CN100402098C - 具有长期稳定性的内置假体 - Google Patents
具有长期稳定性的内置假体 Download PDFInfo
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- CN100402098C CN100402098C CNB008077363A CN00807736A CN100402098C CN 100402098 C CN100402098 C CN 100402098C CN B008077363 A CNB008077363 A CN B008077363A CN 00807736 A CN00807736 A CN 00807736A CN 100402098 C CN100402098 C CN 100402098C
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Abstract
本发明涉及活性物质复合物用于形成生物体部分、特别是活体器官的用途，该活性物质复合物具有下列组分，这些组分是彼此不同的，特异性地适应各自所要形成的生物体部分：至少一种基于细胞外物质的结构组分，它特异性地适应各自所要形成的生物体部分的细胞，至少一种补充组分，至少一种粘连组分，和至少一种生长和/或成熟组分，用于制备内置假体植入物。按照本发明，内置假体的外部(I)至少部分地涂有该活性物质复合物。内置假体还具有中空的腔(II)，其中充满该活性物质复合物。
Description
本发明涉及具有下列组分的活性物质复合物用于形成生物体部分、特别是活体器官的用途，这些组分是彼此不同的，特异性地适应各自所要形成的生物体部分，即，至少一种基于细胞外物质的结构组分，它特异性地适应各自所要形成的生物体部分的细胞，至少一种补充组分，至少一种粘连组分，和至少一种生长和/或成熟组分。
具有所述组分的、用于形成生物体部分、特别是活体器官的活性物质复合物是现有技术已知的。这种已知的活性物质复合物中，结构组分例如可以由不同的胶原、弹性蛋白或蛋白聚糖组成。作为这种活性物质复合物的补充组分，特别可以提到趋化因子类，例如肽类，如N-F-Met-Leu-Phe-，和/或例如花生四烯酸的代谢产物，如白三烯。扮演粘连组分角色的可以是纤连蛋白或层粘连蛋白类型的蛋白质，不过也可以是细胞粘连分子，例如L-CAM、N-CAM，和基质粘连分子，例如腱生蛋白、肌腱蛋白、IV、V、VII型胶原、合成肽类与跨膜化合物蛋白质、例如整合蛋白。关于这里所讨论的活性物质复合物，首先提到的粘连组分的实例、即纤连蛋白和层粘连蛋白归入基质粘连分子类。作为进一步的组分，所述活性物质复合物包含至少一种生长和/或成熟组分，优选地是一种或更多细胞因子的形式。这类细胞因子的实例是血液生成中的集落刺激因子；结缔组织生成中的成纤维细胞生长因子；皮肤生成中的表皮生长因子；软骨生成中的软骨诱导因子；脾或淋巴结生成中的淋巴细胞激活因子与脾肽；用于胸腺生成的T-细胞生长因子与胸腺肽；用于骨生成的骨生长因子与转化生长因子；和用于血管生成的血管生成因子。也使用下列细胞因子：白介素、胰岛素样生长因子、肿瘤坏死因子、前列腺素、白三烯、转化生长因子、血小板衍生生长因子、干扰素和内皮衍生生长因子。
关于这种活性物质复合物的更多细节参见欧洲专利No.0,500,556，其内容清楚地包括在本文中。
本发明的目的是使活性物质复合物具有更广泛的用途。
利用所述活性物质复合物形成内置假体植入物，可实现该目的。与没有活性物质复合物的常用内置假体相比，这提供了内置假体以长期稳定性。
在根据本发明的这种用途中，使用适合于形成骨形式的生物体部分、并且具有下列组分的活性物质复合物，这些组分是彼此不同的，特异性地适应于形成骨，即，至少一种基于细胞外物质的结构组分，它特异性地适应各自所要形成的生物体部分的细胞，至少一种补充组分，至少一种粘连组分，和至少一种生长和/或成熟组分。
根据本发明的这种用途的发现是广泛研究的结果，这些研究针对使活性物质复合物与不同的支撑材料、特别是金属支撑材料结合。支撑材料与活性物质复合物的结合不是不成问题的。基于以前的关于活性物质复合物及其复杂作用模式的经验，人们至少不得不期望减少所要治疗的特定生物体部分的生成或再形成，例如骨再生。组织毒性反应的危险也是令人怀疑的。
因此该问题的解决方案并不是显而易见的，其原因正如已经解释过的，使活性物质复合物与支撑物结合是极成问题的，在这种情况下支撑物是内置假体，因为活性物质复合物在骨缺损中的功能可以被可能的免疫反应破坏或至少复杂化了。
