CN1243573C - 预制的角膜组织镜片及其制备方法(ii) - Google Patents
预制的角膜组织镜片及其制备方法(ii) Download PDFInfo
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- CN1243573C CN1243573C CNB018158285A CN01815828A CN1243573C CN 1243573 C CN1243573 C CN 1243573C CN B018158285 A CNB018158285 A CN B018158285A CN 01815828 A CN01815828 A CN 01815828A CN 1243573 C CN1243573 C CN 1243573C
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Abstract
涉及一种由适合用作接触镜片或移植镜片的供体角膜组织制成的镜片、一种制备该镜片的方法和一种将该镜片安置在眼睛上的技术。该镜片由通过除去天然的上皮和角膜细胞而去细胞的供体主角膜组织制成。这些细胞可以选择地用人体的上皮和角膜细胞置换,以形成一个具有类似于人体角膜的解剖学结构的镜片。该眼睛镜片可以用于校正诸如散光、近视、无晶状体畸形和老视之类的状态。
Description
发明领域
本发明属于眼科学领域。更具体地说,本发明涉及一种活性镜片,适合用作接目镜片或用于上皮下的移植。该镜片用供体角膜组织制成。本发明包括制备该镜片的方法和将镜片安置在眼睛上的技术。
发明背景
视力***使眼睛能够将光线聚焦成有意义的图象。一位眼科医生或验光师遇到的最普遍的问题是球形眼反常的问题,或是由于不适当成形的眼球而由眼睛形成一个经过调节却还在焦点外的图象。眼科医生或验光师确定眼睛的折射状态并用接触镜片或眼镜校正光学误差。
已经研究了许多方法,通过改变角膜的形状来校正球形眼反常。进入眼睛的光首先由角膜聚焦,这占据眼睛总折射能力的约75%。折射操作的大部分涉及减小或增大角膜的前曲率。
早期角膜折射外科学中的操作如角膜透镜移植术和角膜磨镶术最初研究用于校正近视,并涉及用显微角膜刀从病人移去角膜片。然后将该移去的角膜片冷冻,之后用低温车床将后表面重新成形。在解冻之后,将角膜片放回眼睛中,并用缝合术固定。
如在美国专利No.4,662,881中描述的表层角膜镜片术是一种涉及将一个预先切割的具有斜角边缘的供体角膜组织镜片***受体角膜的相应槽中的操作。然后将该镜片缝合在角膜床上。该供体镜片是冻干的,在安置到受体角膜上之前需要重新水合。
由于涉及不规则散光、延迟的外科愈合、角膜疤痕及折射效果的不稳定的经常的复杂性,这些技术及其变化方案通常被认为是不成功的。问题归因于这些操作的技术复杂性以及从属于镜片操纵的角膜组织的结构中的畸变。例如,在表层角膜镜片术中,由于供体镜片的冻干而诱生上皮的不规则性。角膜透镜移植术和角膜磨镶术中微透镜的冷冻也导致严重损伤上皮细胞和基质细胞并破坏角膜的层状结构。
本发明是一种用从组织源如人体角膜或动物角膜获得的供体角膜组织制成的预制镜片。该镜片是一种在后表面上通常成形到符合眼睛前表面形状的角膜片。本发明的镜片可以用一束烧蚀激光如受激准分子激光或其它合适的激光成形。该角膜微透镜是一种没有冷冻、冻干或化学变性(如用戊二醛固定为交联角膜组织)的活性组织。预先存在的角膜细胞被涂去,然后用人体角膜细胞置换,以减少抗原性。在移去受体角膜中心区域中的上皮后,以在眼睛上安置一个接触镜片的同样方式将该镜片安置在该区域上。
先有技术中的眼睛镜片不使用天然角膜,而采用可溶胶原如胶原水凝胶(如聚羟基乙基甲基丙烯酸酯)或其它生物可兼容物料制成。例如,在Civerchia的美国专利No.5,213,720中,可溶胶原被凝胶化和交联化,以生产人造镜片。除了水凝胶以外,Lindstrom的美国专利No.4,715,858公开了用各种聚合物、硅酮和纤维素乙酸丁酸酯制成的镜片。
在眼睛镜片使用角膜组织的情况下,镜片或者是角膜植入物,或者需要一种独立的药剂将镜片附着在角膜床上。Gibson等人的美国专利5,171,318和Peyman的美国专利No.5,919,185涉及一种部分或全部埋置在基质中的角膜组织片。Peyman等人的美国专利No.4,646,720和Ting的美国专利No.5,192,316中公开的眼睛镜片器件利用缝合附着在受体角膜上。Kern的美国专利No.4,676,790中描述的角膜嵌入利用缝合、激光焊接或涂敷胶粘液或交联溶液而结合在受体角膜上。
