CN107412871A - 一种基底膜成分表层的人工生物心脏/血管瓣膜及其制备方法 - Google Patents
一种基底膜成分表层的人工生物心脏/血管瓣膜及其制备方法 Download PDFInfo
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- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
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Abstract
本发明涉及一种基底膜成分表层的人工生物心脏/血管瓣膜及其制备方法,包括生物瓣膜材料和严密包裹其表面的基底膜成分表层。本发明在保留交联生物瓣良好的强度和韧性的基础上,光滑、致密的基底膜成分表层可实现快速内皮化并阻隔钙盐沉积,防止生物瓣膜钙化、隔离交联带来的细胞毒性、降低免疫原性,延长人工生物心脏/血管瓣膜的使用期限。
Description
技术领域
本发明属于人工生物心脏/血管瓣膜及其制备领域,特别涉及一种基底膜成分表层的人工生物心脏/血管瓣膜及其制备方法。
背景技术
人工心脏瓣膜置换是瓣膜病变的主要治疗方法。机械瓣耐用,但需终身服用抗凝药物,血栓栓塞发生率较高,并可能造成出血并发症。生物瓣具备与人体心脏瓣膜相似的流体力学性能且生物相容性优于机械瓣,且患者仅需短期或不需服用抗凝药物。但是易钙化,耐久性差,存在一定的免疫原性是目前限制生物瓣应用的主要因素。细胞碎片或细胞膜所含的磷酸基团、戊二醛交联导致的胶原纤维羧基、醛基、氨基等基团暴露,均会促进磷酸钙晶体形成,造成生物瓣钙化衰败。
因此,研究者开始针对生物瓣易钙化的缺陷进行改良。改良方法主要可分为三类,使用新型交联剂、在戊二醛交联的基础上进行修饰和组织工程构建。
新型交联剂包括乙醛、碳化二亚胺、六甲基二异氰酸、多聚环氧化合物等。CN101690829A应用去甲二氢愈创木酸交联猪主动脉瓣,CN10135870A使用环氧氯丙烷交联去细胞瓣膜,目前生物相容性、免疫原性动物实验、细胞毒性并未显著优于戊二醛,且缺乏体内数据和长期植入结果报告。
在戊二醛交联基础上进行修饰的方法:胶原蛋白表面的游离醛基、羧基、氨基均可成为钙结合的位点,使用氧化还原剂、封端剂、金属竞争性抑制剂等与上述基团反应,减少游离基团暴露,从而缓解生物瓣膜钙化。CN1371750A使用2,3-丁二醇封闭醛基,CN1136780A使用68%-80%的低级脂族醇如乙醇溶液处理戊二醛交联后的瓣膜,CN1084768A使用环氧氯丙烷化学改性戊二醛交联后的心脏瓣膜,以环氧基团封闭游离羧基,CN1093566使用多官能度的环氧化合物封闭游离羧基,CN1162252使用有效量的环氧化物交联剂增强生物材料钙化抗性,CN105363071A使用包含脂肪酸及其衍生物的微乳液联合戊二醛处理生物材料,CN101184516使用pH调节或热处理后的戊二醛溶液交联材料后以封闭剂和还原剂处理材料,CN101161293使用单宁酸结合戊二醛处理生物材料,单宁酸稳定胶原蛋白纤维、弹力纤维、粘多糖等成分,减少游离基团暴露;CN103705980A应用钙化缓和剂如加帽剂或抗氧化剂联合戊二醛处理生物材料,CN102114270A联合使用氨基类封端剂、羧基类封端剂、羰基类封端剂和金属离子竞争剂。金属竞争性抑制剂以金属离子如Mg2+、AL3+、Fe2+等占据钙离子结合位点,以抑制羟基磷灰石晶核积聚,减少钙化。上述方法可改进戊二醛交联带来的部分问题,但步骤复杂,抗钙化效果并不稳定。
组织工程构建是指以天然或合成支架材料,结合种子细胞经体内外培育后形成的人工心脏瓣膜。CN1410036A、CN103157136A采用脱细胞基质作为可降解支架材料,提取血管内皮细胞及成纤维细胞作为种子细胞,经种植培养,支撑组织工程化瓣膜;CN101690683A将胶原蛋白纺丝溶液和聚氨酯纺丝溶液混合静电纺制备静电纺纳米支架。天然支架材料为脱细胞基质材料、胶原支架、多糖支架等,具备免疫原性第、生物安全性良好的优点,但存在体内快速降解、降解时间不可控的缺陷。合成支架材料为聚丙烯、聚乳酸、聚羟基乙酸等,合成材料可能引起机体炎症反应,降解产物可能改变组织微环境,且三维超微结构和力学强度较天然组织差距较大。临床推广仍存在较多问题亟待解决。
