯醇颗粒与去离子水按照质量比为20:80混合，然后加入三偏磷酸钠STMP（WPVA：WSTMP=100:15），用玻璃棒搅拌均匀，得到混合液；
b)将上述步骤得到的混合液放入高压釜中120℃、0.12~0.16MPa熔融2h，熔融过程中高压釜内进行搅拌确保溶液的均匀性，得到溶胶溶液；
c)将上述步骤得到的胶液从出料口流入盘旋状模具中成型，使胶液充分填充模具空隙，静止20分钟除去浇注过程中产生的气泡；
d)将填充满胶液的模具自然冷却到室温后放入冰箱冷冻，在温度为-20℃冷冻8h，再升温至0℃缓冷3-4h，然后在室温解冻8h，完成一次冷冻-解冻循环，如此反复完成四个循环后脱模得到盘旋状PVA水凝胶；
e)将盘旋状PVA水凝胶在真空干燥箱内60℃抽真空处理10h后经过120~40kGy的γ射线辐射交联，得到自然状态下盘旋状的微创经皮-穿刺手术用仿生髓核假体。
进一步，所述自然状态下盘旋状的微创经皮-穿刺手术用仿生髓核假体的抗拉弹性形变＞300%；抗拉强度＞4MPa；轴向压缩强度＞3MPa，压缩弹性模量＜8MPa；形状记忆性好。
进一步，所述自然状态下盘旋状的微创经皮-穿刺手术用仿生髓核假体，可以顺利通过微创经皮-穿刺手术器械植入，通过器械后，恢复盘旋状，形状记忆性好。
一种上述微创经皮-穿刺手术用盘旋状髓核假体的应用，该制品用于微创经皮-穿刺手术植入方式治疗颈椎、腰椎间盘病变。
与现有技术相比，本发明具有以下优点和有益效果：
本发明制备出的水凝胶人工髓核假体具有高含水率，综合力学性能和稳定性优良，生物相容性好，且植入后创伤小、不滑脱稳定性好、最大程度和上下终板之间形成“足印”样结合、减小终板的不均衡负荷、手术难度低的优异特征，并由于盘旋结构具有承载时不限定某一固定轴向生物力学的优势。具有较好的柔韧性和刚度，抗拉弹性形变＞300%；抗拉强度＞4MPa；轴向压缩强度＞3MPa，压缩弹性模量＜8MPa，能够满足微创经皮-穿刺手术对人工髓核材料形状记忆性能、溶胀性能、生物力学性能及微创植入服役要求，并能够通过微创手术安全取出。
附图说明
图1为发明的盘旋状人工髓核成品。
图2为发明的人工髓核微观结构图。
图3为发明的人工髓核溶胀性能曲线图。
图4为发明的人工髓核轴向压缩应力应变曲线图。
图5为发明的人工髓核拉伸强度柱状图。
图6为发明的人工髓核压缩蠕变曲线图。
具体实施方式
下面结合附图和具体实施例，进一步阐述本发明。
实施例1：
本实施例描述了一种微创经皮-穿刺手术用仿生人工髓核假体的制备方法。
a) 将平均聚合度为1750±50的聚乙烯醇颗粒与去离子水按照质量比为20:80混合，用玻璃棒搅拌均匀。
b)将称取好的混合液放入高压釜中120MPa高温高压熔融2h，熔融过程中高压釜内进行搅拌确保溶液的均匀性。
c)胶液从出料口流入盘旋状模具中成型，使胶液充分填充模具空隙，静止20分钟除去浇注过程中产生的气泡。
d)将填充满胶液的模具自然冷却到室温后放入冰箱冷冻，-20℃冷冻8h，冷冻后0℃缓冷3-4h，然后在室温解冻8h，完成一次冷冻-解冻循环。如此反复完成四个循环后脱模得到盘旋状PVA水凝胶。
e)将PVA水凝胶在真空干燥箱内60℃抽真空处理10h后经过40kGy的γ射线辐射交联，得到微创经皮-穿刺手术用仿生盘旋状髓核假体。
本发明制备出的人工髓核假体为盘旋状，三维网络多孔结构，溶胀主要发生在前24小时，达到最大溶胀率的90%，之后趋于稳定，100小时基本完全溶胀。轴向压缩强度＞3MPa，压缩弹性模量＜8MPa，抗拉弹性形变＞300%，抗拉强度＞4MPa，形状记忆性能及稳定性好。满足微创经皮-穿刺手术对人工髓核材料形状记忆性能、溶胀性能、生物力学性能及微创植入服役要求，并能够通过微创手术安全取出。
实施例2：
本实施例的工艺方法与实施例1相同，区别仅在于平均聚合度为1750±50的聚乙烯醇颗粒与去离子水质量比为15:85。
实施例3：
本实施例的工艺方法与实施例1相同，区别仅在于平均聚合度为1750±50的聚乙烯醇颗粒与去离子水质量比为25:75
实施例4：
本实施例的工艺方法与实施例1相同，区别仅在于将平均聚合度为1750±50的聚乙烯醇颗粒与去离子水按照质量比为20:80混合，然后加入三偏磷酸钠（WPVA：WSTMP=100:15），用玻璃棒搅拌均匀，得到混合溶液。
Claims (1)
1. 一种微创经皮-穿刺手术用仿生盘旋状人工髓核假体的制备方法，其特征在于：
a)将平均聚合度为1750±50的聚乙烯醇颗粒与去离子水按照质量比为20:80混合，然后加入三偏磷酸钠，用玻璃棒搅拌均匀，得到混合液；其中，聚乙烯醇颗粒与三偏磷酸钠的质量比为100:15；
b)将上述步骤得到的混合液放入高压釜中120℃、0.12~0.16MPa熔融2h，熔融过程中高压釜内进行搅拌确保溶液的均匀性，得到溶胶溶液；
c)将上述步骤得到的溶胶从出料口流入盘旋状模具中成型，使胶液充分填充模具空隙，静止20分钟除去浇注过程中产生的气泡；
d)将填充满胶液的模具自然冷却到室温后放入冰箱冷冻，在温度为-20℃冷冻8h，再升温至0℃缓冷3-4h，然后在室温解冻8h，完成一次冷冻-解冻循环，如此反复完成四个循环后脱模得到盘旋状PVA水凝胶；
e)将盘旋状PVA水凝胶在真空干燥箱内60℃抽真空处理10h后经过40kGy的γ射线辐射交联，得到自然状态下盘旋状的微创经皮-穿刺手术用仿生髓核假体，所述自然状态下盘旋状的微创经皮-穿刺手术用仿生髓核假体的抗拉弹性形变＞300%；抗拉强度＞4MPa；轴向压缩强度＞3MPa，压缩弹性模量＜8MPa；形状记忆性好。
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| US20140277467A1 (en) | 2013-03-14 | 2014-09-18 | Spinal Stabilization Technologies, Llc | Prosthetic Spinal Disk Nucleus |
| WO2016073587A1 (en) | 2014-11-04 | 2016-05-12 | Spinal Stabilization Technologies Llc | Percutaneous implantable nuclear prosthesis |
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