本发明的眼睛镜片器件并不改变角膜组织的解剖学结构。Tennant等人的美国专利No.4,346,482公开了一种“活体接触镜片”,由已经前面弯曲以校正视力的供体角膜组成。但是,该镜片在车床上重新成形之前是冷冻的,这导致基质的角膜细胞死亡。Cumming等人的美国专利No.4,793,344也描述了一种用戊二醛固定剂处理改性的供体角膜组织镜片,该固定剂保护组织并防止镜片膨胀。这种处理由于交联该组织而改变角膜微透镜的基本结构。
其次,所引证的文献并没有显示任何除去天然角膜组织细胞并用从人体角膜培养的细胞来置换它们的镜片制备方法。本发明器件除去天然的上皮和角膜细胞的活力而产生一种去细胞的角膜组织,然后用人体的上皮和角膜细胞重新赋予活力。parenteau等人的美国专利No.5,374,515中示出一种构造所谓“角膜组织等效物”的尝试。但是,该“等效物”中使用的胶原是从牛腱中得到的而不是从角膜得到的。添加的角膜细胞和上皮也不是从人体源得到的。使用这些细胞培养程序的组织也十分易碎。
使用一束受激准分子激光束通过“原位激光角膜磨镶术”(LASIK)操作程序来重新形成角膜。在该技术中,使用一束受激准分子激光束进行角膜皮片的基质的光烧蚀或暴露的基质床的原位光烧蚀。研究表明,利用该程序的校正的不精确度高达距离希望值1屈光度。与此相反,镜片(接触镜片和眼镜)却能够校正到希望值的0.25屈光度以内。
Jean等人的美国专利No.6,036,683使用激光束对角膜重新成形。但是,由于不可逆地凝固的胶原,激光改变了角膜的天然结构。利用这种处理,胶原的激光后松驰是不可能的。
但是,本发明在某些方案中涉及一种不用缝合而附着在受体角膜上的预制的供体接触镜片。该镜片保留了正常的角膜组织的解剖学特征。该供体镜片可以从人体源和动物源获得,去除了天然的角膜细胞和上皮的活力以产生一种去细胞组织,然后利用人体的角膜细胞和上皮细胞中的至少一种来可以选择地重新赋予活力,以维持镜片的生存力和减小抗原性。本发明的角膜叠置技术可以在局部麻醉也可以在全身麻醉下完成,而使用预切割的镜片将大大减少操作时间、病人费用和操作复杂性的危险。由于使用已经重新聚集角膜细胞的镜片,也缩短了治愈的时间。
引证的文献中没有一篇显示或提示了本文描述的本发明。
发明概要
本发明是一种预制的眼睛镜片器件,有一个用从组织源如人体角膜或动物角膜来的供体角膜组织制成的镜片心。该器件可以用作接触镜片或用作植入镜片,并可以具有普通凸面的前表面和可以选择的凹状的后表面。该镜片心的基质部分可以重新布满置换的角膜细胞,而前表面最好覆盖一层置换的上皮。该镜片心附着在受体角膜上而不需要缝合或其它胶粘物料。
该镜片心可以不同地用于校正散光、近视、无晶状体畸形和老视。该镜片心可以周转基因的或异种基因的角膜组织制成。经过合适的处理,本发明的镜片可以具有相应厚度的人体角膜组织的清晰度的至少85%的清晰度。该镜片心没有冷冻、冻干或用固定剂进行化学处理。但是,本器件的各种方案可以包含治疗药剂、生长要素或免疫抑制剂。
本发明的另一组成部分是一种用于制备镜片器件的方法。在锐利地割开一个从供体角膜组织来的微透镜之后,用烧蚀激光如受激准分子激光或其它合适的成形激光成形后表面。除去天然的上皮和角膜细胞,然后按照需要用人体的上皮和角膜细胞置换。
本发明的另一部分是一种角膜叠置方法,该方法涉及对受体角膜前表面的一部分去上皮和将本发明的眼睛镜片器件安置在该前表面上。另一种方法涉及用抽吸或其它手续暂时分离上皮组织和将本发明的镜片安置在该上皮组织下面。
附图简述
图1是眼睛的上视截面图。
图2A是近视眼中聚焦点的侧视图。
图2B是通过拉平角膜前曲率而校正的聚焦点的侧视图。
图3A是一个预制的供体镜片的侧视截面图。
图3B是一种适合于校正近视的预制的供体镜片的侧视截面图。
图3C是一种适合于校正无晶状体畸形的预制的供体镜片的侧视截面图。
图3D是一种适合于双焦点用途的预制的供体镜片的前视图。
图3E是安置成离开眼睛角膜的图3C镜片的侧视截面图。
图3F是一个有一叠加的上皮层的本发明镜片的前视图。
图3G表示图3F镜片的侧视截面图。
图3H表示在一载体中的本发明镜片的侧视截面图。
