CN101821814B - 等离子体合成的吡咯衍生的聚合物用于中枢神经系统的神经保护和再连接的用途 - Google Patents
等离子体合成的吡咯衍生的聚合物用于中枢神经系统的神经保护和再连接的用途 Download PDFInfo
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Abstract
本发明目的在于证明以聚吡咯和聚乙二醇共聚合物和碘掺杂的以等离子体合成的吡咯聚合物制备的半导体非生物可降解植入物具有创伤后神经保护作用，并可诱导脊髓的重新连接；在涉及大鼠脊髓完全切断模型中证明该作用；功能评价的结果证明植入了聚吡咯-聚乙二醇共聚合物的动物与仅对脊髓进行完全切断的对照组相比，其恢复率高5倍；另外，植入了碘掺杂的聚吡咯的组与对照组相比，恢复率高10倍；在植入和未植入植入物的三个实验组的组织学研究中，鉴别了创伤处的各种炎症和免疫细胞，发现了脊髓神经组织中的聚合物的整合；最后，在任何动物中均未发现呼吸系统、肾脏或皮肤感染、副作用或生物材料的排斥反应。
Description
技术领域
本发明涉及等离子体合成的吡咯衍生的非生物可降解聚合物用于制备植入物的用途，所述植入物可促进创伤后的神经保护和脊髓的再连接。
发明背景
外伤性脊髓损伤(SCI)是与高死亡率有关的公共健康问题(Dryden DM，Saunders LD，Rowe BH，May LA，Yiannakoulias N，Svenson LW，SchopflocherDP，Voaklander DC.The epidemiology of traumatic spinal cord injury in Alberta，Canada.Can.J.Neurol.Sci.2003；30：113-121)，其严重的后果会导致残疾以及长期昂贵的康复治疗。
SCI除了具有高的社会和经济影响外，据报道，在美国、加拿大、澳大利亚、意大利和墨西哥，每年会新增1800万～5500万SCI的病例(Woodruff BA，Baron RC.A description of nonfatal spinal cord injury using a hospital-basedregistry.Am.J.Prev.Med.1994；10：10-14；Dryden DM，Saunders LD，RoweBH，May LA，Yiannakoulias N，Svenson LW，Schopflocher DP，Voaklander DC.The epidemiology of traumatic spinal cord injury in Alberta，Canada.Can.J.Neurol.Sci.2003；30：113-121；O′-Connor P.Incidence and patterns of spinalcord injury in Australia.Accid.Anal.Prev.2002；34：405-415；Pagliacci MC，Celani MG，Zampolini M，Spizzichino L，Franceschini M，Baratta S，Finali G，Gatta G，Perdon L；Gruppo Italiano Studio Epidemiologico Mielolesioni.AnItalian survey of traumatic spinal cord injury.The Gruppo Italiano StudioEpidemiologico Mielolesioni study.Arch Phys Med Rehabil.2003；84：1266-1275，Pardini MC.La epidemiología de la lesión medular traumática en elDistrito Federal.PhD thesis of the Secretaría de Salubridad y Asistencia 1998)。
患有SCI的患者现在已经有了用于防止长期体质恶化的缓解和康复方案(Houle JD，Tessler A.Repair of chronic spinal cord injury.Exp Neurol.2003；182：247-260)。然而，这些患者需要能恢复其自主功能、减少神经疼痛和恢复其行动能力的治疗。由于这种疾病的重要性，因此在世界范围内已经建立了一些研究机构，这些机构每年都会花费数亿美元以支持该课题的研究，然而，直至现在还未有有效的治疗方案(Houle JD，Tessler A.Repair of chronicspinal cord injury.Exp Neurol.2003；182：247-260)。
损伤的病理生理学现象首先表现在神经组织的自毁、再生中断和创伤周围位置的愈合上(Aldskogius H，Kozlova EN.Strategies for repair of thedeafferented spinal cord.Brain Res Brain Res Rev.2002；40：301-308)。在急性期，会观察到局部缺血的过程，对血液微循环的损伤会导致能量衰竭，从而转变为由单价离子(例如K+和Na+)和二价离子(例如Ca2+)的活动所引起的离子调节失控及水肿，导致脊髓休克(Hulsebosch CE.Recent advances inpatophysiology and treatment of spinal cord injury.Adv.Physiol.Educ.2003；26：238-255)。
