CN113651973B - 一种树脂凝胶、凝胶外支架、载药凝胶外支架及其应用 - Google Patents
一种树脂凝胶、凝胶外支架、载药凝胶外支架及其应用 Download PDFInfo
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Abstract
本发明公开了一种树脂凝胶、凝胶外支架、载药凝胶外支架及其应用,树脂凝胶的制备方法为:将儿茶酚胺和乳液聚合引发剂分别加入三(羟甲基)氨基甲烷盐酸盐溶液中,得缓冲液;将三级胺共引发剂加入缓冲液中,并将所得混合液振荡至缓冲液层变为棕黑色;振荡后的混合液经脱水处理,得复合材料A;在甲基丙烯酸酯类化合物中,分别加入一定量的自由基型光引发剂、紫外线吸收剂和光稳定剂,得混合物B;将复合材料A与混合物B适温混合至固体完全溶解;凝胶外支架以树脂凝胶为原料,通过紫外光固化而成;载药凝胶外支架通过将药物混入树脂凝胶中,再紫外光固化而成;树脂凝胶、凝胶外支架、载药凝胶外支架均可用于制备治疗血管疾病的药物。
Description
技术领域
本发明属于生物医用材料技术领域,特别涉及一种树脂凝胶、凝胶外支架、载药凝胶外支架及其应用。
背景技术
冠状动脉疾病(CAD)是一种高度流行且发病率不断增加的疾病。外科对于冠状动脉疾病的主要治疗方法是冠脉搭桥术(CABG),而冠脉搭桥术中使用的替代血管是大隐静脉桥血管,术后5-10年静脉桥血管内的斑块开始破裂并出血。据统计,从术后第一年到第七年静脉桥血管(SVG)的堵塞率为每年2%,从第七年到第十二年增加到5%,而10年后只有38–45%的SVG仍是通畅的。
透析患者需要建立动静脉瘘(AVF),动静脉瘘在临床引用已经超过50年,并广泛用于为血液透析患者提供血管通路,并且是透析患者血管通路的首选。AVF的缺点是,在术后12个月以后只有60%的AVF血管仍然通畅。研究认为AVF血管的再狭窄发病原因与CABG相似,均是由于血管的生理和机械环境的改变而引起的一系列级联反应。
针对上述现有技术的不足,为了有效治疗以上疾病,人们开始研究血管外支架。血管外支架的材质繁多,且仍在不停开发和尝试,早期血管外支架的主要材料是金属材料,金属支架虽然限制了静脉桥血管的扩张,但其并没有抑制桥静脉的再狭窄。研究证明,涤纶材料的血管外支架不光没有抑制静脉桥血管的再狭窄,反而还诱发了血栓的形成,分析原因,可能是由于涤纶支架的刚性过大,导致了血管的扭曲。到目前为止,(KipsBayMedical Inc.)设计的锡钛合金网格支架已经成功上市,在临床的使用也较为安全,但临床报道其效果时,却出现了不同意见,有研究认为其静脉通畅率能达到100%,而有些临床实验却认为其静脉桥血管的通畅率只有28-49%。当然,这些评估中的混杂因素也较多,包括手术的过程,患者的全身情况等。目前仍有一些研究将细胞种植在外支架表面,以提高其性能。例如,/>支架就是将内皮细胞种植在海绵状明胶基质内。虽然其生物安全性高,但抑制静脉桥血管再狭窄的作用并不明显。近年来,载药血管外支架的研究也取得了进展,Vascular WrapTM(Angiotech Pharmaceuticals)是一种紫杉醇洗脱聚(乳酸-羟基乙酸)酸(PLGA)血管外支架,可以改善移植血管的再狭窄,且可以在手术后2-3个月完全降解并完成药物释放。另一种静脉桥血管外支架是包载西罗莫司胶原蛋白,其主要用于血液透析患者的动静脉瘘,通过12和24个月的人体实验证明这种支架的通畅率为78%和38%,但是其实验缺乏合适的对照组,目前这种可包载药物的外支架仍处在临床的初级阶段,且实验过程耗时较长。