图3I是一种环形的本发明镜片的前视图。
图3J表示图3I镜片的侧视截面图。
图4A是制备成待接受本发明光学镜片的去上皮的受体角膜的一个区域的侧视截面图。
图4B是安置在受体角膜上之后的供体镜片的侧视截面图。
图5表示用于将一个本发明的镜片引入眼皮下的一系列步骤。
详细描述
眼睛用来将光聚焦到视网眼膜中的专门的感受器上,该感受器将光能的量子转换为神经动作电位。如图1中所示,光线首先透射通过眼睛的角膜(100)。角膜由于其胶原纤维的高度有机化结构而是透明的。角膜的边缘与韧性的纤维胶原的巩膜(102)结合,并被称为角膜-巩膜层。
角膜(100)是围住眼睛的前六分之一的角膜-巩膜层的一部分。角膜的平滑的曲率是视网眼膜(104)上图象的主要聚焦能力,而且它提供眼睛的60屈光度的会聚能力的大部分。角膜是一种无血管的构造,并受从水状液(106)来的营养素和氧的扩散的维持。一些氧也从外部环境取得。角膜的无血管性质减弱了组织的免疫性,增大了角膜移植的成功率。
角膜由五层组成。外表面由约5个分子厚的复层鳞状上皮贴面。上皮形成的失效导致基质盖的坏死和受体角膜的潜在疤痕。上皮是由称为鲍曼膜(角膜前弹性层)的专门的基膜支承的,该基膜给角膜一个光滑的光学表面。角膜的大部分(基质)由高度规则形状的形成薄层的稠密的胶原连接组织组成。薄层之间是纺锤体形状的角膜细胞,它们可以受激发而合成连接组织的成分。角膜的内表面由一层扁平的内皮细胞贴面,它们由Descemet膜(角膜后弹性层)支承,后者是一种非常厚的弹性的基膜。
如上所述,角膜的聚焦能力主要取决于其外表面的曲率半径。在近视眼中,如图2A所示,角膜(200)的增大的曲率使光线的焦点(202)落在视网眼膜(204)的前面。在图2B中,拉平角膜(206)的前曲率能校正焦点(208)。
本发明镜片的结构
在本发明镜片的第一方案中,镜片物理形状的尺寸和构型通常为当其安装在角膜上时能补充角膜的曲率以校正异常状态如散光、近视、远视、老视和无晶状体畸形。该镜片的其它方案的形状可以做成安置在宿主角膜的前表面下,或用作药疗源。
通常,该镜片心可以包括或主要包含已失去活力的无细胞的供体角膜组织,例如,已处理而除去天然的角膜细胞和上皮,以减少组织排斥的机会,然后至少部分重新赋予活力,例如,已处理而引入至少一个人体角膜细胞和一个上皮层,以允许和支持继续使用在眼睛上的位置中的本发明的镜片。上皮细胞(常常以一个分离层的形式)安置在本发明镜片的至少一部分前表面上,这是处在本发明的范围之中的。在本发明镜片的某些方案中,全部前表面将是这样被复盖的。在下面讨论的一个方案中,一个上皮层将伸展越过镜片心的边缘,该镜片可以选择地被载带在一个可以生物降解的载体上,该载体在眼睛中安置期间使用并在以后消失。
本发明的镜片可以安置在一个从其至少已除去天然上皮主要部分的宿主眼睛上。最好是,在本发明操作程序的该方案中,已从将安置本发明镜片的部位除去基本上全部上皮。也可以在将镜片引到宿主角膜的前表面上的程序期间,将该镜片安置在从眼睛表面抬高的一层上皮的下面,或者在其它情况下,将该镜片安置在宿主角膜的表面下面。本发明的镜片可以以各种方式用于校正折射(由于其形状),或者也可以简单地用于对眼睛提供一个注入药疗源。
供体镜片微透镜或镜片心可以从其它人体(同种)源或异质组织(异种)源获得。合适的异种源包括兔、牛、猪或豚鼠的角膜组织。眼的镜片心也可以来自转基因的角膜组织或在试管内生长的角膜组织。在许多情况下,希望供体组织中的角膜层结构、正常的角膜组织基体,如连接组织或连接基体,都基本上是保存的。“角膜组织基体”用胶原纤维薄层制成。此处使用的术语“供体角膜组织”意味着包括供体的或采集的角膜或包含“角膜组织基体”的角膜组织。此外,在本发明的大多数方案中,高度希望保存如在天然上皮下面找到的供体角膜组织的前表面。该供体角膜组织没有遭受诸如真空冻干、冷冻或其它化学固定之类粗糙的处理。然而,有时候希望仅仅利用供体镜片的一部分前表面,例如在本发明镜片结构为环形的情况下。
在供体组织包括鲍曼膜的场合下,本发明的眼睛镜片器件希望包括鲍曼膜(角膜前弹性层),以维护人体上皮的天然结构。再一次高度希望以这样的方式从供体源采集,使得能保存上皮下面的天然前表面。发明人已经发现,这些天然的结构具有卓越的性能(特别在下面讨论的重新赋予活力的步骤之后)来支承和维持也在下面讨论的置换的上皮。以这样一种方式处理的本发明的组织镜片心的清晰度通常为相应厚度的人体角膜组织的清晰度的至少85%,优选的为75%-100%之间,而最优选的为至少90%。