所要稳定的内置假体具有一个外表面，它至少部分涂有活性物质复合物和/或它具有至少一个充满活性物质复合物的腔。
涂以和/或充满活性物质复合物的目的是使内置假体在有机体内更加迅速和永久的一体化。内置假体在植入部位的一体化得以加速且提高，带来长期稳定性，使内置假体的可负载性更高、更早。
按照进一步的实施方案，内置假体具有至少一个充满活性物质复合物的腔，另将活性物质复合物涂在进一步的支撑材料上。胶原或适合的聚合物可以用作这样一种进一步的支撑材料。这里可以确切地提到I、IV、V和VII型胶原。胶原例如可以使用网或凝胶的形式，它们特别地具有固有的良好的免疫相容性，易于加工。
可以采用的聚合物支撑材料确切地是天然单体的聚合物，例如聚氨基酸(聚赖氨酸、聚谷氨酸等)和乳酸的聚合物。也可以采用共聚物，例如聚乳酸与羟基乙酸的共聚物。
聚乳酸酯是具有下列化学式的乳酸的聚酯：
单体的直接聚合作用得到具有相对低分子量的聚合物。上限为约20,000Da。在催化剂的存在下，在高温和低压下连接环状二聚物可以得到更高的分子量。乳酸聚合物是生物可降解的、生物可相容的、水不溶性的，是以高强度为特征的。
进一步的支撑材料、例如胶原或所述聚合物的另外作用在于减少完全充满内置假体腔所需活性物质复合物的量，而不会对活性物质复合物的基本效率带来不利影响。按照这种方法，活性物质复合物的使用从经济角度上说是更加可取的。
本发明还涉及内置假体，它在根据该用途的实施方案之一中涂有或者包含活性物质复合物。
下面，根据实施例并参照附图对发明作更加详细的解释，其中：
图1为与未治疗的样本相比，使用活性物质复合物的兔新骨生成作用图示；
图2为与纯的磷酸三钙相比，使用活性物质复合物并以磷酸三钙作为支撑材料的绵羊新骨生成作用图示；
图3为与纯的胶原相比，使用活性物质复合物并以不同的胶原作为支撑材料的大鼠新骨生成作用图示；
图4a为涂以活性物质复合物的内置假体侧视图；
图4b为图4a旋转90°后的内置假体侧视图。
I、活性物质复合物的制备
制备活性物质复合物的主要步骤描述如下：清洗小牛、绵羊、兔或大鼠管状骨，尤其除去骨髓，然后将骨冷冻。将冷冻的骨研磨成粒径小于2mm。将研磨后的骨碎片在丙酮中脱脂，在0.6N盐酸中脱钙。然后将产物冷冻干燥，得到脱矿质的骨基质，在4摩尔盐酸胍溶液中萃取。将萃取溶液对蒸馏水透析，离心，冷冻干燥沉淀，得到活性物质复合物。
这种基本制备方法以下列流程图表示。
图1：表示活性物质复合物制备的流程图
屠宰后的新鲜管状骨骨干
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研磨成粒径＜2mm
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在丙酮中脱脂
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在0.6N HCl中脱钙
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洗涤，冷冻干燥
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脱矿质的骨基质
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在4M GuHCl中萃取
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残余物 上清液
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对蒸馏水透析
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沉淀：含有活性物质复合物
II、不使用支撑材料的活性物质复合物的功效
为了说明活性物质复合物本身是有效的，首先进行这样一种试验，其中在植入活性物质复合物时没有另外的支撑材料。
1、试验用动物
使用平均体重为3089g的雌性毛丝鼠兔。它们摄入兔维持饲料和用盐酸酸化至pH4.5的双臭氧化自来水。
皮下注射氯胺酮与赛拉嗪的混合物，使动物麻醉。
2、兔骨缺损的制备
使用内部冷却钻在兔膝关节内(股骨远端)制备直径4mm、深约9mm的植入床。然后在每种情况下向所形成的孔洞内各自装入30与90mg已如I下所述制备的活性物质复合物。在每种情况下另有一个孔洞不作处理，充当新骨生成的对照。
