CN1172724C - 骨移植基质 - Google Patents

骨移植基质 Download PDF

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Publication number
CN1172724C
CN1172724C CNB961988835A CN96198883A CN1172724C CN 1172724 C CN1172724 C CN 1172724C CN B961988835 A CNB961988835 A CN B961988835A CN 96198883 A CN96198883 A CN 96198883A CN 1172724 C CN1172724 C CN 1172724C
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collagen
substrate
mineral
bone
described substrate
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CN1204245A (zh
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M��K��������
M·K·夸
I
S·D·帕瑟蒂
��Ī������
R·K·雅马莫托
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DePuy Spine LLC
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DePuy Acromed Inc
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
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  • Materials For Medical Uses (AREA)
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  • Prostheses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Diaphragms For Electromechanical Transducers (AREA)
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Abstract

本发明提供了可生物降解的、多孔的三维骨移植基质。此基质优选有矿化的胶原形成，其中矿物质含有固定在基质中的颗粒性磷酸钙且其粒度为5微米或更小。

Description

骨移植基质
发明背景
本发明涉及用于骨修复的物质。
已有一定数量的试验物质被用来引发骨修复和/或用来恢复或替换坏损的骨骼，这提出了在特定位点促进骨形成的课题。
针对此问题的研究中，有构造(conformational)方法，在此方法中移植物质被插入需要进行骨移植的部位。该移植物质通常由金属陶瓷或其它矿物质制成，其形式模拟坏损的骨骼。这存在受者排斥此物质的危险性或移植物不能与正常骨骼组织整合。虽然，一些陶瓷物质如磷酸三钙陶瓷，对受者及骨骼来说，其生物相容性是可接受的，但当用作移植物时，似乎在骨骼的总体作用上缺乏足够的机械性能，并且骨组织不会在其中相容地生长并与其结合。
另一项研究包括用基质替换坏损的骨组织，该基质作为一种支撑物，而新骨组织可在其中生长。其理论是该基质吸引用于成骨路径的细胞，通过所谓骨引导(osteoconduction)的方法新骨组织在该基质中生长并可穿过该基质。同种骨(非自体骨)移植物用于此方法，但成功率不高。即使同种骨移植物能被受者接受时，与同源骨(自体骨)移植相比合并愈合期及机械应力恢复期也较长。同种骨骼的使用也存在可传染病毒试剂的问题。