总言之,现有血管支架仍存在各种技术弊端,如:现有血管支架主要为血管内,血管外支架研究缺乏;现研究的血管外支架操作不便,运输,使用环境苛刻;现研究的血管外支架载药效果不佳,组织相容性差。目前国际上仍无一款合适的血管外支架,血管外支架的研发仍在不停进行中。
发明内容
本发明所要解决的技术问题是针对上述现有技术的不足,提供一种树脂凝胶、凝胶外支架、载药凝胶外支架及其应用。
为实现上述技术目的,本发明采取的技术方案为:
一种树脂凝胶,所述树脂凝胶的制备方法包括如下步骤:
将儿茶酚胺和乳液聚合引发剂以一定浓度分别加入三(羟甲基)氨基甲烷盐酸盐溶液中,得缓冲液;
将三级胺共引发剂以一定质量比率加入上述缓冲液中,并将所得混合液振荡至缓冲液层变为棕黑色;
振荡后的混合液经脱水处理,获得深棕色胶状物,即复合材料A;
在甲基丙烯酸酯类化合物中,分别加入一定量的自由基型光引发剂、紫外线吸收剂和光稳定剂,得到混合物B;
将复合材料A与混合物B在一定温度下进行混合,至固体完全溶解,得到树脂凝胶。
进一步地,所述缓冲液的制备方法为:向10mmol/L,pH为8.5±1.5的三(羟甲基)氨基甲烷盐酸盐或其缓冲液中,按0.1mg/ml的浓度加入儿茶酚胺(CA),按1.2mg/ml的浓度加入乳液聚合引发剂。
进一步地,所述三级胺共引发剂以10%~90%的质量比率加入缓冲液中。
进一步地,所述振荡后的混合液进行脱水处理的条件为:将振荡后的混合液在1500~3000转/分的高速搅拌条件下加热至100℃~300℃进行脱水。
进一步地,在混合物B的制备中,在一定量的甲基丙烯酸酯类化合物中,按1.5%的质量分数加入自由基型光引发剂,按0.1%的质量分数加入紫外线吸收剂,按0.1%~10%的质量分数加入光稳定剂。
进一步地,所述复合材料A与混合物B在80℃下进行混合,所述复合材料A与混合物B的混合质量比为1:5~5:1。
进一步地,所述儿茶酚胺为多巴胺、盐酸多巴胺、酪氨酸、左旋多巴胺、去甲肾上腺素中的任一种或多种。
进一步地,所述乳液聚合引发剂可选用过硫酸铵、过硫酸氢胺、过硫酸钠、过硫酸钾中的任一种或多种。
进一步地,所述三级胺共引发剂为三甲胺、三(3-氨丙基)胺、三异丙胺、三正丁胺、三乙醇胺、四甲基乙二胺、乙醇胺衍生物、二乙基乙醇胺、N-乙基二乙醇胺、N-二苯甲基氮杂环丁烷、N-甲基氮杂环戊烷、N-甲基哌啶、N,N二甲基环己胺、2-甲基哌嗪、N,N-二甲基苯胺中的任一种或多种。
进一步地,所述甲基丙烯酸酯类化合物为甲基丙烯酸羟乙酯(HEMA)、2-羟甲基丙烯酸乙酯、丙烯酸羟丙酯(HPA)、丙烯酸羟乙酯(HEA)、甲基丙烯酸羟丙酯(HPMA)中的任一种或多种。
进一步地,自由基型光引发剂可选用二苯基(2,4,6-三甲基苯甲酰基)氧化膦(TPO)、2,4,6-三甲基苯甲酰基苯基膦酸乙酯、2-羟基-2-甲基-1-苯基丙酮、2-甲基-2-(4-吗啉基)-1-[4-(甲硫基)苯基]-1-丙酮、2-二甲氨基-2-苄基-1-[4-(4-吗啉基)苯基]-1-丁酮、2-羟基-2-甲基-1-[4-(2-羟基乙氧基)苯基]-1-丙酮或苯甲酰甲酸甲酯等。
进一步地,紫外线吸收剂可选用2-羟基-4-甲氧基-5-磺酸二苯甲酮(HMBS)、邻羟基苯甲酸苯酯、2-(2ˊ-羟基-5ˊ-甲基苯基)苯并三氮唑、2,4-二羟基二苯甲酮、2-羟基-4-正辛氧基二苯甲酮、2-(2’-羟基-3’,5’-二叔苯基)-5-氯化苯并三唑、单苯甲酸间苯二酚酯、水杨酸酯类、二苯甲酮类、苯并三唑类、取代丙烯腈类或三嗪类等。