本发明镜片的总直径在功能上适合于完成所要的校正,最常小于约25mm,最优选的是在10和15mm之间。最终镜片的厚度又一次在功能上适合于完成所要的校正,例如通常小于300μm,最优选的在5-100μm之间。
如图3B中所示,最好利用下面讨论的程序以这样的方式制造用于近视病人的镜片心(316),使得中心的通常圆形区(318)在其前曲率方面被拉平。在无晶状体畸形的校正中,制造一个如图3C中所示的具有较厚中心(322)和较薄周边(324)的镜片。通常,此处讨论的形状类似于在所谓“软性”接触镜片中采用的形状,而指导说明则可以从有关选用来校正特定眼病的镜片的所有形式的技术中得到。
如图3D和3E中所示,本发明的镜片也可以用于校正老视。特别是,为了医治老视,镜片(330)同时设置一个邻近该器件中心的通常不透明的环形区(332)。开口中心(334)优选地具有平镜片特性和小于约1.5mm的有效直径,更优选地在约0.5-1.5mm之间,最优选地在0.75和1.75mm之间。该开口中心(334)或中心区或“针孔”的直径通常制成和选定为小于白天光线下宿主眼睛的瞳孔直径。这产生一种“针孔”效应,从而延长眼睛的总有效焦距和尽可能缩小眼睛调节的需要。也可以包括其它双焦点镜片设计,如同心环、环形区或环的切割部分或区段、或者渐进衍射。
图3E表示图3D中示出的本发明镜片(330)的邻近角膜(344)前表面的侧视截面图,以例示该方案的某些特点。不透明的圆环(332)的外径(336)通常这样选取,使得该外径小于弱光条件下虹膜(342)中瞳孔(340)的直径(338)。在这种方式下,眼睛的角膜和晶状体与本发明的镜片以这样的方式相互配合,使得入射光穿过不透明环的中心(334)而通过两者,但更重要的是,在不透明环(332)的周边的周围通过两者,以便允许在弱光条件下校正视力。
圆环(332)安置在镜片心上可以或者是通过在后表面上安置一种合适的染剂如通过“角膜染色术”,或者是在后表面上安置一种基本上不透明的可以生物兼容的部件如涤轮网眼之类,以滤去光线。安置圆环(332)的其它方法可以设想例如安置在本发明镜片的前表面上。圆环(332)本身最好是非常不透明的,例如通过少于约80%的入射可见光,但可以选成不透明程度较小,或者通过利用颜色折射之类办法将入射光颜色移至可见光范围来校正其它疾病如色盲。
如图3F(前视图)和3G(截面图)中所示,本发明镜片器件的另一方案(346)包括一个如上所述但有一延伸越过该镜片心(348)的周边(350)的上皮层(352)的镜片心(348)。用于产生具有周边外上皮层(352)的方案(346)的方法类似于本文别处描述的方法,不同之处是镜片心(348)最好安置在一个其形状全面符合供体镜片心(348)的前表面的载体(图3H中的354)中。
如图3H中所示,载体(354)希望起几个作用。首先,在将镜片心(348)安置在该上皮层(352)上之前,该载体提供一个用于生长上皮层(352)的衬底。该超越镜片心(348)周边的外表面为否则易碎的上皮层(352)提供支承。载体(354)可以安置在一合适形状的容器中或在该容器中形成,这转过来又在生长一个上皮层(352)的步骤期间为易碎的载体(354)提供支承。
如图3H中所示,载体(354)、上皮层(352)不管上皮层(352)是否延伸超越镜片心(348)的周边,例如上皮层(352)仅安置在镜片心(348)的一部分或全部上和安置在该上皮层(352)上的镜片心(348)的组合(356),是本发明的另一方案。在适当选择载体材料后,图3H中所示的构造(356)可以直接安置在宿主眼睛中,从而为上皮层(352)和镜片心(348)提供支承,以及可以选择地,在最初安置期间为眼睛提供药疗物料或其它医治物料。
当该载体用于安置在眼睛中时,载体(354)最好包括一种满足两个相关判据的物料。首先,该物料希望是一种在载体(354)、上皮层(352)和供体镜片(348)的组合(356)引入该眼睛后从待医治的眼睛中溶解、消蚀或以其它方式很快变透明的物料。同时最好是,该载体是一种用作供一个预先生长的上皮层用的衬底的物料。最希望的是,载体(354)满足两个判据。载体(354)可以包括一种物料例如胶原、明胶、淀粉、葡萄糖胺、葡聚糖、蛋白质、碳水化合物、聚酐(如聚交酯和聚乙交酯)、其混合物和共聚物等。