所有这些过程的结果是非常不利的，其不利于受损组织的创伤处及其周围组织的愈合过程(Beattie MS，Farooqui AA，Bresnahan JC.Review of currentevidence for apoptosis after spinal cord injury.J Neurotrauma.2000，17：915-925)，在星形神经角质瘢痕(astroglial scar)的周围会形成空洞，其会演变成多叶的囊腔(multi-lobed cystic cavity)，该囊腔用作防止轴突再生(axonalregeneration)的物理和化学屏障(Houle JD，Tessler A.Repair of chronic spinalcord injury.Exp Neurol.2003；182：247-260；Profyris C，Cheema SS，Zang D，Azari MF，Boyle K，Petratos S.Degenerative and regenerative mechanismsgoverning spinal cord injury.Neurobiol Dis.2004；15：415-436)。
数年来，在患上SCI后已经使用了组织和细胞的移植来促进轴突生长、脊髓再生，并因此促进功能恢复(Zompa EA，Cain LD，Everhart AW，Moyer MP，Hulsebosch CE.Transplant therapy：recovery of function after spinal cord injury.J Neurotrauma.1997；14：479-506；Taoka Y，Okajima K.Spinal cord injury in therat.Prog Neurobiol.1998；56：341-358)。已经使用胚胎和胎儿的神经干细胞和多潜能前体细胞在创伤处进行移植(Stokes BT，Reier PJ.Fetal grafts alterchronic behavioral outcome after contusion damage to the adult rat spinal cord.Exp Neurol.1992，116：1-12，McDonald JW，Liu XZ，Qu Y，Liu S，Mickey SK，Turetsky D，Gottlieb DI，Choi DW.Transplanted embryonic stem cells survive，differentiate and promote recovery in injured rat spinal cord.Nat Med 1999，5：1410-1412)，也进行了胎儿细胞或胎儿脊髓组织的移植(Zompa EA，Cain LD，Everhart AW，Moyer MP，Hulsebosch CE.Transplant therapy：recovery offunction after spinal cord injury.J Neurotrauma.1997，14：479-506，Coumans JV，Lin TT，Dai HN，MacArthur L，McAtee M，Nash C，Bregman BS.Axonalregeneration and functional recovery after complete spinal cord transection in ratsby delayed treatment with transplants and neurotrophins.J Neurosci.200；21：9334-9344)，还进行了外周神经细胞和许旺细胞(Schwann cell)的移植(MeneiP，Montero-Menei C，Whittemore SR，Bunge RP，Bunge MB.Schwann cellgenetically modified to secrete human BDNF promote enhanced axonal regrowthacross transected adult rat spinal cord.Eur J Neurosci 1998，10：607-621)。为促进髓鞘再形成(remyelinization)，移植少突胶质细胞(Jeffery ND，Crang AJ，O′Leary MT，Hodge SJ，Blakemore WF.Behavioral consequences ofoligodendrocyte progenitor cell transplant into experimental demyelinating injuryin the rat spinal cord.Eur J Neurosci 1999；11：1508-1514)，但是因为少突胶质细胞会表达轴突生长抑制分子，结果导致对再生具有负面影响(Tessier-Lavigne M，Goodman CS.Perspectives：neurobiology.Regeneration inthe nogo zone.Science 2000 287：813-814)。