光稳定剂可选用2,2,6,6-四甲基哌啶-1-氧自由基(TEMPO)、苯甲酸(2,2,6,6-四甲基-4-羟基哌啶)酯、癸二酸双(2,2,6,6-四甲基-4-羟基哌啶)酯、氮基三[乙酸(2,2,6,6-四甲基-4-羟基哌啶)酯]、N、N′-双(2,2,6,6-四甲基哌啶基)己二胺、亚磷酸三(1,2,2,6,6-五甲基-4-羟基哌啶)酯、癸二酸双(1,2,2,6,6-五甲基-4-羟基哌啶)酯、2-乙基-2-(4-羟基-3,5-三级丁基苄基)丙二酸双(1,2,2,6,6-五甲基-4-羟基哌啶)酯等啶衍生物、咪唑酮衍生物或氮杂环烷酮衍生物等。
本发明还提供了一种凝胶外支架,以上述树脂凝胶为原料,通过紫外光固化(5-30s)而成。
其中,紫外光光谱范围210~300nm;
优选地,凝胶外支架以树脂凝胶为材料,通过紫外光固化相关的3D打印技术固化成型,可定制成不同尺寸,以满足临床对不同尺寸外支架的需求,且该凝胶外支架本身可以有效抑制血管病变。
本发明还提供了一种载药凝胶外支架,由载药凝胶通过紫外光固化而成,具体包括以下步骤:
将药物直接混入上述树脂凝胶中或将药物混入脂溶剂中后再混入上述树脂凝胶中,获得载药凝胶;
所述药物可为白芨药物、雷帕霉素等其他可用于预防/抑制/治疗血管病变的药物;
将载药凝胶通过紫外线固化成型,得到载药凝胶外支架。
本发明还提供了上述树脂凝胶或凝胶外支架或载药凝胶外支架在制备治疗血管疾病药物中的应用。
与现有技术相比,本发明具有以下有益效果:
1)本发明的凝胶外支架以液态的树脂凝胶为原材料,性质稳定,树脂凝胶在紫外光照射5-30s左右即可固化,可用于制备凝胶外支架或包载药物的载药凝胶外支架,操作方便,对运输及使用环境无特殊要求;
2)本发明的凝胶外支架以树脂凝胶为原材料,采用紫外光固化3D打印技术制备,可定制成不同尺寸,以满足临床对不同尺寸外支架的需求;凝胶外支架组织相容性佳,且该支架本身可以有效抑制血管病变;
3)本发明的树脂凝胶通过直接包载或溶剂包载方式包载药物,形成载药凝胶,载药凝胶通过紫外线固化成型即可得到载药凝胶外支架,制备工艺简单,而且采用紫外光固化3D打印技术还可根据所需制成不同尺寸的载药凝胶外支架,以满足临床对不同尺寸载药凝胶外支架的需求;
4)本发明的载药凝胶外支架可在血管周围稳定释放,且具有良好的组织相容性,凝胶外支架和载药凝胶外支架均可抑制静脉移植血管的再狭窄,提高其通畅率;而且包载相应药物后的载药凝胶外支架可抑制静脉桥血管内平滑肌细胞的增殖和迁移,对于抑制血管病变的效果增加,可用于治疗心脏外科冠心病,肾内科透析患者动静脉瘘,神经内外科颈动脉狭窄等各种血管疾病。
附图说明
图1是本发明实施例6的白芨凝胶中白芨药物的包封率检测结果;
图2是本发明实施例6的白芨凝胶体外药物释放曲线;
图3是本发明实施例7的术后第3天小鼠脾脏中免疫细胞流式细胞分析图;
图4是本发明实施例7的流式细胞分析标记术后第3天小鼠脾脏中免疫细胞数量结果;
图5是本发明实施例7的术后第7天小鼠脾脏中免疫细胞流式细胞分析图;
图6是本发明实施例7的流式细胞分析标记术后第7天小鼠脾脏中免疫细胞数量结果;
图7是本发明实施例8的彩色多普勒超声图;
图8是本发明实施例8的彩色多普勒超声分析结果图;
图9是本发明实施例8的HE染色结果图;
图10是本发明实施例8的Masson染色结果图;
图11是本发明实施例8的血管内腔面积与总血管面积的比例分析图。
具体实施方式