第三种方法包括被称为骨诱导(osteoinduction)的方法，一般在暂时性基质周围，当一种物质由受者未分化的细胞或组织中引起新骨生长时，骨诱导作用就发生了。一些化合物显示出这种能力。例如，授予Glowacki的美国专利4440750，授予Urist的美国专利4294753和4455256，以及授予Seyedin等的美国专利4434094和4627982。这些化合物中最有效的似乎是能促进骨生成的蛋白质。但是，当由天然物质合成时它们以极低的浓度存在，即使要得到小量的物质用于试验，也需要大量的原料。通过重组方法提供这些蛋白质可能最终使这些蛋白质本身的使用更具实用价值。但是，这些蛋白质也仍然会需要在适当的基质中移植到需要的部位。
含胶原和多种形式的磷酸钙、直接用于愈合及骨生长的组合物已公开。
授予Bauer等的专利5338772公开了含磷酸钙陶瓷颗粒和生物可吸收聚合物的复合物质，其中至少含磷酸钙陶瓷50％(重量)且该颗粒通过聚合物桥接。公开的该磷酸钙陶瓷颗粒的粒度约20微米至约5毫米。
授予Piez等的专利4795467公开了含与非端肽重构原纤维胶原混合的磷酸钙无机颗粒的组合物。公开的该磷酸钙无机颗粒的粒度为100-2000微米。
授予Sauk等的专利4780450公开了含颗粒性多晶磷酸钙陶瓷、phosphophorin钙盐和I型胶原，用于骨修复的组合物，它们的比例为775-15∶3-0.1∶1。该陶瓷颗粒为直径约1至10微米的高密度羟基磷灰石或直径大于约100微米的较大高密度羟基磷灰石陶瓷颗粒。
Ammann等的PCT申请WO94/15653公开了含磷酸三钙(TCP)、TGF-β并含或不含胶原的组合物。TCP为TGF-β的转运载体，TCP的粒度大于5微米并优选大于约75微米。TCP粒度首选的范围为125-250微米。
PCT申请WO95/08304公开了与不溶性胶原混合的羟基磷灰石的复矿化前体颗粒。该复矿化前体颗粒的粒度范围为0.5微米至5微米。前体矿物通过水解转化为羟基磷灰石，据信此方法将此矿物稠合为单片的羟基磷灰石。
FMC公司的英国专利说明书1271763公开了磷酸钙和胶原的复合物。
发明概述
本文提供了一种骨移植基质，它是多孔的并在移植后足以增强换骨过程的时期内保持结构完整和多孔性。该基质含有与粘合剂结合的矿化的原纤维不溶性胶原、胶原衍生物或修饰的明胶。该无机物含有固定于基质中的颗粒化磷酸钙，其粒度小于约5微米。所得产品被冻干、交联、干燥并灭菌以形成多孔基质。该基质可以用作移植物和/或骨生长因子的转运载体。该基质可与同源骨髓混合并植入以进行骨再生。
具体实施方式的描述
用不溶于水的生物可降解胶原、胶原衍生物或修饰的明胶制备骨移植基质。经修饰后的明胶在水环境中不溶。胶原可以来自矿化或非矿化胶原源，通常为非矿化的胶原源。因此，胶原可来自骨、腱、皮肤等，优选I型胶原，其中含有两条α2和一条α1胶原链的结合形式。胶原可来自年轻的供者，如小牛，或成熟的供者，如一岁或几岁龄的母牛。胶原的来源可以是任何方便的动物来源(哺乳动物或鸟类)，并可包括牛、猪、马、鸡、火鸡或其它驯养动物来源。使用的不溶性胶原组织一般分散于pH升高的基质中，pH至少约为8，更常用的是pH约11-12。虽然可使用其它氢氧化物，如其它碱金属氢氧化物或氢氧化铵，但通常使用氢氧化钠。
本发明可利用天然的胶原。天然胶原含有区域的每个末端上无三联体甘氨酸序列。人们认为这些区域(端肽)负责与大多数胶原制剂有关的免疫原性。可以通过用蛋白酶如胰蛋白酶和胃蛋白酶消化除去这些区域来制备非端肽胶原降低此免疫原性。
用来矿化的胶原的浓度一般为约0.1至10％(重量)，更常用的是约1至5％(重量)。胶原基质中碱的浓度为约0.0001至0.1N。此反应过程中pH一般保持在约11-13，优选约12。
优选使用不溶性的、原纤维胶原，它可以通过常规方法制备。一般来说，通过首先与异丙醇(IPA)、乙醚、己烷、乙酸乙酯或其它适宜溶剂混合，并将胶原分离完成此制备过程。一般pH降至约3，然后冷却至约4℃，并让其膨胀。所得的浆液可以匀浆化直至得到所需的粘度。