载体(354)也可以浸渍药疗物料或其它医治物料、抗血管生成物料等等。
图3I和3J分别表示一种具有通过镜片体的中心孔(362)的本发明镜片(360)的前视图和侧视截面图。虽然图示的该镜片方案(360)没有上皮层,但它处在包括该层的本发明的范围内。
镜片成形过程
返回图3A,供体镜片心(300)最好是在用微角膜刀从供体切下角膜组织薄片以形成该镜片心(300)之后获得的。供体镜片(300)有一结构表面,镜片心的前表面用作供体角膜组织的结构表面。镜片心前表面最好采集时保留鲍曼膜(此处供体镜片包含一个膜)和上皮(302)。最终的本发明镜片的后表面(304)通常为凹状,虽然它并不必须如此。镜片的前表面可以通过一种成形步骤来成形,该步骤最好包括使用烧蚀激光如受激准分子激光,以获得镜片的所需能力。另一种合适的成形步骤是高压水流切割。
消毒、去活力和重新赋予活力的步骤
虽然下面列举的处理步骤的顺序是典型的,但应当理解,这些步骤在需要时可以变化,以产生所需效果。
通常,镜片首先成形到上述一个合适的形状。然后该镜片心可以接受消毒、去活力和重新赋予活力的处理。从供体镜片除去上皮(去上皮)和角膜细胞(去细胞)被称为“去活力”。人体的上皮和角膜细胞的添加被称为“重新赋予活力”。一种理想的完成这些步骤的方法如下。其它等效的方法是已知的。
在这些处理期间使用的溶液是带有抗菌素的磷酸盐缓冲的盐水(PBS)、上皮细胞培养基和角膜细胞培养基。该“带有抗菌素的PBS”溶液可以包含:
带有抗菌素的PBS:
1.两性霉素B(ICN生物医药)0.625μg/ml
2.青霉素(Gibco BRL)100IU/ml
3.链霉素(Gibco BRL)100μg/ml
4.磷酸盐缓冲的盐水(Gibco BRL)
上皮细胞培养基的成分可以包含:
上皮细胞培养基:
1.Dulbecco改性鹰培养基/Ham F12培养基(Gibco BRL)3∶1
2.10%胎儿腓肠血清(Gibco BRL)
3.表皮生长要素(ICN生物医药)10ng/ml
4.氢化可的松(Sigma-Aldrich)0.4μg/ml
5.霍乱毒素(ICN生物医药)10-10M
6.腺嘌呤(Sigma-Aldrich)1.8×10-4M
7.胰岛素(ICN生物医药)5μg/ml
8.转铁蛋白(ICN生物医药)5μg/ml
9.谷氨酰胺(Sigma-Aldrich)2×10-3M
10.三碘甲状腺氨酸(ICN生物医药)2×10-7M
11.两性霉素B(ICN生物医药)0.625μg/ml
12.青霉素(Gibco BRL)100IU/ml
13.链霉素(Gibco BRL)100μg/ml
角膜细胞培养基的成分可以包含:
角膜细胞培养基:
1.DMEM
2.10%新生儿腓肠血清(Gibco BRL)
3.谷氨酰胺(Sigma-Aldrich)2×10-3M
4.两性霉素B(ICN生物医药)0.625μg/ml
消毒步骤
在从供体角膜组织采集镜片心和遵循成形步骤之后,镜片可以例如通过在室温下浸入98%甘油中来消毒。三个星期的甘油处理能使细胞内的病毒和任何细菌或真菌失去活性。也可以使用氧化乙烯气体消毒性,但该法往往对基质组织诱发可变的损伤。
去活力步骤
去上皮
发明人比较喜爱通过将供体镜片在室温4-25℃下放置在1克分子浓度的盐(最好是氯化钠)溶液中来对供体镜片去上皮。在4-8小时的孵育后,整个上皮层通常会从角膜基质上分离并可以容易地除去。然后可以在带有抗菌素的PBS溶液中清洗镜片,以除去盐和细胞物质。
除去上皮的另一方法是使用真空。可以利用抽吸(-100mm Hg至-450mm Hg)从基质分离上皮。在15分钟至1小时后,上皮通常与基膜层上的基质分开。然后可以在带有抗菌素的PBS溶液中清洗镜片,以除去盐和细胞物质。
最后,可以通过将供体镜片放置在带有抗菌素的消毒的PBS中4小时并多次变换溶液来对供体镜片去上皮。然后可以将镜片心在37℃下浸入PBS溶液1星期,以产生上皮和基质之间的分离。然后可以例如通过物理刮擦或用液流冲洗来除去上皮。小量的镜片可以用镊子轻轻刮擦来剥离上皮。
去细胞
然后可以将已去上皮的镜片浸入一种洗涤剂溶液(如0.025%至15%在硫酸十二烷基钠)中来洗去角膜细胞物质。一种洗涤剂将溶解和洗去该角质化细胞物质。这可以在1至8小时内发生。然后该细胞物质可以在一种带有抗菌素的缓冲溶液中清洗来除去洗涤剂和细胞物质。