下面结合实施例对本发明的技术方案作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。下述实施例中所使用的实验方法,如无特殊说明,均为常规方法;所用的试剂和材料,如无特殊说明,均可从商业途径获得。
本发明提供了一种树脂凝胶,其制备方法包括如下步骤:
配置10mmol/L,pH为8.5±1.5的三(羟甲基)氨基甲烷盐酸盐溶液,并按0.1mg/ml的浓度加入儿茶酚胺(CA),按1.2mg/ml的浓度加入乳液聚合引发剂,得缓冲液;
将三级胺共引发剂以10%~90%的质量比率加入上述缓冲液中,并将所得混合液振荡至缓冲液层变为棕黑色;
将振荡后的混合液在高速搅拌(1500~3000转/分)的条件下加热至100℃~300℃使其脱水,获得深棕色胶状物,即复合材料A;
其中,脱水时间按原料量有所不同,以加入20g三级胺共引发剂AR AgiSyn008为例,脱水时间为12h;
在一定量的甲基丙烯酸酯类化合物中,按1.5%的质量分数加入自由基型光引发剂,按0.1%的质量分数加入紫外线吸收剂,按0.1%~10%的质量分数加入光稳定剂,得到混合物B;
将复合材料A与上述混合物B按照1:1,1:2,1:3,1:4,1:5,2:1,2:3,2:5,3:1,3:2,3:4,3:5,4:1,4:3,4:5,5:1,5:2,5:3,5:4中的任一种质量比在80℃下进行混合,至固体完全溶解,得到树脂凝胶。
其中,三(羟甲基)氨基甲烷盐酸盐溶液中还可以加上PBS,MES等缓冲溶液;
其中,儿茶酚胺(CA)可选用多巴胺、盐酸多巴胺、酪氨酸、左旋多巴胺、去甲肾上腺素中的任一种或多种;
其中,乳液聚合引发剂可选用过硫酸铵、过硫酸氢胺、过硫酸钠、过硫酸钾中的任一种或多种;
其中,三级胺共引发剂可选用三甲胺、三(3-氨丙基)胺、三异丙胺、三正丁胺、三乙醇胺、四甲基乙二胺、乙醇胺衍生物、二乙基乙醇胺、N-乙基二乙醇胺、N-二苯甲基氮杂环丁烷、N-甲基氮杂环戊烷、N-甲基哌啶、N,N二甲基环己胺、2-甲基哌嗪、N,N-二甲基苯胺中的任一种或多种;
其中,甲基丙烯酸酯类化合物可选用甲基丙烯酸羟乙酯(HEMA)、2-羟甲基丙烯酸乙酯、丙烯酸羟丙酯(HPA)、丙烯酸羟乙酯(HEA)、甲基丙烯酸羟丙酯(HPMA)等;
其中,自由基型光引发剂可选用二苯基(2,4,6-三甲基苯甲酰基)氧化膦(TPO)、2,4,6-三甲基苯甲酰基苯基膦酸乙酯、2-羟基-2-甲基-1-苯基丙酮、2-甲基-2-(4-吗啉基)-1-[4-(甲硫基)苯基]-1-丙酮、2-二甲氨基-2-苄基-1-[4-(4-吗啉基)苯基]-1-丁酮、2-羟基-2-甲基-1-[4-(2-羟基乙氧基)苯基]-1-丙酮或苯甲酰甲酸甲酯等;
其中,紫外线吸收剂可选用2-羟基-4-甲氧基-5-磺酸二苯甲酮(HMBS)、邻羟基苯甲酸苯酯、2-(2ˊ-羟基-5ˊ-甲基苯基)苯并三氮唑、2,4-二羟基二苯甲酮、2-羟基-4-正辛氧基二苯甲酮、2-(2’-羟基-3’,5’-二叔苯基)-5-氯化苯并三唑、单苯甲酸间苯二酚酯、水杨酸酯类、二苯甲酮类、苯并三唑类、取代丙烯腈类或三嗪类等;
其中,光稳定剂可选用2,2,6,6-四甲基哌啶-1-氧自由基(TEMPO)、苯甲酸(2,2,6,6-四甲基-4-羟基哌啶)酯、癸二酸双(2,2,6,6-四甲基-4-羟基哌啶)酯、氮基三[乙酸(2,2,6,6-四甲基-4-羟基哌啶)酯]、N、N′-双(2,2,6,6-四甲基哌啶基)己二胺、亚磷酸三(1,2,2,6,6-五甲基-4-羟基哌啶)酯、癸二酸双(1,2,2,6,6-五甲基-4-羟基哌啶)酯、2-乙基-2-(4-羟基-3,5-三级丁基苄基)丙二酸双(1,2,2,6,6-五甲基-4-羟基哌啶)酯等啶衍生物、咪唑酮衍生物或氮杂环烷酮衍生物等;