另外，已经使用了未成熟的或非反应性的星形细胞来促进再生和增加髓鞘再形成并减少胶质瘢痕的形成(Franklin RJ，Crang AJ，Blakemore WF.Transplanted type-1 astrocytes facilitaterepair of demyelinating injuries by host oligodendrocytes in adult rat spinal cord.J Neurocytol 1991，20：420-430)。为产生允许再生的环境，移植了小胶质细胞(Rabchevsky AG，Weinitzen JM，Coulpier M，Fages C，Tinel M，Junier MP.Arole for transforming growth factor alpha as an inducer of astrogliosis.J Neurosci.1998，18：10541-10552)、嗅球的神经胶质细胞(Keyvan-Fouladi N，Li Y，Raisman G.How do transplanted olfactory ensheathing cells restore function？Brain Res Brain Res Rev.2002；40：325-327)，为诱导例如神经营养因子(neurotrophin)、神经递质、酶、细胞外基质分子和表面粘附分子的特异的蛋白合成，即使使用了干细胞，由遗传工程学家操作或不由其操作，都未在功能恢复上取得良好的结果(McDonald JW，Liu XZ，Qu Y，Liu S，Mickey SK，Turetsky D，Gottlieb DI，Choi DW.Transplanted embryonic stem cells survive，differentiate and promote recovery in injured rat spinal cord.Nat Med 1999，5：1410-1412；Barami K，Diaz FG.Cellular transplant and spinal cord injury.Neurosurgery.2000；47：691-700)。
尽管有这些治疗上的尝试，但是用于治疗SCI的大多数移植由于不能显著恢复损失的神经功能而已经失败，因此需要开发使用生物材料的新方法来尝试修复脊髓。世界上首例报道显示可使用炭丝植入物(carbon filamentsimplants)用作大鼠脊髓中受损轴突进行生长的桥。Khan等人将炭丝植入脊髓完全切断模型处理的大鼠(Khan T，Dauzvardis M，Sayers S.Carbon filamentimplants promote axonal growth across the transected rat spinal cord.Brain Res1991；541：139-145)，他们观察到轴突在炭丝上和炭丝之间生长，因此推断炭丝可用作一个表面以与生长的轴突有利地结合，以及炭丝可能起机械引导的作用。
在1999年，Cao和Shoichet开发了一种促进轴突再生过程的生物工程学技术(Cao X，Schoichet MS.Delivering neuroactive molecularles frombiodegradable microspheres for application in central nervous system disorders.Biomaterials.1999，20：329-339)，该技术使用了含有神经生长因子(NGF)并以卵清蛋白包封的微球，该微球与位于创伤处的生物可降解聚合物连接。在PC12细胞中测定此技术已确定了释放的NGF的生物活性。结果显示在多至91天内，NGF仍然保持有生物活性。
合成了生物相容性的水凝胶聚[N-(2-羟丙基)甲基丙烯酰胺](PHPMA)，且具有纤维素结合蛋白的Arg-Gly和Asp细胞粘附区域，Woerly等人确定了其流变学结构和介电性能(Woerly S，Pinet E，de Robertis L，Van Diep D，Bousmina M.Spinal cord repair with PHPMA hydrogel containing RGD peptides(NeuroGel).Biomaterials.2001；22：1095-1111)。在斯普拉格-道利鼠(Sprague-Dawley rats)的脊髓半切除损伤模型中测试该生物材料。将水凝胶植入脊髓内。结果显示此水凝胶聚合物提供了一个三维结构并连续穿过损伤区域，促进细胞的迁移和重组。在微结构中观察到了血管发生和轴突生长，并在其上有新组织，以及轴突生长进入了再生脊髓部分中的刺突上的区域，另外水凝胶的存在减少了坏死和空洞的形成，因此作者指出该聚合物有助于受损脊髓的修复。
Oudega等人使用了一种能引导生长的轴突的管状结构的聚合物，并且将其用作过渡区域之间的桥的方法(Oudega M，Gautier SE，Chapon P.FragosoM，Bates ML，Parel JM，Bunge MB.Axonal regeneration into Schwann cellgrafts within resorbable poly(alpha-hydroxyacid)guidance channels in the adultrat spinal cord.Bio-materials.2001，22：1125-1136)。可再吸收的聚合物由聚(D，L-乳酸)(PLA50)与一共聚合物(copolymer)制备，所述共聚合物是高分子量的聚(L-乳酸)混合有10％的聚(L-乳酸)(PLA100/10)低聚物的共聚合物，将所述可再吸收的聚合物植入脊髓完全切断的Fisher属(Fisher strain)成年大鼠的神经组织中，然后进行4个月的跟踪研究。结果显示，自第2周后，管状物具有了脊髓神经组织和血管。在植入1个月后可发现许多有髓鞘的轴突。在这篇论文中，其认为在将以PLA100/10聚合物制备的植入物植入脊髓后的2个月会有有髓鞘的神经纤维生长于所述植入物中。但是此现象在4个月后明显减少，因此作者认为需进一步研究以优化该技术。