匀浆与溶剂混合、搅拌并将pH升至7。将原纤维胶原分离、用去离子水清洗并冻干。为了制备矿化的原纤维胶原，可将纯化的不溶性胶原原纤维均浆化，置于反应器中，并向其中以控制的速度、搅拌下加入氯化钙(一般0.05M)和磷酸钠(一般0.03M)。在此过程中，需要用氢氧化钠将pH调至11.0±0.5。矿化后，用去离子水或磷酸缓冲液洗涤此胶原，将其与粘合剂混合并将pH调至7.5±1.5的范围内。加入磷酸盐和钙离子的方法描述于美国专利5231169。
磷酸钙中可含有其它离子，如碳酸根、氯离子、氟离子、钠离子或铵离子。产品中碳酸根的存在导致该产品中含有碳酸磷灰石(碳酸羟基磷灰石)，而氟离子使产品具有氟化磷灰石的性质。碳酸盐的重量百分含量通常不超过10％，而氟化物的重量百分含量通常不超过2％。优选在0至1％的范围内。只要离子是相容的并在试剂溶液中不引起沉淀，这些离子可以与钙离子和/磷酸根离子源以结合的方式存在。钙离子和磷酸根离子的加入速度一般为约1小时并不超过约72小时，以便使粒度为约5微米或更小。一般来说，加入时间为约2至18小时，更常用约4至16小时。使用中等温度，通常不超过约40℃，优选为约15至30℃。胶原与磷酸钙矿物质的重量比一般为约8∶2至1∶1，典型的是约7∶3。
在此基质中可以含有其它非胶原或因子，如骨形态发生蛋白、TGF-β、降钙素等，这些物质在加入钙离子和磷酸根前或紧随其后加入胶原浆液中。这些添加剂的含量一般占用作基质的生物聚合物(如胶原)的约0.0001至2％(重量)。加入的蛋白质可象胶原那样与矿物质结合，这样便将加入的蛋白质结合在胶原上。
在矿化产品中胶原的存在量一般为约80至30％。
或者，固定的磷酸钙颗粒可通过将颗粒与用来粘合胶原纤维的粘合剂混合而包括在基质中。
为了形成多孔的、三维骨移植基质，矿化的胶原纤维与粘合剂混合。
优选纯化的水溶性胶原用作粘合剂。方法是先将水溶性胶原与溶剂如异丙醇(IPA)混合，再将胶原分离。将ph降至约3.0，然后当胶原溶解时，将pH升至5.0，用此溶剂洗涤两次，用去离子水洗涤，过筛，并冻干。
可以使用其它粘合剂，包括但不限于明胶、聚乳酸、聚羟基乙酸(polyglycolic acid)、乳酸和羟基乙酸的共聚物、聚己酸内酯、羧甲基纤维素、纤维素酯(如甲酯或乙酯)、醋酸纤维素、葡萄糖、葡聚糖、脱乙酰壳多糖、透明质酸、菲可、硫酸软骨素、聚乙烯醇、聚丙烯酸、聚丙二醇、聚乙二醇、水溶性甲基丙烯酸酯或丙烯酸酯聚合物。
为了制备多孔基质，将优选的水溶性胶原粘合剂加至矿化的胶原浆液中并搅拌。水溶性胶原与不溶性胶原的比例优选约10％(重量∶重量)。如果需要，将pH调至7.5±0.5。当达到所需混合物浓度时，在-20℃至-80℃将此分散液冷冻。
将冷冻的浆液冻干。可将多孔基质交联以提高物理稳定性，延长基质所吸收时间并使最终产品易于控制。优选使用戊二醛溶液(一般浓度为0.01％)或蒸汽将此冻干基质交联。如果使用溶液，除去过量的溶剂后，将此基质冻干脱水。也可通过将矿化胶原纤维的浆液和粘合剂过滤形成网状物来制备多孔基质。然后可将干燥的网状物交联。
也可通过将矿化胶原纤维、粘合剂及可沥滤去的颗粒(水溶性盐，如氯化钠)和/或以后可通过升华除去的高蒸汽压固体混合，得到多孔结构。可将此浆液干燥，然后除去可沥滤去的或可升华的颗粒以形成多孔结构。可将此多孔基质交联。
交联基质的其它优点包括较长的移植物残留时间且形状保持较好(无移植物碎裂现象)。
可使用其它交联方法和试剂，如甲醛、铬盐、二异氰酸酯类、碳化二亚胺类、二官能团酰氯类、二官能团酸酐类、二官能团琥珀酰亚胺类、二溴代异丙醇、表氯醇、双环氧化合物，用脱水热法交联、干燥时UV辐射，或在水溶液中用电子束或γ辐射。
可使用γ辐射、电子束、加热干燥或环氧乙烷完成最终产品的灭菌。
本发明的优点为将胶原纤维和固定的磷酸钙矿物质形成一种基质，该基质特别有利于骨的替换或增强。此基质在移植后至少约三天内保持其物理完整性并在其移植到发生骨替换的生理环境中后约七至十四天内保持其多孔性。物理完整性是指移植基质的形状和大小基本保持不变。这与组合物相反，组合物在移植后立即或短时间内变为无定型的、无孔物质。基质也保持其多孔性是有利的，这对骨替换或加强过程是重要的。