采用以上方法制备的树脂凝胶为液体,性质稳定,可用于紫外光固化制备凝胶外支架或载药凝胶外支架,对运输及使用环境无特殊要求。
本发明还提供了一种凝胶外支架,由上述树脂凝胶通过紫外光固化(5-30s)而成。
其中,紫外光光谱范围210~300nm;
优选地,凝胶外支架以树脂凝胶为材料,通过紫外光固化相关的3D打印技术固化成型,可定制成不同尺寸,以满足临床对不同尺寸外支架的需求,且该凝胶外支架本身可以有效抑制血管病变。
紫外光固化相关的3D打印技术包括FDM熔融沉积成型3D打印技术、SLA光固化快速成型3D打印技术、DLP数码影像投射3D打印技术、SLS选择性激光烧结3D打印技术、DMLS直接金属激光烧结3D打印技术、PolyJet紫外(UV)光固化喷射的液体感光树脂3D打印技术、MJP多喷嘴喷墨高解析度逐层堆叠3D打印技术、CJP彩色喷墨打印技术、3DP三维打印3D打印技术、DED多层激光熔覆3D打印技术、LOM薄板层压成型3D打印技术等。
本发明还提供了一种载药凝胶外支架,该载药凝胶外支架的制备方法包括以下两种,分别为:
①直接包载式:将药物混入液体的树脂凝胶中,然后紫外线固化成型得到。
②溶剂包载式:将药物混入脂溶剂中后再直接包载入树脂凝胶中,最后紫外线固化成型得到。
其中包载的药物可为白芨药物、雷帕霉素等其他可用于预防/抑制/治疗血管病变的药物;
采用以上方法制备的载药凝胶外支架可在血管周围稳定释放,且具有良好的组织相容性,包载相应药物后载药凝胶外支架抑制血管病变的效果增加,可用心脏外科冠心病,肾内科透析患者动静脉瘘,神经内外科颈动脉狭窄等各种血管疾病;同样采用紫外光固化3D打印技术定制成不同尺寸载药凝胶外支架,可满足临床对不同尺寸外支架的需求。
实施例1:一种树脂凝胶
试验原料:三(3-氨丙基)胺(Tris(3-aminopropyl)amine,4963-47-7,阿拉丁),三(羟甲基)氨基甲烷盐酸盐(Tris-HCl,≥99%,阿拉丁),多巴胺(DA,98%,阿拉丁),过硫酸铵((NH4)2S2O8,99.99%,阿拉丁),二苯基(2,4,6-三甲基苯甲酰基)氧化膦(TPO,97%,阿拉丁),2-羟基-4-甲氧基-5-磺酸二苯甲酮(HMBS,98%,阿拉丁),2,2,6,6-四甲基哌啶-1-氧自由基(TEMPO,98%,阿拉丁),甲基丙烯酸羟乙酯(HEMA,96%含250ppmMEHQ稳定剂,阿拉丁);
以上仅是本实施例涉及的原料的可选购厂家,在原料成分相同的情况下,本发明的原料不限于以上获得途径。
一种树脂凝胶,其制备步骤如下:
配置10mmol/L,pH约为8.5的三(羟甲基)氨基甲烷盐酸盐溶液中,并按0.1mg/ml的浓度加入多巴胺(DA),按1.2mg/ml的浓度加入过硫酸铵,得缓冲液;
将三(3-氨丙基)胺以50%的质量比率加入缓冲液中,混合液用超声波振荡器振荡30min左右,至混合液的缓冲液层变为棕黑色;
将振荡后的混合液在集热式恒温加热磁力搅拌器(DF-101S)中于高速搅拌(2000转/分)的条件下加热至180℃使其脱水,最终产物为深棕色胶状物,即复合材料;
在一定量的甲基丙烯酸羟乙酯(HEMA)中:按1.5%的质量分数加入二苯基(2,4,6-三甲基苯甲酰基)氧化膦(TPO),按0.1%的质量分数加入2-羟基-4-甲氧基-5-磺酸二苯甲酮(HMBS),按0.1%的质量分数加入2,2,6,6-四甲基哌啶-1-氧自由基(TEMPO),得到HEMA混合物。