另一种被制造出的用于在SCI后促进再生过程和引导轴突的生长的生物可降解材料是，以聚-β-羟基丁酸酯(PHB)和纤维结合蛋白藻酸盐+水凝胶制备的丝。在由Novikov等人进行的研究中(Novikov LN，Novikova LN，Mosahebi A，Wiberg M，Terenghi G，Kellerth JO.A novel biodegradable implantfor neuronal rescue and regeneration after spinal cord injury.Biomaterials.2002；23：3369-3376)，在脊柱L1位置切断红核脊髓束，观察到植入PHB后细胞死亡率降低50％。使用单独的组分对神经元存活率没有影响。而且，将新生许旺细胞加入PHB移植物，可观察到轴突在植入物中再生并且遍布神经组织，这表明这些生物材料以及许旺细胞可用于支持SCI后的增加的神经再生。
另一种修复脊髓损伤的方法是使用由聚(2-羟乙基-甲基丙烯酸酯-共聚-甲基丙烯酸甲基酯)(p(HEMA-co-MMA))制备的水凝胶管，其在中枢神经系统中用作潜在的轴突生长引导通道。这些管状物的特征在于：与具有层之间以大孔相互连接的凝胶相似的柔软性和弹性，通过化学制剂控制(Dalton PD，Flynn L，Shoichet MS.Manufacture of poly(2-hydroxyethylmethacrylate-co-methyl methacrylate)hydrogel tubes for use as nerve guidancechannels.Biomaterials.2002，23：3843-3851)。
但是，已显示这些聚合物的降解可引起炎症反应，虽然其中一些在中枢神经系统中是免疫惰性的，特别是免疫抗性的(Marchant RE，Anderson JM，Dillingham EO In vivo biocompatibility studies.VII.Inflammatory response topolyethylene and to a cytotoxic polyvinylchloride.J Biomed Mater Res 1986，20：37-50；Gautier SE，Oudega M，Fragoso M，Chapon P，Plant GW，Bunge MB，Parel JM.Poly(alpha-hydroxyacids)for application in the spinal cord：resorbability and biocompatibility with adult rat Schwann cells and spinal cord.JBiomed Mater Res 1998，42：642-654)。其他作者已报道了对于一些聚合物，轴突与这些化合物的粘连较差，但是Rangappa等人(Rangappa N，Romero A，Nelson KD，Eberhart RC，Smith GM.Laminin-coated poly(L-lactide)filamentsinduce robust neurite growth while providing directional orientation.J BiomedMater Res 2000，51：625-634)使用了层粘连蛋白基质涂覆的网状物，这样能增加轴突对基质的粘连。另一策略是开发具有结合缓释的包封肽(营养因子、药物等)能力的生物材料(Pechar M，Ulbrich K，Subr V，Seymour LW，SchachtEH.Poly(ethylene glycol)multiblock copolymer as a carrier of anti-cancer drugdoxorubicin.Bioconjug Chem 2000，11：131-139)，但是此策略未获得满意的结果。胶原纤维单独使用或与其他材料组合可用作轴突生长的引导和支持，并诱导再生(Heffner CD，Lumsden AG，O′Leary DD.Target control of collateralextension and directional axon growth in the mammalian brain.Science.1990；247：217-220；Tong XJ，Hirai K，Shimada H，Mizutani Y，Izumi T，Toda N，Yu P.Sciatic nerve regeneration navigated by laminin-fibronectin double coatedbiodegradable collagen grafts in rats.Brain Res 1994，663：155-162)。使用生物相容性材料恢复损伤的神经组织的进展迅速，开发用作桥的材料以修复脊髓，然而这些聚合物通常通过化学方法和电化学聚合合成(Wang J，Neoh KG，Kang ET.Comparative study of chemically synthesised and plasma polymerizedpyrrole and thiophene thin films.Thin Solid Films 2004，446：205-217)，由于已显示这些聚合物的降解可引起炎症反应，因此会干扰这些聚合物的有益作用。