发明内容
本发明所要解决的技术问题是提供一种基底膜成分表层的人工生物心脏/血管瓣膜及其制备方法,本发明在保留交联生物瓣良好的强度和韧性的基础上,光滑、致密的基底膜成分表层可实现快速内皮化并阻隔钙盐沉积,防止生物瓣膜钙化、隔离交联带来的细胞毒性、降低免疫原性,延长人工生物心脏瓣膜的使用期限。
本发明的一种基底膜成分表层的人工生物心脏/血管瓣膜,所述人工生物心脏/血管瓣膜由生物瓣膜材料和严密包裹其表面的基底膜成分表层组成。
所述基底膜成分表层为膜片状材料或液化后的基底膜成分表层。
本发明的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,包括:
(1)将基底膜经过处理得到基底膜成分表层;
(2)将基底膜成分表层包裹生物瓣膜材料的外在面,二者间无缝隙、无空腔,即得基底膜成分表层的人工生物心脏/血管瓣膜。
所述步骤(1)中基底膜为取自同种或异种动物的皮肤、血管、胃肠膀胱等器官或组织。
所述步骤(1)中处理为:经过分离、清洗、脱脂、脱细胞、洗涤进行处理,得到膜片状材料。
所述洗涤进行处理后再进行液化,具体为经过粉碎、酶解、中和、酸碱平衡进行液化,得到液化的基底膜成分表层。
所述生物瓣膜材料具体为:原材料进行部分去细胞化处理、交联处理制得生物瓣膜材料;
其中原材料为:包括但不仅限于牛、猪、马、骡等异种来源的心脏/血管瓣膜、心包、小肠粘膜下层、真皮、腹膜、胸膜或羊膜。
所述部分去细胞化处理为:使用一定的方法将材料表层的细胞膜成分去除而不要求彻底脱除材料细胞成分,处理方法为化学试剂处理和/或物理处理;其中化学试剂处理去垢剂、表面活性剂、核酸酶、胰酶中的一种或几种进行处理;物理处理为超声和/或超高压处理。
所述交联处理为化学试剂处理和/或物理处理,其中化学试剂处理为戊二醛、乙醛、碳化二亚胺、六甲基二异氰酸、多聚环氧化合物中的一种或几种处理;物理处理为辐照、微波、压力中的一种或几种。
所述步骤(2)中基底膜成分表层包裹生物瓣膜材料的外在面具体为:基底膜成分表层为膜片状材料,则通过医用粘合剂粘合、加压方法包裹生物瓣膜材料的外在面;或基底膜成分表层为液化后的基底膜成分表层,则通过均匀涂布于生物瓣膜材料的外在面后固化。
本发明从三个方面解决生物瓣膜钙化的问题:1)基底膜是构成血管、皮肤等内皮组织细胞生长的支撑层,免疫原性极低,组织相容性高,应用后利于内皮细胞黏附并快速形成细胞单层,模拟正常心脏瓣膜表面附有的单层内皮细胞,阻止血液成分和组织液成分渗入、钙盐的沉积及血栓的形成;2)基底膜成分表层光滑、致密,在天然组织中的功能为细胞和物质的选择性透过屏障,自身即可起到隔离钙盐沉积,防止血小板、纤维素黏附渗入的效果;3)基底膜成分表层未经交联处理,可保留粘多糖糖蛋白类物质,阻隔胶原与钙、磷结合而形成晶体,而生物瓣膜材料虽然经过交联处理,但其表面的脱细胞处理可以清除组织中的磷脂,影响组织表面电荷,因此即使在极端情况下基底膜成分表层降解,生物瓣膜材料同样抑制钙盐的形成。
有益效果
本发明在保留交联生物瓣良好的强度和韧性的基础上,光滑、致密的基底膜成分表层可实现快速内皮化并阻隔钙盐沉积,防止生物瓣膜钙化、隔离交联带来的细胞毒性、降低免疫原性,延长人工生物心脏瓣膜的使用期限;
本发明良好保留了交联生物瓣膜的优点:质地柔韧,弹性良好,组织性能稳定,不易降解;
本发明生物相容性良好的基底膜成分表层和快速内皮化可阻隔交联试剂缓慢释放所带来的细胞毒性,血液相容性良好,进一步延长生物瓣膜的使用期限。
附图说明
图1一种基底膜成分表层的人工生物心脏瓣膜HE染色图;其中1为基底膜成分表层2为生物瓣膜材料。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