或者是,可以将该已去上皮的镜片浸入带有抗菌素的消毒的PBS中一段适当的时期如数星期也许六星期来除去天然的角膜细胞。该溶液可以每星期换两次。在某些情况下,可以不需要从供体镜片上除去角膜细胞,例如当该供体组织是从转基因源获得并具有极少的抗原性时。
重新赋予活力的步骤
细胞的制备
在重新赋予活力的处理中使用人体的上皮细胞和角膜细胞。上皮细胞可以从组织库获得,但最好从胎儿组织或新生儿组织获得。胎儿细胞是最优选的,因为在任何创伤愈合过程中胎儿组织的性能使留下的疤痕最少。
在任何场合下,通过角膜组织的受胰蛋白酶作用而获得的新鲜分离的上皮细胞可以在上皮细胞培养基中接种于一个预先涂敷的致死地在辐照的3T3纤维细胞(i.3T3)的饲养层上。细胞被培养,培养基每三天换一次,直到细胞有80%融合(约7-9天)。在用胰蛋白酶(ICN生物医药)分离上皮细胞之前,用0.02%EDTA(Sigma-Aldrich)除去残余的i.3T3。另一种重新产生上皮的方法包括在人体羊膜上培养自身的上皮细胞,如《新英格兰医学杂志》2000年343:86-93的Tsai等人的“通过移植自身的肢体上皮细胞来重新构造受伤的角膜”中描述的。
角膜细胞可以从剩余的基质组织中取出。该基质在PBS中清洗,精细切碎,并在37℃下放置在0.5%胶原酶A(ICN生物医药)中16小时。然后将从该酶消化液中获得的角膜细胞顺序地在角膜细胞培养基中培养。在该重新赋予活力的步骤中产生的上皮细胞和角膜细胞将被称为“置换的”上皮细胞和角膜细胞。
供体镜片的产生
然后可以将该去细胞的供体镜片心安置在吸水的聚合电解质凝胶上,以完成重新赋予活力的步骤。优选的聚合电解质是软骨素硫酸盐、透明质酸和聚丙烯酰胺。最优选的是聚丙烯酸。镜片浸在角膜细胞培养基中,在37℃用约3×105个角膜细胞孵育48小时。然后将大约同等数量的上皮细胞加在前基质表面上。组织培养孵育继续另外48小时。每两至三天换一次角膜细胞培养基。一旦上皮重新产生,聚合电解质凝胶在约20-30mm Hg的压力下吸出镜片的水分,直到获得原来的镜片尺寸。
置换的上皮复盖该方案的本发明镜片的至少一部分前表面,而在重新赋予活力后置换的角膜细胞重新布满镜片心的基质。
如上所述,本发明镜片的另一方案包括一个从镜片心(348)周边延伸的上皮层(图3G中352)。在将镜片心(348)放置在预制的上皮细胞层上之前,可以使用刚才陈述的同一程序来制备载体(354)中的上皮细胞层。
在某些情况下,同时将治疗药剂、生长要素或免疫抑制剂合并在镜片心中,以减小排斥的危险或治疗疾病状态,可能是有益的。
将镜片安置在眼睛上
装贴本发明镜片的程序示于图4A和4B中。在该程序期间,如图3A中所示,供体镜片(300)安置在一部分已经去上皮的受体角膜(308)上。结果是图4B中所示的安置和构造(312)。镜片的置换的上皮和宿主上皮最终生长而形成一个连续的防水层(310)。发明人发现,本发明的镜片不用缝合线或胶粘剂就能贴合或粘附在受体角膜上,但也能够没有显著困难地移去。
安置程序的另一方案示于图5中。在该方案中,最好使用一个已置换角膜细胞而未置换上皮层的仅仅部分重新赋予活力的镜片心。当然,一个已经部分复盖一个上皮细胞种子层的镜片心也是可以接受的。在任何情况下,图5的步骤a表示一只有一上皮层(602)和角膜基质(604)的天然眼睛(600)。图5的步骤b表示在眼睛(600)的前表面上安置一个抽吸器件(606)。抽吸器件(606)对上皮层(602)外加。一个适度的真空,如在约-100mm Hg和-450mm Hg之间,以便升高一部分上皮层(602),如步骤c中所示。该水疱(608)通常充满生理液体。显然,抽吸器件(606)在角膜的表面上有一个与待安置在该角膜上的镜片的尺寸相似的痕迹。步骤d显示打开的上皮皮片(608)和镜片向着该上皮皮片(608)下面的角膜基质边缘(612)的安置。图5的步骤e表示完成了镜片(610)在角膜上天然上皮膜下面的安置。该程序有很多优点,包括比起简单地除去上皮来眼睛表面的创伤更少。
在本发明中使用供LASEK程序用的制备程序作为暴露角膜表面用于装贴本发明镜片的步骤,也处在本发明的范围内。该LASEK程序是已知的,与LASIK程序不同,不涉及用外科器械暂时移去角膜组织的前皮片,而仅仅利用乙醇清洗和为激光治疗暂时移开上皮层。这样一种预备步骤,用乙醇清洗以扰动角膜基质和上皮之间的结合部,足以提供一个暂时移去而在该角膜表面上***本发明镜片的上皮层。