Schmidt等人说明了为促进降解，使用了吡咯和噻吩片段与柔性的脂肪族酯链的混合物和组合合成的生物可降解聚合物(U.S.Patent No.6,696,575B2，2004)，这些聚合物由于其化学和电性能，被认为可以在组织工程学领域用作供选的治疗方法。这些材料是柔性的，且其化学结构使得电子可在链间自由运动，从而提高了其导电性质。在这篇专利中，作者提示将这些生物材料用于促进脊髓外周神经组织以及其他组织(骨、肌肉等)的再生。然而，并没有证据支持其这样的用途。
用于合成聚合物的另一方法是使用等离子体(plasma)获得导电性的聚合物膜。在合成过程期间，单体在气相中反应，并且在反应中不需要化学介质。观察到使用此方法合成的聚合物的化学结构不同于化学合成的聚合物，其纯度更高、粘性更大并且交联及扩展性更好(Wang J，Neoh KG，Kang ET.Comparative study of chemically synthesised and plasma polymerized pyrroleand thiophene thin films.Thin Solid Films 2004，446：205-217)。Cruz等人(CruzGJ，Morales J，Olayo R.Films obtained by plasma polymerization of pyrrole.Thin Solid Films 1999，342：119-126)报道了吡咯衍生的材料的等离子体合成方法，在其中发现了碘掺杂(doping)的材料。这些材料不是生物可降解的，因此将其用于神经系统会降低炎症应答，从而使其具有更高的效率，这是因为在一些研究中表明炎症应答是二次损伤的机理之一，二次损伤可破坏位于创伤周围的神经组织。
导电性材料是通过具有交替或共轭的双键的长链烃形成的那些材料，这使得其具有金属的导电性能和塑料的机械性能。其导电性主要是由于加入了某些量的其他化学产品(掺杂)，也是由于能传导电子流的共轭双键的存在。掺杂技术涉及加入具有电负性的原子。这些原子可向聚合键提供自由电子或除去电子，所述除去电子等同于产生了正电荷。在两种情况下，聚合物链均变得电不稳定，并且若应用了电位差，电子会运动通过聚合物(Cruz GJ，Morales J，Olayo R.Films Obtained by plasma polymerization of pyrrole.Thinsolid films 1999，342：119-126)。虽然将聚合物转变成导体的物理机理还不清楚，但是纯度及聚合物链的组织看起来具有重要的影响。因此，当修饰了聚合的结构组织时会改善聚合物的导电性。用作导体的聚合物主要由碳和氢原子组成，与任何其他的聚合物相似，碳和氢原子排列于重复的单体单元中。通常这些单元具有例如氮和硫的杂原子。碳原子通过交替设置的单键和双键相互连接(...＝C-C＝C-C＝C-...)，即其表现为超共轭键，这是所有导电聚合物的一般特征。由于电子(e-)的移动会形成电的传导。电子在材料中自由移动是必要的。在固体导体中，电子穿过被称为层的离散的能态(来自分子轨道理论(Molecular Orbital Theory)对整个固体晶体网状结构的延伸)。固体仅在其最外层是半充满状态时(良好的导体或金属导体)，或虽最外层为空但可从最外层附近激发时(半导体)，是可以导电的。如果电子从满带跃迁至空带所需能量较大，则其可以被认为是绝缘体(Cruz GJ，Morales J，Olayo R.FilmsObtained by plasma polymerization of pyrrole.Thin solid films 1999，342：119-126)。
聚吡咯(PPy)是带有正电荷化学结构的导电性聚合物，可向其中加入各种化学物质(掺杂剂)以改变其电性质。PPy由于其生物相容性，已用作生物传感器来检测血糖(Lopez-Crapez E，Livache T，Marchand J，Grenier J.K-rasmutation detection by hybridization to a polypyrrole DNA chip.Clin Chem 2001；47：186-194)。另外，由于其导电性，聚吡咯(PP)具有刺激下列细胞增殖的能力：神经细胞(Kotwal A，Schmidt CE.Electrical stimulation alters proteinadsorption and nerve cell interactions with electrically conducting biomaterials.Biomaterials.2001；22：1055-1064)、嗜铬细胞(Aoki T，Tanino M，Sanui K，Ogata N，Kumakura K.Secretory function of adrenal chromaffin cells cultured onpolypyrrole films.Biomaterials.1996；17：1971-1974)及内皮细胞(Garner B，Georgevich A，Hodgson AJ，Liu L，Wallace GG.Polypyrrole-heparin compositesas stimulus-responsive substrates for endothelial cell growth.J Biomed MaterRes 1999，44：121-129)。