本发明的基质最终被生物降解或被吸收，故超过此期限后此多孔性和物理完整性就不再保持。此过程一般平均约2至12星期，并当然依赖于植入的此基质的大小。但是，在骨替换或加强过程前，基质的吸收或生物降解未彻底完成前的时间内，生物降解的速率应是充分的。
本发明的一个方面是磷酸钙矿物质，一般为羟基磷灰石，固定在基质中，这与可通过此基质自由流动正相反。现已发现，本发明的磷酸钙矿物质固定在基质内并含有平均直径小于约5微米的颗粒。移植后，物质的粒度可改变生物相互作用，这可影响对此物质的组织反应。细胞反应可改变为吞噬细胞如巨细胞和巨噬细胞更显著地围绕在颗粒物质周围，常常形成肉芽肿。小得足以被吞噬的颗粒(粒度约3至5微米或更小)被吞噬细胞摄入，该细胞进一步引发一种局部组织反应。例如，观察到在骨愈合期间，在邻近组织的巨噬细胞中有与人工关节有关的颗粒性磨损碎屑，且在动物模型中该碎屑以剂量依赖的方式与骨吸收的增加相关(“巨噬细胞/颗粒相互作用：粒度、组份及表面积的影响”，ShanbhagAS等，J.Biomed.Mater.Res.28(1)，81-90(1990))。因此，本发明的优点是在延长的时期内以5微米或更小粒度的颗粒(被吞噬细胞摄入的理想粒度)释放固定的磷酸钙矿物质。本发明的另一个优点是磷酸钙矿物质颗粒的任何释放都是被控制的，这是矿物质被固定在增加内的结果。粒度和固定作用的优点将如下文中实施例III所示。
作为有骨引导作用的骨移植物质，骨移植物质可用于脊柱融合术、填补骨缺损、断裂修复及牙周缺损移植术。通过将本发明的组合物与下列成骨物质结合使用，例如，同源骨骼或自体抽出的骨髓、或有骨诱导作用的骨生长因子、骨形态发生蛋白(BMP)、降钙素或其它生长因子，骨诱导作用和生长作用可以被进一步加强。此基质也可提供一种底物，骨生长因子可结合在此底物上，以便受者产生或外部引入的这些因子可集中在此基质中。本发明的组合物可用于断裂修复、上颌面(maxifacial)重整、脊柱融合术、关节重整及其它矫形外科手术。
下面的实施例旨在举例说明，而并不是要以任何方式限制本发明。
实施例I
本发明的矿化胶原基质被植入8周龄大鼠顶骨上的裂缝内。在第14和28天进行组织学评价。14天后，观察到骨组织由此裂缝的切割边缘生长进入胶原基质中。新形成的网状骨组织围绕在残余基质片和疏松的结缔组织区域周围，在其中血管形成明显。28天时，显式了显著的再成型，整个新骨内都存在骨细胞。随着骨生长的继续，在第14天已看到的结缔组织空隙减小。
实施例II
将实施例I的磷酸钙矿化胶原基质与加入的骨髓一起植入成年的雄性新西兰白兔(3.7至4.1千克)体内。在右前腿的前-中表面中间部位做一切口以暴露桡骨。用风钻在桡骨上除去1.5厘米片断，使其产生严重的裂缝。在进行骨切除术时，利用冲洗法减少骨过热和损伤。用混有骨髓或自体移植物的矿化胶原基质填入裂缝内。骨髓有同一动物的胫骨中抽出。此自体移植物为网状骨组织，用与目前骨增强或移植方法类似的方法，从额骨的嵴上获得。术后，每天观察这些动物，在头8周每隔两周，以后在第12周尸体解剖前每个月拍摄术后桡骨的放射照片。术后，这些兔子计划存活12及24周。
尸体解剖时，切除右和左桡骨，并评价术后桡骨总愈合迹象(骨痂形成及愈合)。评价包括：在裂缝内，成骨出现表明愈合，而软骨、软组织或裂缝的存在表明可能的、不稳定的愈合。
然后将这些桡骨在10％中性缓冲福尔马林中固定并进行组织学及形态测定评价。
在0、2、4、6、8及12周拍摄的放射照片表明早在第2周就发生了强烈的愈合反应，并且裂缝部位继续改善并重成型，直至桡骨天然皮层的重整。在磷酸钙胶原基质处理组和自体移植对照组之间观察到的进行性愈合是一致的。在两个交联组之间放射照片显示的愈合几乎没有差别。
在较早的研究中，已发现不填充任何物质或不予治疗(阴性对照组)的裂缝中含极少的或不含新骨组织。在本试验中，自体移植(阳性对照组)形成稳定的骨愈合。与自体移植所见相比，用含骨髓的磷酸钙胶原处理的裂缝也显示出与新骨组织有稳定的连接。
实施例III(比较实施例)