发明人已经描述了该供体眼睛镜片的结构和生理特性及优点。但是,本发明的这种描述方式不应当以任何方式限制本发明的范围。
Claims (64)
1.一种眼睛镜片器件,包括:
一个包括具有一凸状前表面和一后表面供体角膜组织的镜片心,该镜片心包括下列两项中的至少一项:a.)在所述镜片心中被置换的角膜细胞和b.)覆盖至少一部分所述前表面的被置换的上皮细胞。
2.权利要求1的眼睛镜片器件,其特征在于,所述后表面是凹状的。
3.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括去细胞的角膜组织。
4.权利要求1的眼睛镜片器件,其特征在于,所述镜片心由去细胞的角膜组织组成。
5.权利要求1的眼睛镜片器件,其特征在于,所述后表面已经受一个成形步骤。
6.权利要求5的眼睛镜片器件,其特征在于,所述后表面是通过烧蚀激光成形的。
7.权利要求1的眼睛镜片器件,其特征在于,所述眼睛镜片具有的清晰度至少为相应厚度的人体角膜组织的清晰度的85%。
8.权利要求1的眼睛镜片器件,其特征在于,所述眼睛镜片具有的清晰度为相应厚度的人体角膜组织的清晰度的75%至100%之间。
9.权利要求8的眼睛镜片器件,其特征在于,所述镜片心具有的清晰度至少为相应厚度的人体角膜组织的清晰度的90%。
10.权利要求1的眼睛镜片器件,其特征在于,所述镜片心由供体角膜组织组成。
11.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括人体角膜组织。
12.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括同种基因的角膜组织。
13.权利要求10的眼睛镜片器件,其特征在于,所述镜片心包括异种基因的角膜组织。
14.权利要求13的眼睛镜片器件,其特征在于,所述异种基因的镜片心包括选自一组由兔、牛、猪和豚鼠角膜组织组成的角膜组织。
15.权利要求10的眼睛镜片器件,其特征在于,所述镜片心包括转基因角膜组织。
16.权利要求10的眼睛镜片器件,其特征在于,所述供体角膜组织有一个结构表面,而所述镜片心前表面是该供体角膜组织的结构表面。
17.权利要求1的眼睛镜片器件,其特征在于,所述尺寸和构型选成能校正选自由散光、近视、无晶状体畸形和老视组成的一组中的至少一种。
18.权利要求17的眼睛镜片器件,其特征在于,所述尺寸和构型选成能校正近视,而所述器件有一圆形的、扁平的镜片心中心区。
19.权利要求17的眼睛镜片器件,其特征在于,所述尺寸和构型选成能校正无晶状体畸形,而所述器件有一平坦的周边。
20.权利要求17的眼睛镜片器件,其特征在于,所述尺寸和构型选成双焦点的。
21.权利要求17的眼睛镜片器件,其特征在于,所述尺寸和构型选成能校正老视,并有一个无校正的圆形的镜片心中小区。
22.权利要求21的眼睛镜片器件,其特征在于,所述镜片心还包括一个具有一中心开口区和圆周直径的不透明的圆环。
23.权利要求22的眼睛镜片器件,其特征在于,所述环是通过“角膜染色术”或在所述后表面上安置不透明物料而形成的。
24.权利要求22的眼睛镜片器件,其特征在于,所述中心开口区有一小于1.5mm的直径。
25.权利要求24的眼睛镜片器件,其特征在于,所述中心开口区有一在0.5mm和1.5mm之间的直径。
26.权利要求24的眼睛镜片器件,其特征在于,所述中心开口区有一在0.75mm和1.25mm之间的直径。
27.权利要求23的眼睛镜片器件,其特征在于,所述环包括一个涤纶网眼。
28.权利要求22的眼睛镜片器件,其特征在于,所述不透明圆环圆周直径在3-5mm之间。
29.权利要求28的眼睛镜片器件,其特征在于,所述环的圆周直径选成小于选定的受体眼睛在弱光下的瞳孔直径。
30.权利要求1的眼睛镜片器件,其特征在于,所述镜片心还包含一种治疗药剂、免疫抑制剂或生长要素。
31.权利要求1的眼睛镜片器件,其特征在于,所述镜片心没有受到冷冻、冻干或通过固定剂的化学处理。
32.权利要求10的眼睛镜片器件,其特征在于,所述镜片心包括在试管内生长的角膜组织。
33.权利要求1的眼睛镜片器件,其特征在于,所述上皮细胞和角膜细胞包括人体角膜细胞。
34.权利要求33的眼睛镜片器件,其特征在于,所述上皮细胞和角膜细胞包括新生儿、胎儿或组织库的角膜细胞。