图1显示手术后28天后未经处理的孔洞和植入活性物质复合物后的孔洞内的新骨生成作用，以及周围预先存在的海绵物质的密度(n＝2/活性物质量)。
试验结果分析揭示了植入30mg活性物质复合物后孔洞周围的海绵物质的密度比未处理孔洞高45％，植入90mg活性物质复合物后比未处理孔洞高69％。预先存在的海绵物质的量对缺损的再生作用完全没有影响，因为插入活性物质复合物之后的新骨生成作用不是从孔洞外周开始的，而是均匀分布在缺损部位中的。
III、使用磷酸三钙(TCP)生成绵羊下颌骨
磷酸三钙(TCP)是基于CaO/P2O5系统的磷酸钙陶瓷，通过压制随后烧结原料氧化钙(CaO)与五氧化二磷(P2O5)而制备。或者，也可以通过热压步骤制备。
1、试验用动物
在下述试验中使用来自Viehzentrale Südwest AG，Stuttgart的成熟驯养绵羊。向它们供应干草和水，在手术前三天供应Altromin颗粒浆液。
向动物预先i.m.给以1ml赛拉嗪/1ml氯胺酮。然后用戊巴比妥钠麻醉绵羊。
2、植入物的制备
将TCP悬浮在100mg活性物质复合物的10ml水溶液中，在恒定搅拌下用液氮深度冷冻。冷冻干燥24小时后，气体灭菌(环氧乙烷)，将掺有活性物质复合物的TCP植入绵羊下述下颌骨缺损内。另外，向出于对照目的的另一下颌骨缺损内装入经过高压釜内灭菌的未掺杂TCP。
3、绵羊下颌骨缺损的制备
适当地制备绵羊下颌骨，以生理盐水作为冷却剂，用直径5mm的环锯切断，分别取骨的标准柱体。然后向所形成的孔洞之一装入TCP，按照试验操作1该TCP已经掺有活性物质复合物，第二个孔洞装入未经掺杂的TCP。
为清楚起见，下颌骨缺损内的骨生长结果以图面形式如图2所示。试验的持续时间分别为26天和41天。
发现在最初阶段，掺有活性物质复合物的TCP促进No.811和No.86绵羊下颌骨缺损的骨再生作用达约100％。41天后，对骨再生作用的促进率仍有10％。因此特别是在开始阶段，骨的愈合要比没有掺有活性物质复合物的植入物的成骨作用更加迅速。
该发现对涂有活性物质复合物的内置假体来说是特别重要的。例如在股骨颈部骨折的情况下，涂有活性物质复合物的内置假体相应地有利于假体更加迅速的结合，从而有利于更加迅速的再生和患者的恢复。因此缩短了住院期。
IV、用胶原作为支撑材料的试验
上文所讨论的已知活性物质复合物可以用于内置假体的结合。在活性物质复合物的制备中，具有所需程度纯度的定量收率是非常低的。我们因此检查了是否存在这样的支撑材料，它们能够与活性物质复合物结合，以便减少特定目的所需活性物质复合物的量，但又不会降低它的骨生成效率。
1、活性物质复合物
用于下述试验目的的活性物质复合物完全按I下所述方式制备，并使用来自小牛的管状骨。
2、试验用动物
使用体重在350与400g之间的雄性Wistar大鼠，饲养在带空调的动物房内，温度23℃，相对湿度约50％。对它们给以大鼠与小鼠维持饲料。
将两个相同支撑材料的植入物植入每只试验动物的腹部肌肉系统，其中一个植入物涂有活性物质复合物，而另一个保持未涂状态，充当对照植入物。21天后处死动物，移出植入物在腹部肌肉系统内的作用区域，进行组织学评价。
3、所用支撑材料
这些试验中，所用胶原材料都是商业上可得到的。胶原A是纯的、无菌的、天然的、可吸收的牛皮肤胶原，不合任何外来的添加剂，例如稳定剂或消毒剂。
胶原B是经过纯化的、冷冻干燥的、轻微交联的、无菌与无热原的牛皮肤胶原，具有弱抗原的性质。胶原的螺旋结构得以保留。
胶原C包含纯的、天然的和可吸收的牛胶原纤维。
所有所用的胶原都是网状。切成胶原网的切片，各重50mg，分别加入1ml活性物质复合物溶液(3mg/ml)。在对照植入物中，代之以加入1ml蒸馏水。将处理后的胶原网切片冷冻在-20℃下，冷冻干燥，得到直径约10mm、厚约5mm的植入物。图3显示在21天后，关于涂有和未涂有活性物质复合物的胶原植入物A、B和C对用环孢菌素A免疫抑制动物与非免疫抑制动物的骨生成结果。这里，评价数值(BZ)相当于每组三人对六个植入物的评价数值的算术平均值。
涂有活性物质复合物的胶原A在该时间阶段之后对免疫抑制动物显示骨生成作用，而这种作用在胶原B中没有得到证明。不过相形之下，胶原C显示非常显著的骨生成作用。
由此可见，这取决于所用特定胶原的制剂，并且显示了作为支撑材料的适应性。致免疫性胶原不适合用作支撑材料。
IV、试验支撑材料的生物可相容性