制备一批不加入胶原的磷酸钙矿物质。将此矿物质回收、洗涤开冻干成干粉。红外光谱表明它们是羟基磷灰石。
通过将不溶性原纤维胶原纤维与水溶性胶原以9/1的重量比混合(占总固体重量的4％)来制备混合基质。人工混合此浆液并加入占总固体重量25％的游离矿物质。将此浆液倒入2英寸见方的特氟龙模型中，其深度为约5mm，在-80℃冷冻，并冻干。用戊二醛处理30分钟交联此干燥的基质、洗涤并再冻干。所得基质厚约4mm，并在用于移植的基质上做直径为8mm的钻孔。为了比较，最近制备的一批矿化胶原(固定的矿物质)，其中灰的含量为28％，用于存在直径8mm钻孔的移植物。
将此移植物双向皮下置于胸筋膜内，在3、7和14天的每个移植时间，在4只大鼠体内使用相同类型的两种移植物。尸体解剖时，对移植物进行组织反应评分，并将组织团块进行组织学检查。检查每个时间点的每个动物的移植物和周围组织的H&E染色切片以确定组织反应和整合作用。
尸体解剖时的观察结果
              混合物(非固定矿物质)     矿化的胶原
3天           周围组织清晰，移植物软    周围组织清晰，移植
              糊糊的                    物软
7天           周围组织清晰，移植物      周围组织清晰，移植
              软，但感觉厚              物软至硬
14天          周围组织红肿，移植物硬    周围组织清晰，移植
              但感觉厚                   物硬
尸体解剖时的临床观察表明，在大鼠皮下移植模型中，与固定的矿化胶原相比，混合制剂具有更大的炎性反应及降解作用。观察中第3天见到软糊糊的移植物。在第7和第14天，观察到厚的移植物，正如组织学观察到的，可能是由于对混合制剂的剧烈的纤维性囊反应。比较而言，含公开矿物质的制剂显示出清晰的周围组织，且在所有3个时间点的移植物外观正常。
如试验后期(第14天)所示，组织学检查表明混合制剂导致高水平的急性和慢性炎性反应、多形核白细胞活性及早期(第3天)巨细胞活性。巨细胞表明巨噬细胞活性可能被激发，这是对大量的矿物质松散颗粒的反应。还观察到成纤维细胞侵入，而组织坏死不明显。
相反，矿物质颗粒固定在胶原纤维上的制剂显示了更典型的移植物-组织反应。在此三个时间点，观察到急性炎性反应，在第7天该反应减退为较慢性的移植物反应，只有中等程度的炎症，而在移植物周围发生成纤维细胞的侵入及新血管形成。在第14天，见到炎症反应增加的迹象，可能表明由于胶原的降解由胶原纤维中释放出更多的矿物质。
在皮下大鼠移植物中，胶原和羟基磷灰石成分的混合制剂表现出显著的急性炎性反应。在可见的胶原组合物中矿物组份的固定似乎降低了矿物的生物利用度，在伤口愈合期间继续支持组织整合作用的同时，降低了炎性反应。

Claims (18)

1.一种用于骨替换的多孔的、生物可降解的基质，此基质在移植后至少约三天内保持其物理完整性并在其移植到发生骨替换的生理环境中后约七至十四天内保持其多孔性，其中包括不溶性生物聚合物纤维的结合网状物、粘合剂及固定的磷酸钙矿物质，其中所述粘合剂将所述矿物质固定在所述基质中。
2.权利要求1所述的基质，其中所述粘合剂选自水溶性胶原、明胶、聚乳酸、聚羟基乙酸、乳酸和羟基乙酸的共聚物、聚己酸内酯、羧甲基纤维素、纤维素酯、葡萄糖、葡聚糖、脱乙酰壳多糖、透明质酸、菲可、硫酸软骨素、聚乙烯醇、聚丙烯酸、聚丙二醇、聚乙二醇、水溶性聚丙烯酸酯及聚甲基丙烯酸酯。
3.权利要求1所述的基质，其中所述生物聚合物包括原纤维胶原。
4.权利要求1所述的基质，其中所述矿物质包括羟基磷灰石。
5.权利要求1所述的基质，其中所述矿物质由直径约5微米或更小的颗粒组成。
6.权利要求1所述的基质，其中所述矿物质在骨替换过程中以颗粒形式释放进入所述生理环境中，在各个的时期内其时间-释放特性可分别维持所述物理完整性和多孔性。
7.权利要求3所述的基质，其中所述胶原和固定的磷酸钙的存在形式为矿化胶原，其中含有约30-80重量％的胶原。
8.权利要求1至7任一项所述的基质，其中还含有骨髓。