35.权利要求1的眼睛镜片器件,其特征在于,所述镜片心有一厚度,而所述厚度小于300μm。
36.权利要求35的眼睛镜片器件,其特征在于,所述镜片心厚度在5-100μm之间。
37.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括被置换的角膜细胞。
38.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括覆盖至少一部分所述前表面的被置换的上皮细胞。
39.权利要求1的眼睛镜片器件,其特征在于,所述镜片心具有周边,还包括一个超越所述镜片心周边而延伸的上皮细胞层。
40.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括覆盖至少一部分该前表面的被置换的上皮细胞,并且还包括一个支承该被置换的上皮细胞和镜片心的载体。
41.权利要求40的眼睛镜片器件,其特征在于,所述镜片心具有周边,还包括一直超越所述镜片心周边而延伸的上皮细胞层。
42.权利要求40的眼睛镜片器件,其特征在于,该载体包括一种可以生物消融或可以生物降解的物料。
43.权利要求42的眼睛镜片器件,其特征在于,该载体的尺寸和形状适合于引用到眼睛上。
44.权利要求42的眼睛镜片器件,其特征在于,该载体包括一种选自下列一组的物料:胶原、明胶、淀粉、葡萄糖胺、葡聚糖、蛋白质、碳水化合物、聚交酯和聚乙交酯的聚酐、其混合物和共聚物。
45.权利要求1的眼睛镜片器件,其特征在于,所述镜片心是环状的,并在前表面和后表面之间有一孔。
46.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括在所述镜片心中的被置换的角膜细胞。
47.权利要求1的眼睛镜片器件,其特征在于,所述镜片心包括覆盖至少一部分所述前表面的被置换的上皮细胞。
48.权利要求47的眼睛镜片器件,其特征在于,所述镜片心包括覆盖全部所述前表面的被置换的上皮细胞。
49.一种用于制备一个眼睛镜片器件的方法,包括:
a)采集一个镜片心,该镜片心包括供体主角膜组织,并有一个凸状的前表面和一后表面;以及
b)具有覆盖至少一部分所述大体上凸状的前表面的被置换的上皮;以及
c)具有重新填充所述镜片心的被置换的角膜细胞,包括下列步骤:
i)对所述镜片心去活力;以及
ii)对所述镜片心重新赋予活力。
50.权利要求49的方法,其特征在于,还包括对所述后表面成形的步骤。
51.权利要求50的方法,其特征在于,所述成形步骤包括将一束烧蚀激光应用于该后表面。
52.权利要求51的方法,其特征在于,所述成形步骤包括将一束受激准分子激光或成形激光应用于该后表面。
53.权利要求50的方法,其特征在于,所述成形步骤包括将一个水喷切割刀具应用于所述后表面。
54.权利要求49的方法,还包括采集所述镜片心的步骤。
55.权利要求54的方法,其特征在于,所述镜片心是从人体、兔、牛、猪或豚鼠的角膜组织中采集的。
56.权利要求49的方法,其特征在于,所述重新赋予活力的步骤包括置换从人体角膜组织培养的细胞。
57.权利要求56的方法,其特征在于,所述细胞是从新生儿组织、胎儿组织或组织库组织培养的。
58.权利要求57的方法,还包括在所述成形步骤后对所述镜片心进行消毒的步骤。
59.权利要求58的方法,其特征在于,所述消毒步骤包括使所述镜片心与甘油接触的步骤。
60.权利要求58的方法,其特征在于,所述消毒步骤包括使所述镜片心与氧化乙烯气体接触的步骤。
61.权利要求49的方法,其特征在于,所述去活力步骤包括从所述前表面除去上皮和从所述镜片心除去角膜细胞的步骤。
62.权利要求49的方法,其特征在于,所述重新赋予活力的步骤包括向至少一部分所述前表面添加上皮细胞和向所述镜片心添加角膜细胞的步骤。
63.权利要求49的方法,其特征在于,所述重新赋予活力的步骤包括将所述镜片心安置在一种聚合电解质凝胶上的步骤。
64.权利要求49的方法,其特征在于,所述镜片心的角膜组织基体没有更换。
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WO2002006883A2 (en) | 2002-01-24 |
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