Schmidt等人表明电刺激可加速在聚吡咯(PP)膜上的PC-12细胞中的轴突生长(neurite growth)(Schmidt CE，Shastri VR，Vacanti JP，Langer R.Stimulation of neurite outgrowth using an electrically conductingpolymer.Proc Natl Acad Sci U.S.A.1997；94：8948-8953)。最近的研究表明聚吡咯(PP)在体外(Zhang Z，Roy R，Dugre FJ，Tessier D，Dao LH.In vitrobiocompatibility study of electrically conductive polypyrrole-coated polyesterfabrics.J Biomed Mater Res 2001，57：63-71)和体内(Jiang X，Marois Y，TraoreA，Tessier D，Dao LH，Guidoin R，Zhang Z.Tissue reaction to polypyrrole-coatedpolyester fabrics：an in vivo study in rats.Tissue Eng.2002；8：635-647)均有可接受的生物相容性，此结果给予了将PPy及其衍生物用于某些生物医学和组织工程学应用的支持。基于这些信息，决定将两种半导体聚合物，聚吡咯与聚乙二醇的共聚合物(PPy/PEG)和碘掺杂的聚吡咯(PPy/I)，用于大鼠脊髓全切断模型中。
发明概述
聚吡咯/聚乙二醇共聚合物及碘掺杂聚吡咯的合成
聚合物在薄膜中合成，此薄膜借助于亮度电休克法(electric shocks ofbrilliance)在一带有不锈钢凸缘(flange)的直径为9厘米长为30厘米的玻璃管式反应器中形成。将压力设为1.5×10-2托以引发聚合反应，压力设为5×10-2托以延续化学反应。电场振荡频率为13.5MHz。不锈钢电极直径为7厘米。其中一个电极接地，其他电极连接至RF信号，它们之间间隔为9厘米。将单体和掺杂剂置于不同的容器中，由于反应器与容器之间的压力差，将单体和掺杂剂的小蒸汽流引入反应器，并将两者在反应器中混合。反应物的温度约为20℃。聚合时间为300分钟。反应开始在气相中发生，随着聚合物分子量的增加，反应在固相中结束。起始反应物的结构简式为：C4H5N：
吡咯单体
将聚合物用丙酮润湿并干燥数个循环之后，将其从反应器表面分离。在2～3个循环之后，以刮铲机械地回收聚合物，然后将其研磨成片状物，且将该片状物用作测试受试者的脊髓植入物。制备碘掺杂的聚吡咯(PPy/I)衍生物和聚吡咯和聚乙二醇共聚合物(PPy/PEG)片状物作为对比(tablets)。
等离子体合成的聚合物的物理化学性质
以红外光谱分析结构
图1A的光谱显示了3个对应于PPy/PEG共聚合物的复合吸收谱带。第一个吸收谱带在400和1200cm-1之间，第二吸收谱带在1200和2000cm-1之间，第三吸收谱带在2400和3600cm-1之间。覆盖在400和1200cm-1之间的宽峰包含许多对应于烯烃的吸收。峰宽表明了分支、交联和PPy环之间的相互作用。最强的峰对应于PPy的共振(vibration)。
图1B显示了PPy/I样品的透射光谱，可以看到有两个共振的复合的宽共振谱带，这是等离子体合成的聚合物的特征。第一个共振谱带在2400和3600cm-1之间，其他的在500和1800cm-1之间。在3600和2400cm-1之间的区域表示处于不同结构的N-H、O-H和C-H键的吸收，特征的是伯胺在3349cm-1的共振峰，以及饱和脂肪链位于2932cm-1的峰。在第二复合吸收谱带中，对应于伯、仲、叔胺的在1639cm-1的共振是特征的。甲基(C-H)的变形在1452cm-1。在747cm-1，显示了对应于碳-碳键的共振。
电性质
PPy/PEG的电阻为GΩ，因此其被认为是一种半导体聚合物。PPy/I的电阻(resistance)为1.3MΩ，电阻率(resistivity)为45.94MΩ-cm，电导率约为21nS/cm。
形态学
图2A显示了以扫描电子显微镜拍摄的PPy/PEG共聚合物表面的图像，其中可观察到均质的结构并且该结构外观为海绵状。图2B显示了对应于PPy/I聚合物的图像，在表面上可以看到大小约为5～10μm的材料的小块。
PPy/PEG共聚合物微细地在薄膜中获得，将聚合物压成细粉然后压制形成片状物。
附图说明
图1：(A)聚吡咯/聚乙二醇共聚合物的红外光谱；(B)碘掺杂的聚吡咯聚合物的红外光谱。
图2：以扫描电子显微镜拍摄的植入生物材料的显微照片。(A)聚吡咯与聚乙二醇的共聚合物。(B)碘掺杂的聚吡咯。标尺对应于50μm。
图3：显示了以BBB评级(Basso，Beattie和Bresnahan)评估的运动恢复结果的图，其从脊髓完全切断之后的首日(D1)起至4周(S)结束。