9.权利要求1至7任一项所述的基质，其中含有自体骨组织。
10.权利要求1至7任一项所述的基质，其中含有一种或多种骨生长因子。
11.一种制备可生物降解、多孔的骨移植基质的方法，包括如下步骤：
(a)形成分散液，其中含有一种可生物降解的不溶于水的生物聚合物、一种溶于水的粘合剂及通过所述粘合剂或生物聚合物固定的颗粒性磷酸钙矿物质；
(b)将所述分散液制成多孔基质；
(c)将所述多孔基质交联。
12.权利要求11所述的方法，其中所述步骤(b)包括将所述分散液冷冻并冻干。
13.权利要求11所述的方法，其中所述分散液中还含有可沥滤去的颗粒，且所述步骤(b)中包括将所述分散液干燥并从所述基质中沥滤去所述颗粒。
14.权利要求11所述的方法，其中所述分散液中还含有可升华的颗粒，且所述步骤(b)中包括将所述分散液干燥并将所述颗粒从所述基质中升华以形成所述基质。
15.权利要求11所述的方法，其中所述可生物降解的不溶于水的生物聚合物中含有胶原含量为约30-80重量％的矿化胶原纤维。
16.权利要求11所述的方法，其中所述粘合剂包括水溶性胶原.
17.权利要求11所述的方法，其中所述矿物质包括羟基磷灰石。
18.权利要求11所述的方法，其中所述矿物质由直径约5微米或更小的颗粒组成。
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AU7516796A (en) 1997-05-07
JPH11513590A (ja) 1999-11-24
WO2003071991A1 (en) 2003-09-04
US5776193A (en) 1998-07-07
AU2003213235A1 (en) 2003-09-09
ATE270078T1 (de) 2004-07-15
US20040220680A1 (en) 2004-11-04
EP1482872A1 (en) 2004-12-08
DE69632829D1 (de) 2004-08-05
CN1646070A (zh) 2005-07-27
CA2232986A1 (en) 1997-04-24
DK0855884T3 (da) 2004-08-16
US6187047B1 (en) 2001-02-13
US7842097B2 (en) 2010-11-30
AU2003213235B2 (en) 2008-09-11
ATE490744T1 (de) 2010-12-15
US6764517B2 (en) 2004-07-20
WO1997014376A1 (en) 1997-04-24
NZ321756A (en) 1999-11-29
JP4275732B2 (ja) 2009-06-10
CN1646070B (zh) 2012-06-13
NZ535466A (en) 2005-08-26
EP1482872A4 (en) 2006-02-15
JP2007007452A (ja) 2007-01-18
AU705303B2 (en) 1999-05-20
EP0855884A1 (en) 1998-08-05
CN1204245A (zh) 1999-01-06
EP0855884B1 (en) 2004-06-30
PT855884E (pt) 2004-09-30
ES2224182T3 (es) 2005-03-01
EP0855884A4 (en) 2001-08-08
US20020183855A1 (en) 2002-12-05
JP4526525B2 (ja) 2010-08-18
CA2232986C (en) 2008-11-25
DE69632829T2 (de) 2005-04-14
EP1482872B1 (en) 2010-12-08
CA2476929C (en) 2011-06-21
CA2476929A1 (en) 2003-09-04

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