取新鲜猪主动脉瓣膜,清洗后Triton X-100溶液处理2h后漂洗,戊二醛交联后制得生物瓣膜材料;取猪皮肤来源基底膜层,经过分离、清洗、脱脂、彻底脱细胞、洗涤处理后制得基底膜成分表层;将基底膜成分表层紧密包裹生物瓣膜材料外在面,以医用壳聚糖粘合剂粘合,-200mmHg下压合为一体。组织切片,HE染色可观察到材料表面完整的基底膜成分。以下实验均以本实例中制备的基底膜成分包裹的生物瓣膜材料为实验组。对照组为新鲜主动脉瓣膜经过戊二醛交联后制得。包埋切片,HE染色可观察到基底膜表层(1)结构(图1)。
细胞毒性实验
根据GB/T 16886.5规定的方法评价材料细胞毒性。以HUVEC为模式细胞。以细胞培养基为浸提介质,以梯度浓度的浸提液替代培养基培养细胞,MTT法测定细胞存活率。实验组的细胞毒性为0~Ⅰ级。
力学性能检测
根据GB/T528-2009,取3个样品制作成25mm×4mm的哑铃状,用材料力学试验机固定样品两端,以10mm/min速度拉伸,测算材料抗张强度为28±3N/mm2。
体内植入实验
皮下植入小鼠背部,35天后取出瓣膜,测定平均干组织钙含量数据为实验组:5.4μg/mg,对照组:32.6μg/mg。
Claims (10)
1.一种基底膜成分表层的人工生物心脏/血管瓣膜,其特征在于:所述人工生物心脏/血管瓣膜由生物瓣膜材料和包裹其表面的基底膜成分表层组成。
2.根据权利要求1所述的一种基底膜成分表层的人工生物心脏/血管瓣膜,其特征在于:所述基底膜成分表层为膜片状材料或液化后的基底膜成分表层。
3.一种如权利要求1所述的基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,包括:
(1)将基底膜经过处理得到基底膜成分表层;
(2)将基底膜成分表层包裹生物瓣膜材料的外在面,即得基底膜成分表层的人工生物心脏/血管瓣膜。
4.根据权利要求3所述的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,其特征在于:所述步骤(1)中基底膜为取自同种或异种动物的器官或组织。
5.根据权利要求3所述的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,其特征在于:所述步骤(1)中处理为:经过分离、清洗、脱脂、脱细胞、洗涤进行处理。
6.根据权利要求5所述的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,其特征在于:所述洗涤进行处理后再进行液化,其中液化具体为经过粉碎、酶解、中和、酸碱平衡进行处理。
7.根据权利要求3所述的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,其特征在于:所述生物瓣膜材料具体为:原材料进行部分去细胞化处理、交联处理制得生物瓣膜材料;其中原材料为:异种来源的心脏/血管瓣膜、心包、小肠粘膜下层、真皮、腹膜、胸膜或羊膜。
8.根据权利要求7所述的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,其特征在于:所述部分去细胞化处理为:化学试剂处理和/或物理处理;其中化学试剂处理去垢剂、表面活性剂、核酸酶、胰酶中的一种或几种进行处理;物理处理为超声、超高压处理。
9.根据权利要求7所述的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,其特征在于:所述交联处理为化学试剂处理和/或物理处理,其中化学试剂处理为戊二醛、乙醛、碳化二亚胺、六甲基二异氰酸、多聚环氧化合物中的一种或几种处理;物理处理为辐照、微波、压力中的一种或几种。
10.根据权利要求2所述的一种基底膜成分表层的人工生物心脏/血管瓣膜的制备方法,其特征在于:所述步骤(2)中基底膜成分表层包裹生物瓣膜材料的外在面具体为:基底膜成分表层为膜片状材料,则通过医用粘合剂粘合、物理加压或真空层压方法包裹生物瓣膜材料的外在面;或基底膜成分表层为液化后的基底膜成分表层,则通过涂布于生物瓣膜材料的外在面后固化。
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