图4：脊髓完全切断并未植入植入物的动物创伤后一个月的脊髓纵切片。(A)创伤区域及残留的组织(2.5×)；(B)过渡区域的放大图(5×)；(C)创伤区域细胞结构的缺失(20×；(D)存在的炎症细胞(40×)。苏木素/曙红技术。SB：白色物质，SG：灰色物质，ZL：创伤区域，CI：炎症细胞。
图5：脊髓完全切断并植入聚吡咯/聚乙二醇共聚合物的动物创伤后一个月的脊髓纵切片。(A)表明植入物整合至神经组织的图片(2.5×)；B)过渡区域的放大图(5×)；(C)创伤区域(20×)；(D)存在的炎症细胞(40×)。SB：白色物质，SG：灰色物质，ZL：创伤区域，CI：炎症细胞。苏木素/曙红技术。SB：白色物质，SG：灰色物质，ZL：创伤区域，PPy/PEG：聚吡咯和聚乙二醇共聚合物的移植物，MM：修饰过的巨噬细胞。
图6：脊髓完全切断并植入卤素掺杂的聚吡咯的动物创伤后一个月的脊髓纵切片。(A)表明植入物整合至神经组织的图片(2.5×)；B)过渡区域的放大图(5×)；(C)创伤区域(20×)；(D)存在的炎症细胞(40×)。SB：白色物质，SG：灰色物质，ZL：创伤区域，CI：炎症细胞。苏木素/曙红技术。SB：白色物质，SG：灰色物质，ZL：创伤区域，PPy/I：碘掺杂的聚吡咯植入物，CGCE：异物巨细胞。
图7：表明在研究结束时动物的总体健康和功能恢复状况的图。(A)未植入植入物的对照动物；(B)植入了聚吡咯/聚乙二醇共聚合物的动物，及(C)植入了聚吡咯/碘的动物。
具体实施方式
等离子体合成的吡咯衍生聚合物对神经元再连接作用的评估
在大鼠脊髓完全切断模型中评估用作神经功能的神经保护体和神经再生体的等离子体合成的聚合物。
组成三个实验组，每组三只动物，分组如下：A)对照组，在第九胸椎处(T9)完全切断脊髓的动物，B)PPy/PEG组，脊髓完全切断并植入了PPy/PEG的动物，C)PPy/I组，以上述外科手术过程处理的并植入了PPy/I片状物的动物。所有的实验组每组均有3只大鼠。
动物通过每千克体重肌肉注射77.5毫克氯胺酮和12.5毫克的盐酸赛拉嗪的混合物麻醉。麻醉后清理外科手术处，在皮肤中切开一纵向切口，然后切开脊椎骨突(spinal apophysis)的椎旁肌肉。
从T9-T10中切除两个脊椎骨突以观察这些椎骨的层状结构(laminarprocess)。最后，进行两个水平的椎板切除术，将其双向延伸以形成平面结构。保持脑脊膜(meninges)完整。在椎板切除手术完成后，在脑脊膜上切开一约5毫米长的纵切口，两侧切口均以9-0缝合线的单点(single point)缝合(聚酰胺6单丝)，然后完全切断脊髓，并通过显微外科牵引钩(microsurgical hook)确认没有神经通路仍然连接。
在完成通过完全切断大鼠脊髓的创伤过程后，立即在切断位置处横向引入直径约为3毫米的聚合物片状物。在植入植入物后，以单点缝合用9-0缝合线缝合脑脊膜。最后，外科切口处缝合2排，肌肉筋膜和皮肤分别用5-0缝合线(聚丙烯单丝)单点和连续缝合。
在手术后，在单鼠笼中在室温下观察动物，饲以市售的食物和水，视情况可以混合浓度为3.2克/100毫升对乙酰氨基酚(将10毫升以水稀释至2升，以饮用水给药72小时)，也通过肌肉注射给予250微升/250克重量的苄星青霉素(每单剂量1,200,000国际单位)。
聚合物再生作用的评价
为测定生物材料的再生引导作用，在切断脊髓后的4周，使用BBB评级(Basso，Bettie and Bresnahan)(Basso DM，Beattie MS，Bresnahan JC.Gradedhistological and locomotor outcomes after spinal cord contusion using the NYUweight-drop device versus transection.Exp Neurol.1996；139：244-256)评价动物运动功能的恢复，所述BBB评级如下所述：
BBB评级
级别0
未发现下肢(EP)的主要活动。
级别1
一个或两个关节，通常是髋关节和/或膝关节的活动受限(arc＜50％)。
级别2
一个关节自由活动(arc＞50％)，另一关节不能自由活动或可以自由活动。
级别3
两个关节自由活动。
级别4
下肢的三个关节(髋、膝和踝)活动受限。
级别5
两个关节活动受限，第三个自由活动。
级别6
两个关节自由活动，第三个活动受限。
级别7
下肢的三个关节(髋、膝和踝)自由活动。
级别8
下肢腿部均可节律性运动(协调)，但不能支撑重量或者能以足底站立(plantar placement)但不能支撑重量。
级别9
在不走动或偶然走动(＜0＝50％)时以足底站立并支持重量，频繁地(51％～94％)或持续地(95％～100％)以背部支持重量而不能以足底支持重量。
级别10
偶然走动时以足底支持重量，但前肢(EA)与后肢之间不协调。
级别11
频繁地或持续地走动时以足底支持重量，但是前肢与后肢之间不协调。
级别12
频繁地或持续地走动时以足底支持重量，前肢与后肢之间偶然是协调的。
级别13
频繁地或持续地走动时以足底支持重量，前肢与后肢之间通常是协调的。
级别14
持续地走动时以足底支持重量，ES和EI之间保持持续协调，并且会有腿的向外或向内偏转，主要是在与地面接触时或离开地面时。也能频繁地足底走动(plantar step)，EA与EP之间保持持续协调，偶尔背侧走动。
级别15
持续地足底走动、且EA与EP之间保持协调地走动。。脚趾不能分开或偶尔仅在其向前迈步的时候分开。当与地面接触时，腿部经常与身体平行排列。
级别16
