CN1232310C - 用于再生脊椎与管状骨的植入物 - Google Patents
用于再生脊椎与管状骨的植入物 Download PDFInfo
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- CN1232310C CN1232310C CNB008079269A CN00807926A CN1232310C CN 1232310 C CN1232310 C CN 1232310C CN B008079269 A CNB008079269 A CN B008079269A CN 00807926 A CN00807926 A CN 00807926A CN 1232310 C CN1232310 C CN 1232310C
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Abstract
本发明涉及植入物，用于至少部分地形成、再生或稳定椎体或管状骨。所述植入物中，金属、非金属或陶瓷的中空体涂有活性成分复合物或者包含所述活性成分复合物。该活性成分复合物具有下列成分，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，它特异性地适应所要形成的骨细胞，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。金属中空体优选地由钛或钛合金组成，是包含晶格结构的圆柱体形状。非金属中空体由碳纤维组成，陶瓷中空体由磷酸钙、氧化铝或羟基磷灰石陶瓷组成。活性成分可以涂在选自聚合物和胶原的支撑材料上，目的是减少必要的活性成分的量。
Description
本发明涉及包含具有下列组分的活性物质复合物的植入物，这些组分是彼此不同的，即至少一种结构组分、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。
在其制备之后，这种活性物质复合物最初具有棉毛的稠度。如果所要填充的是大骨缺损，作为植入物引入的活性物质复合物必须具有充分的固有强度，以确保不受周围软组织或骨结构的挤压。因此必须在所述应用之前就已经被压紧，形成更高的机械强度，但也导致材料的高消耗，或者必须与活性物质复合物一起使用充分稳定的支撑材料。不过，支撑材料与活性物质复合物的结合决不是不成问题的。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。
另外，迄今还不可能将活性物质复合物用于这样的疾病或缺损，其中由该活性物质复合物组成的植入物受到如此高的机械应力，以致压紧材料的机械强度都可能是不充分的。
基于上述，本发明的目的因此是提供植入物，利用它达到较高的机械强度，从而扩展活性物质复合物的可能的使用范围。
该目的是借助这样一种植入物来实现的，其中金属、非金属或陶瓷的中空体涂有所述活性物质复合物或者包含这种活性物质复合物，其结果是所得植入物至少能够部分地用于形成、再生或稳定椎体或管状骨。活性物质复合物的组分适于形成骨，这也包括生成所有供给骨或脊椎的结构，例如血管和神经。
该目的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涂有或包含活性物质复合物的支撑物结合是极成问题的，因为活性物质复合物例如在骨缺损中的功能可能被可能的免疫反应破坏或至少复杂化了。
金属中空体优选地由钛组成，也可以是钛合金的形式。特别是检查了钛、铝和钒的合金。在优选的实施方案中，所用金属支撑物是圆柱中空体的形式，具有晶格结构。
这里提到的主要非金属材料是碳，可以使用其“碳笼”的形式，由碳纤维组成，它也可以形成圆柱中空体。钛(中空)体和碳笼都充满活性物质复合物或者在其内表面涂有活性物质复合物。
当充满或涂有活性物质复合物时，所述钛中空体和碳笼可以用于形成、再生或稳定椎体。通过椎体的连锁和椎骨的完全再生，修复脊柱的椎骨缺损或椎骨损害的可能性是独一无二的。
椎间盘的变性过程、脊柱椎体肿瘤或转移瘤或甚至是骨质疏松损害脊柱载荷容量的结果，是存在脊柱骨折或神经损伤的威胁，这时椎体的连锁通常是必要的。在这些情况下，有必要利用机械稳定的植入物例如钛体或碳笼保证脊柱的连续性。为此迄今只能用自体海绵物质尝试骨桥连接，例如来自通过二次干预所得髂嵴的海绵物质。这带来一系列问题，例如二次干预与有关的手术风险、另外感染的危险、有限的可回复海绵物质量和供体部位的并发症，例如感染或慢性疼痛。这种自体移植物的可利用性也是有限的。
通过向钛中空体或碳笼填充或涂以活性物质复合物，有可能在短时间内实现骨桥连接，无需自体海绵物质。钛中空体的晶格结构也有利于在尺寸稳定的组分内部迅速形成血管，以便活性物质复合物能够发挥其活性，在全部必要体积内发生骨生成作用，使机械力不会破坏新生成骨的形状。除了在椎体区域的用途以外，这样一种钛中空体或碳笼以及下述陶瓷中空体还可以用在任何其他所需的植入部位，例如颌内、管状骨上，主要用于骨质量的增长。迄今可利用的活性物质复合物不可能实现椎骨的连锁，因为活性物质复合物经不住脊柱内地机械应力。现在，充满或涂有活性物质复合物的中空体或碳笼给予机械稳定性，但又不会导致免疫逆反应或者削弱活性物质复合物的功效。
除了金属或非金属的中空体以外，使用由陶瓷材料制成的中空体也是可能的。可以提到的陶瓷支撑材料确切地是玻璃陶瓷，例如磷酸钙陶瓷、氧化铝陶瓷和羟基磷灰石陶瓷。
磷酸钙陶瓷是基于CaO/P2O5系统的。根据这种系统，存在五种不同的二元化合物。其中，磷酸三钙(TCP)和磷酸四钙已经被证实适合本发明的目的。
TCP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。
磷酸四钙象TCP一样，分两步制备，首先压缩原料至晶格间距为5至10μm，然后在1100至1500℃下烧制组合物。
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，从珊瑚的天然骨架开始，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。
具有多晶结构的氧化铝陶瓷含有约99.7％氧化铝以及少量氧化镁和/或氧化锆。在高压下预压制后，在约1500至1800℃的温度下烧结得到固体。出于本发明的目的，使用微孔氧化铝陶瓷。也可以使用单晶型(蓝宝石)。
活性物质复合物本身可以另外涂在选自聚合物和胶原的支撑材料上。这种方法可以减少填充各中空体所需的活性物质复合物量，目的是在降低成本的同时，基本上保持相同的骨生成功效。
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。
也可以使用不同的胶原作为支撑材料。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。
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4为无晶格结构的由碳纤维制成的中空体图示，具有两个腔，供活性物质复合物与自体海绵物质之间的对比；