将复合材料与上述HEMA混合物按照2:3的质量比例在80℃下进行混合,至固体完全溶解,最终得到树脂凝胶。
实施例2
一种树脂凝胶,其制备步骤如下:
配置10mmol/L,pH约为7的三(羟甲基)氨基甲烷盐酸盐溶液(三(羟甲基)氨基甲烷盐酸盐中加入PBS缓冲液)中,并按0.1mg/ml的浓度加入酪氨酸,按1.2mg/ml的浓度加入过硫酸钠,得缓冲液;
将三异丙胺以10%的质量比率加入缓冲液中,混合液用超声波振荡器振荡30min左右,至混合液的缓冲液层变为棕黑色;
将振荡后的混合液在集热式恒温加热磁力搅拌器(DF-101S)中于高速搅拌(1500转/分)的条件下加热至100℃使其脱水,最终产物为深棕色胶状物,即复合材料;
在一定量的丙烯酸羟丙酯(HPA)中:按1.5%的质量分数加入2,4,6-三甲基苯甲酰基苯基膦酸乙酯,按0.1%的质量分数加入邻羟基苯甲酸苯酯,按5%的质量分数加入癸二酸双(2,2,6,6-四甲基-4-羟基哌啶)酯,得到HPA混合物。
将复合材料与上述HPA混合物按照3:1的质量比例在80℃下进行混合,至固体完全溶解,最终得到树脂凝胶。
实施例3
一种树脂凝胶,其制备步骤如下:
配置10mmol/L,pH约为10的三(羟甲基)氨基甲烷盐酸盐溶液(三(羟甲基)氨基甲烷盐酸盐中加入MES缓冲液)中,并按0.1mg/ml的浓度加入儿茶酚胺(左旋多巴胺与去甲肾上腺素混合液),按1.2mg/ml的浓度加入乳液聚合引发剂(过硫酸氢胺与过流酸钾混合液),得缓冲液;
将三甲胺以90%的质量比率加入缓冲液中,混合液用超声波振荡器振荡30min左右,至混合液的缓冲液层变为棕黑色;
将振荡后的混合液在集热式恒温加热磁力搅拌器(DF-101S)中于高速搅拌(3000转/分)的条件下加热至300℃使其脱水,最终产物为深棕色胶状物,即复合材料;
在一定量的丙烯酸羟乙酯(HEA)中:按1.5%的质量分数加入2-羟基-2-甲基-1-苯基丙酮,按0.1%的质量分数加入2,4-二羟基二苯甲酮,按10%的质量分数加入氮基三[乙酸(2,2,6,6-四甲基-4-羟基哌啶)酯],得到HEA混合物。
将复合材料与上述HEA混合物按照5:1的质量比例在80℃下进行混合,至固体完全溶解,最终得到树脂凝胶。
对照组1
一种树脂凝胶,本实施例与实施例1的区别在于,三(3-氨丙基)胺以9.8%的质量比率加入缓冲液中;振荡后的混合液在高速搅拌条件下加热至97℃脱水;在甲基丙烯酸羟乙酯(HEMA)中,以0.08%的质量分数加入2,2,6,6-四甲基哌啶-1-氧自由基(TEMPO);复合材料与混合物以1:6的质量比在80℃下进行混合;
对制备的液体凝胶产物进行紫外光固化处理,结果发现,凝胶产物无法固化成型,即无法用于制备凝胶外支架或载药凝胶外支架。
对照组2
一种树脂凝胶,本实施例与实施例1的区别在于,三(3-氨丙基)胺以91%的质量比率加入缓冲液中;振荡后的混合液在高速搅拌条件下加热至305℃脱水;在甲基丙烯酸羟乙酯(HEMA)中,以10.2%的质量分数加入2,2,6,6-四甲基哌啶-1-氧自由基(TEMPO);复合材料与混合物以5.1:1的质量比在80℃下进行混合;
对制备的液体凝胶产物进行紫外光固化处理,结果发现,凝胶产物无法固化成型,即无法用于制备凝胶外支架或载药凝胶外支架。
实施例4:一种凝胶外支架
本实施例的凝胶外支架以实施例1制备的树脂凝胶溶液为原料,采用PolyJet紫外(UV)光固化喷射的液体感光树脂3D打印技术制备而成。