在涉及内置假体长期稳定性提高的试验中，使用来自Friedrichsfeld公司的具有不同表面粗糙度(100、20和0.5μm)的钛盘、TiAl6V4合金(0.5μm)和Al2O3盘，和来自Feldmühle AG公司的羟基磷灰石盘。羟基磷灰石是通过五氢氧化钙三磷酸盐粉末在1250℃下的陶瓷烧制作用而得到的。另外，羟基磷灰石也可以利用天然材料制备，例如红藻的碳酸盐骨架。经过洗涤和干燥操作后，首先通过在约700℃温度下的热解作用除去有机成分。然后在高压和高温下加入磷酸盐溶液，转化为羟基磷灰石。
在进一步的制备羟基磷灰石陶瓷的方法中，从天然的珊瑚骨架开始，珊瑚的碳酸钙被水热转化为羟基磷灰石或羟基磷灰石与其他矿物结构的混合物。所得材料中，保留了珊瑚状结构，也就是珊瑚的互连孔系统。
利用浸涂法涂以已用上述通用操作制备的活性物质复合物。浸涂法被理解为这样一种涂层方法，其中将所要涂覆的对象——在这种情况下是盘片——浸入具有所需预定浓度的涂覆剂溶液中，在这种情况下是活性物质复合物。然后冷冻干燥。得到薄薄的覆盖层或涂层。测定指定材料、特别是关于表面粗糙度的生物可相容性(n＝20；各四只盘片)。
所研究材料的这种生物可相容性试验揭示了钛作为支撑材料是非常适合的，具有最高数量的活细胞和最佳的活细胞与死细胞之比。羟基磷灰石得到近似好的结果，TiAl6V4相当差。
至于表面粗糙度，一般发现最光滑的表面、也就是孔径为0.2-0.5μm的表面获得最佳结果，TiAl6V4例外。随着粗糙度或孔径的增加，活细胞数及活细胞与死细胞之比下降。约0.5μm的孔径使活体(骨)组织与盘片表面直接接触的比例最高。
表1：
| 支撑材料 | 每cm<sup>2</sup>的活细胞数 | 每cm<sup>2</sup>的死细胞数 |
| 羟基磷灰石0.2-0.5μm | 1792±700 | 200±37 |
| 20μm | 7469±2614 | 2238±715 |
| 50μm | 4477±408 | 1692±427 |
| Osprovit(Feldmuhle) | 7930±2007 | 1638±377 |
| 钛0.5μm | 11377±2538 | 1054±308 |
| 20μm | 9600±3038 | 1754±439 |
| 100μm | 2308±669 | 2085±623 |
| TiAl<sub>6</sub>V<sub>4</sub>0.5μm | 7200±1062 | 2800±954 |
| Al<sub>2</sub>O<sub>3</sub>，特纯，抛光 | 11446±1500 | 2292±600 |
这些试验结果现在能够转换成将内置假体涂以活性物质复合物。所用内置假体的视图如图4所示。
在使用内置假体之前，通过浸涂过程将它们的外表面(I)涂以活性物质复合物，另外将活性物质复合物加入到假体茎(II)的内腔中，内腔在茎表面上具有开口。其优点是，万一将来可能发生内置假体松弛，随后能够施用活性物质复合物，而无需巨大努力，并且引起骨生成，从而使内置假体稳定。如果需要的话，也可以在螺钉连接(III)区域涂以活性物质复合物。
表2阐述了涂以活性物质复合物使负载能力比未涂表面更高这一事实，以羟基磷灰石(HA)为例。不同植入材料之间界面上的拉伸强度值以N/mm2±标准偏差表示。将通过热等压压制(HIP)法制备的羟基磷灰石与另外涂以活性物质复合物的羟基磷灰石进行比较。将植入材料植入兔股骨远区，84天后检查。拉伸强度值列在下表中。
表2：
| 材料 | SR(μm) | 天数 | n | 拉伸强度 |
| HA HIP | 0.5 | 84 | 10 | 1.53±0.24 |
| HA HIP AS | 0.5 | 84 | 6 | 2.27±0.31 |
N＝植入物数目
AS＝涂有活性物质复合物
HIP＝热等压压制
SR＝表面粗糙度
最后必须再次指出，出于本发明目的所进行的试验都是经过小心设计的模型试验，这是由于实际主体(也就是例如植入股骨区域的内置假体)不能为试验所利用，因为对人体进行这些试验将是不可被接受的。
另外，本发明能够应用于所有可以想象得到的内置假体。关于股骨颈部区域中的内置假体实例的说明仅仅是说明性例证。
Claims (4)
1.内置假体植入物，该内置假体具有至少部分地涂有活性物质复合物的孔径为0.2-0.5μm的外表面(I)，所述活性物质复合物具有下列彼此不同的，特异性地适应各自所要形成的生物体部分的组分，即至少一种基于细胞外物质的结构组分，它特异性地适应各自所要形成的生物体部分的细胞，至少一种补充组分，至少一种粘连组分，和至少一种生长和/或成熟组分。
2.如权利要求1所要求保护的内置假体植入物，其特征在于该内置假体具有至少一个充满该活性物质复合物的腔(II)。