图5a-c为具有晶格结构的由钛制成的中空体图示，它充满活性物质复合物，用于连锁椎体；
图6显示笼式插入装置，它具有有两个腔的碳笼；
图7a-b显示手术前大为减少的L5/S 1段腰椎间距的X-射线；
图8a-b显示腰椎L4与L5椎骨之间的植入物的X-射线，安装有用于保持稳定的内部固定器；和
图9显示安装碳笼植入物后三、六和九周通过计算机X线断层扫描所得一系列图片，植入物具有活性物质复合物和自体海绵物质。
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
↓
在丙酮中脱脂
↓
在0.6N HCl中脱钙
↓
洗涤，冷冻干燥
↓
脱矿质的骨基质
↓
在4M GuHCl中萃取
↓ ↓
残余物 上清液
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对蒸馏水透析
↓
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物或支撑材料。
1、试验用动物
使用平均体重为3089g的雌性毛丝鼠兔。它们随意摄入兔日常饲料和用盐酸酸化至pH 4.5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
1、试验用动物
在下述试验中使用来自Viehzentrale Sudwest 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。
IV、用胶原作为支撑材料的试验
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50％。对它们给以大鼠与小鼠日常饲料。
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，不含任何外来的添加剂，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、试验金属与陶瓷材料的生物可相容性
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FeldmühleAG公司的羟基磷灰石盘。
利用浸涂法涂以已用上述通用操作从小牛的管状骨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)。表1显示所得结果。
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cm2的活细胞数 | 每cm2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(Feldmühle) | 7930±2007 | 1638±377 |
| 钛0.5μm | 11377±2538 | 1054±308 |
| 20μm | 9600±3038 | 1754±439 |
| 100μm | 2308±669 | 2085±623 |
| TiAl6V4 0.5μm | 7200±1062 | 2800±954 |
| Al2O3，特纯，抛光 | 11446±1500 | 2292±600 |
V、钛体和碳笼
由于IV下所述试验已经证明了钛的必要的生物可相容性，这指出了活性物质复合物在尺寸稳定的钛笼中的特定用途，用于连锁椎体(脊椎融合术)。另外发现碳笼也适合于该目的。
关于脊椎融合术，能够对人体脊柱进行手术干预，这有利于在自体海绵物质与活性物质复合物之间进行对比。
为此使用具有两个腔的碳笼。这样一种碳笼如图4所示。代替该碳笼的，使用钛中空体也是同样可能的，后者如图5a、b和c所示。图5a-5c显示充满活性物质复合物的钛中空体的不同视图。
关于这里所涉及的试验，使用无晶格结构的碳笼，因为它有两个腔(I，II)可用，一个接受活性物质复合物，另一个接受自体海绵物质作为对比。
所用活性物质复合物是从小牛骨得到的，如I下所述，加入到碳笼的一个腔(I)中，另一个腔(II)填充来自所治疗患者的自体海绵物质。利用笼插入药具，将如此制得的碳笼安装在脊柱L5/S1段(椎间盘区域中的腰椎)。已经带有碳笼的插入药具如图6所示。图中右手腔(I)含有活性物质复合物，左手腔(II)含有自体海绵物质。
图7a和7b显示在L5与S1之间插入植入物之前间距大为减少。图8a和8b显示在椎骨L4与L5之间插入植入物所得支撑物，和出于稳定目的而引入的内部固定器。
图9显示安装笼植入物后三、六和九周的计算机X线断层扫描图序列，从左至右看。笼的左手腔含有自体海绵物质，右手腔含有活性物质复合物。可以清楚地看到，含有海绵物质的左手腔内X-射线密度连续减少，这是骨损失的迹象，而含有活性物质复合物的右手腔内X-射线密度在整个阶段内都是增加的，这是骨生长的迹象。九周后，按照现有技术关于骨损失的“黄金标准”进行评估，根据本发明的植入物在骨生成作用中显示至少与自体移植相同的结果。当使用根据本发明的植入物时，伴有风险的二次干预是不必要的，原发性骨损失也不需要时间。
表3显示图9所示试验的光密度测量结果。
表3：植入物中矿化骨的光密度(％)
| 3周 | 6周 | 12周 | |
| 自体海绵物质 | 100 | 42 | 26 |
| 活性物质复合物 | 4 | 12 | 28 |
Claims (4)
1、植入物，用于至少部分地形成、再生或稳定椎体或管状骨，其中金属中空体、选自碳或碳纤维的非金属中空体或选自磷酸钙、氧化铝或羟基磷灰石陶瓷的陶瓷的中空体涂有衍生自骨的活性物质复合物或者包含所述活性物质复合物，该活性物质复合物包含下列组分，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，它特异性地适应所要形成的骨细胞，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所要求保护的植入物，其特征在于金属中空体由钛或钛合金组成。
3、如权利要求1所要求保护的植入物，其特征在于金属中空体是具有晶格结构的圆柱体形状。
4、如权利要求1所要求保护的植入物，其特征在于该中空体充满活性物质复合物，所述活性物质复合物涂在选自聚合物和胶原的支撑材料上。
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| 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 |
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| 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 |
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2000
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