实施例5:一种载药凝胶外支架
本实施例的载药凝胶外支架为包载白芨的凝胶外支架(简称“白芨凝胶”),其以实施例1制备的树脂凝胶溶液为原料,将白芨药物混入树脂凝胶溶液中,然后采用紫外光固化3D打印技术固化成型得到。
实施例6:载药凝胶外支架的药物释放分析
6.1、药物包封率
以包载白芨的凝胶外支架为例,采用紫外分光光度计对溶液中的白芨进行定量测定,以确定凝胶的载药率,具体方法如下:
分别将20mg、50mg、100mg、150mg和200mg的白芨胶与1ml的树脂凝胶超声摇动1min,得到载药凝胶;载药凝胶放在一个玻璃片(15mm*15mm)上,并置于紫外线下照射20s,得到载药凝胶薄膜;在EP管中用磷酸盐缓冲液洗脱载药凝胶薄膜,浸泡3min;取泡膜液,用紫外分光光度计定量,计算树脂凝胶对白芨的载药量和包封率;
结果如图1和表1所示,可见,树脂凝胶对药物的包载性能良好,凝胶的最佳载药量是100mg/ml。
表1树脂凝胶对药物白芨的包封率
白芨药物剂量(mg)/1ml树脂凝胶 | 包封率(%) |
20 | 95.056 |
50 | 89.967 |
100 | 80.011 |
150 | 65.054 |
200 | 49.801 |
6.2、体外药物释放率
将100mg白芨胶加入1ml树脂凝胶中,均匀化后,分别在紫外光下照射14s、17s和20s,形成三种薄膜,分别记为14S-BS gel、17s-BS gel、20s-BS gel;用磷酸盐缓冲液清洗薄膜表面三次;将薄膜置于pH为7.5,15ml的磷酸盐缓冲液中,37℃孵育,确保整个过程中孵育环境不变(试管内液体环境不变);在预定采样点,收集试管中1.5ml PBS,并用新鲜1.5mlPBS补入;用紫外分光光度计测定样品的释药量,并绘制药物随时间的累计,释放药物的百分比。
三种白芨凝胶(14S-BS gel、17s-BS gel、20s-BS gel)的体外药物释放曲线如图2所示,可见白芨在凝胶中的释放稳定,一个月共计释放凝胶中30%-40%的白芨药物,本发明的载药凝胶的药物释放性能良好。
实施例7:凝胶外支架和载药凝胶外支架对机体的免疫反应
由于脾脏对炎症的反应更加明显,为了更准确地评估凝胶外支架和载药凝胶外支架对小鼠的免疫反应,本发明以实施例4制备的凝胶外支架(简称凝胶)和实施例5制备的包载白芨的载药凝胶外支架(简称白芨凝胶)为例,将凝胶(gel)和白芨凝胶(BS-gel)包埋到小鼠体内,包埋方法为:麻醉小鼠,通过酒精浸泡消毒凝胶,切开小鼠皮肤,将消毒后的凝胶放入小鼠皮下后缝合皮肤;在包埋后第3天和第7天收集小鼠的脾脏;对照组(control):正常小鼠,未进行包埋凝胶处理;分别用CD3+标记脾脏中的T细胞、CD45R+标记脾脏中的B细胞、CD11b+标记脾脏中的粒细胞;
用流式细胞仪分析标记脾脏中免疫细胞的数量;具体分析方法如下:
1)组织单细胞悬液制备
剪取部分小鼠脾脏组织加入1ml PBS漂洗后置于200目的不锈钢网上;用注射器针芯轻轻研压组织30s,分批加入10ml PBS冲洗滤网;单细胞悬液1500转/分钟,离心10min,弃上清;100μl PBS重悬细胞。
2)组织细胞检测
细胞悬液加入各抗体3μl混匀;4℃避光孵育30min;1500转/分钟,离心5min,弃上清;加入1ml PBS重悬细胞,再次离心弃上清,重复洗一次;0.5ml PBS重悬细胞,4℃避光,上机检测。