3.如权利要求1或2要求保护的内置假体植入物，其特征在于所述活性物质复合物进一步与支撑材料组合。
4.如权利要求3所要求保护的内置假体植入物，其特征在于使用除了致免疫的胶原外的胶原或聚合物作为进一步的支撑材料。
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| Application Number | Priority Date | Filing Date | Title |
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| DE19917696.5 | 1999-04-20 | ||
| DE19917696A DE19917696A1 (de) | 1999-04-20 | 1999-04-20 | Mittel für die Herstellung biologischer Teile mit einem Wirkstoffkomplex und für diesen geeigneten Trägermaterialien |
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| CNB008077363A Expired - Fee Related CN100402098C (zh) | 1999-04-20 | 2000-04-20 | 具有长期稳定性的内置假体 |
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| CN101890187B (zh) * | 2005-11-28 | 2012-11-14 | 独立行政法人科学技术振兴机构 | 用于制造体内留置型医疗器具的方法 |
| DE102006026592A1 (de) * | 2005-12-01 | 2007-06-06 | Ossacur Ag | Träger mit Colloss |
| RU2507316C1 (ru) * | 2012-07-12 | 2014-02-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Национальный исследовательский Томский политехнический университет" | Кальций-фосфатное биологически активное покрытие на имплантате |
| RU2555777C2 (ru) * | 2013-11-12 | 2015-07-10 | Общество с ограниченной ответственностью "Мед-Инж-Био" | Имплантат для замещения тотальных протяженных дефектов длинных трубчатых костей |
| RU2609832C1 (ru) * | 2015-09-25 | 2017-02-06 | Олег Викторович Барзинский | Углеродный имплантат для замещения костных дефектов |
| CN105272323A (zh) * | 2015-09-30 | 2016-01-27 | 苏州蔻美新材料有限公司 | 一种用于牙齿矫正的托槽及其制备方法 |
| CN106075584B (zh) * | 2016-08-24 | 2019-07-05 | 天津市天津医院 | 可注射性软骨脱细胞外基质混合脱钙骨基质水凝胶及其制备方法 |
| CZ309165B6 (cs) * | 2016-10-20 | 2022-04-06 | Ústav Struktury A Mechaniky Hornin Av Čr, V. V. I. | Příprava nanokompozitní vrstvy na bázi kolagenových nanovláken |
| KR102219852B1 (ko) * | 2018-12-07 | 2021-02-25 | 주식회사 메디팹 | 중공형 케이지(hollow cage)를 포함하는 생체적합 구조체 및 이의 제조방법 |
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