在行走过程中，EA与EP之间保持协调且足底走动。当腿向前迈出时脚趾分开可经常发生。当与地面接触时，腿部经常与身体平行排列，但是当其提腿时会发生偏转。
级别17
在行走过程中，EA与EP之间保持协调且足底走动。当腿向前迈出时脚趾分开可经常发生。当与地面接触时，腿部经常与身体平行排列，但是当其提腿时仍然保持对齐(不发生偏转)。
级别18
在行走过程中脚趾保持持续分开。当与地面接触时，腿部经常与身体平行排列，但是当其提腿时会发生偏转。
级别19
在行走过程中，EA与EP之间保持协调且足底走动。在运动期间脚趾保持持续分开。当与地面接触时，腿部经常与身体平行排列。有时或总是摇动尾部。
级别20
足底走动，协调走动，并持续保持脚趾分开。当与地面接触并抬腿时，腿部经常与身体平行排列，尾部持续抬起，躯干不稳定。
级别21
与上相似，但是躯干稳定。
聚合物神经保护作用的评价
神经保护作用及聚合物的整合(polymers integration)可在创伤一个月后的组织学切片上看到。动物通过心内途径麻醉(perfuse)。在麻醉之后，切出脊髓，以在在创伤的中心区域向脊柱的尾部和头部切出获得1.5厘米的片段。将组织置于固定剂中5天，然后嵌入石蜡。以显微镜用薄片切片机制备10微米厚的连续的纵向切片，从10片切片中选择获得4个样品。将选定的切片通过在45℃下的浮选水浴，将其置于玻璃板上通过Harris法以苏木素与曙红染色。
统计分析
当结果表现为正态分布和方差齐性时，使用参数统计分析结果。使用重复测量的ANOVA检测，然后使用邓奈特检验。
值取在p＜0.05以确定统计显著性的极限。
结果
功能评价的结果在图3中显示。在此实验中观察到，植入了PPy/PEG的动物的恢复率比对照组高5倍，植入了PPy/I的动物的恢复率也比对照组高10倍(p＜0.05)。在两组接受植入的组中，功能恢复率表明动物具有自主神经功能，因为使用BBB评级将观察到的植入了PPy/PEG的动物评为4级，表明后肢三个关节(髋、膝和踝)活动受限，然而植入了PPy/I的动物平均级别为7，表明后肢三个关节(髋、膝和踝)发展到能自由活动。图中的缩写分别对应于：切片：脊髓完全切断但未植入植入物，切片+聚吡咯(PP)/PEG：脊髓完全切断并植入了聚吡咯和聚乙二醇共聚合物，切片+PPy/I：脊髓完全切断并植入了碘掺杂的聚吡咯。结果以每组3只动物的平均值±SE表示。结果以重复测量的ANOVA检测分析，然后以邓奈特检验分析。*p＜0.05。
在图4、5和6中显示了组织学实验的结果。在对照组中，神经组织损伤扩大并且观察到炎症细胞的存在。在PPy/PEG组中，发现神经组织损伤较轻，没有发现异物巨细胞，但是存在海绵状巨噬细胞、炎症细胞和T淋巴细胞。在PPy/I中，植入的聚合物与脊髓的神经组织结合，并发现了炎症细胞，T淋巴细胞、被称为异物巨细胞的修饰的巨噬细胞。在图像中显示的缩写是指：图4，(A)创伤区域和残留组织(2.5×)；(B)过渡区域放大图(5×)；(C)创伤区域中细胞结构的缺失(20×)；(D)存在的炎症细胞(40×)。SB：白色物质，SG：灰色物质，ZL：损伤区域，CI：炎症细胞。图5，(A)植入物整合至神经组织的图像(2.5×)；(B)过渡区域放大图(5×)；(C)创伤区域(20×)；(D)存在的炎症细胞(40×)。SB：白色物质，SG：灰色物质，ZL：创伤区域，CI：炎症细胞。苏木素/曙红技术。SB：白色物质，SG：灰色物质，ZL：创伤区域，PPy/PEG：聚吡咯和聚乙二醇共聚合物移植物，MM：修饰过的巨噬细胞。图6，(A)植入物整合至神经组织的图像(2.5×)；(B)过渡区域放大图(5×)；(C)创伤区域(20×)；(D)存在的炎症细胞(40×)。SB：白色物质，SG：灰色物质，ZL：创伤区域，CI：炎症细胞。苏木素/曙红技术。SB：白色物质，SG：灰色物质，ZL：损伤区域，PPy/I：碘掺杂的聚吡咯植入物，CGCE：异物巨细胞。
图7显示了每周对动物总体健康状况的观察结果。在这些图片中，可以观察到皮肤感染的存在。同样，在研究性分析中确认了在检测期间，没有观察到呼吸系统和肾感染。最后，此实验没有发现副作用或生物材料排斥反应，生存率为100％。图中的各组对应于：(A)未植入植入物的对照动物；(B)植入了聚吡咯/聚乙二醇共聚合物的动物，及(C)植入了聚吡咯/碘的动物。
结果表明等离子体合成的聚合物可用作脊髓有效的神经保护器和神经再生器，所述脊髓是完全切断大鼠脊髓导致的创伤之后的脊髓，并且没有严重的副作用。
通过上述说明，认为将等离子体合成的吡咯衍生的聚合物用于制备促进创伤后神经保护和神经再连接的植入物的用途具有新颖性。同时也将考虑聚吡咯和聚乙二醇共聚合物的等离子体合成方法。因此，本文要求了以上权利要求。
Claims (2)
1.等离子体合成的碘掺杂聚吡咯或聚吡咯/聚乙二醇共聚合物用于制备植入物的用途，所述植入物用于促进创伤后的神经保护和脊髓再连接，其中通过包括以下步骤的等离子体合成方法来获得所述碘掺杂聚吡咯或聚吡咯/聚乙二醇共聚合物：
a)通过在反应器中混合单体的蒸气流并应用亮度电休克法聚合所述单体，其中所述聚合发生在1.5×10-2托的压力以引发聚合反应，并聚合物在5×10-2托的压力以延续化学反应；电场振荡频率为13.5MHz；反应物的温度为20℃；聚合时间为300分钟；
b)所得到的聚合物通过用丙酮润湿2～3个循环而分离；
c)干燥所述聚合物；以及
d)机械地回收所述聚合物。
2.权利要求1所述的用途，其中可在创伤后的任何时间应用。
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