流式细胞分析标记术后第3天、第7天的小鼠脾脏中免疫细胞数量,结果如图3-6所示,可见,凝胶和白芨凝胶并未引起脾脏中粒细胞,单核细胞,淋巴细胞的增殖;说明凝胶并未对脾脏中炎症相关细胞产生影响,凝胶引起的炎症细胞增殖只是短时间,少量的;由于白芨凝胶埋入体内后表面会逐渐形成覆膜包被,这可能是其免疫反应逐渐消退的原因。
实施例8:载药凝胶外支架对血管病变的功能验证
8.1、动物静脉血管冠脉搭桥模型的构建
1)大鼠腹腔注射氯胺酮麻醉后,将大鼠平躺,维持麻醉;检查麻醉深度是否足够,方法是捏住后脚,确认没有反射;在眼睛上涂一些兽医药膏,以防止在麻醉状态下眼睛干燥,固定受体大鼠;
2)用剃刀刮右侧颈部毛,用碘伏和80%乙醇消毒三次;
3)监测麻醉的深度,确保在掐后脚时没有反射,以确保麻醉的深度足够;从右锁骨上到右颈根部作直切口;在显微镜下,将颈静脉分离,结扎各分支后,结扎主干并取出,放入1%肝素中浸泡,作为桥血管;
4)将颈动脉与其周围组织分开;
5)使用止血夹来阻止血液流动,剪短颈动脉,并用10-0丝线牵引血管断端,套入1.5mm套管后将动脉壁翻到套管外侧结扎固定;
6)将取出颈静脉两端分别套入套管外,注意静脉的方向并打结固定;
7)小心地打开远端钳,然后是近端钳;
8)通过检查移植血管和远端动脉的可见脉搏来确认手术成功;
9)用5-0丙烯缝线缝合皮肤,再次消毒后贴敷料。
8.2、彩色多普勒超声分析
参照8.1,我们将大鼠颈静脉移植到同侧颈动脉上,制作静脉血管冠脉搭桥模型;
将0.3ml白芨凝胶(紫外光固化前包载白芨药物的凝胶)或凝胶(即树脂凝胶)均匀涂抹于静脉桥血管周围,并用紫外线固化20s;清洗切口后将其缝合,大鼠正常饲养28天后,评估其狭窄程度;
实验分为四组:对照组(control),空白组(sham),凝胶组(gel)和白芨凝胶组(BS-gel),每组8只;各组处理如下:
凝胶组(gel):将0.3ml凝胶(树脂凝胶)均匀涂抹于静脉桥血管周围,并用紫外线固化20s;清洗切口后将其缝合,大鼠正常饲养28天后,评估其狭窄程度;
白芨凝胶组(BS-gel):将0.3ml白芨凝胶(包载白芨药物的凝胶)均匀涂抹于静脉桥血管周围,并用紫外线固化20s;清洗切口后将其缝合,大鼠正常饲养28天后,评估其狭窄程度;
对照组(control):与凝胶组(gel)的区别仅在于,未涂抹凝胶;
空白组(sham):正常大鼠,未进行静脉血管冠脉搭桥模型构建处理;
在各组大鼠饲养至第28天时,对上述大鼠颈静脉搭桥后,进行彩色超声多普勒分析(图7),并记录移植静脉血管内的血流速度,比较各组血流速度,结果如图8所示。
由图8可见,大鼠移植静脉control组的血流速度比sham组的血流速度增加,gel组静脉血流速度(47.116±4.435cm/s)明显低于control组(125.615±19.221cm/s)(P<0.05);BS-gel组的静脉血流速(36.325±3.063cm/s)显著低于control组,也低于gel组(P<0.05)。以上结果表明,凝胶外支架和载药凝胶外支架均可有效抑制血管病变,且载药凝胶外支架抑制血管病变的效果更佳。
8.3、HE和Masson染色
待上述四组大鼠饲养至28天时,我们取出大鼠颈部移植静脉标本,进行HE和Masson染色。
8.3.1、苏木素(HE)染色
1)将切片连同染色架一起放入烧杯中,自来水流水缓慢冲洗,洗去酒精,直到切片干净透明;
2)苏木素染色3~5min,自来水洗数次;
3)1%盐酸酒精溶液分化数秒,水洗数次;
4)稀碳酸锂水溶液蓝化30s,然后水洗数次;
5)入伊红染色液(醇溶性),切片应先经80%乙醇脱水后再入伊红染色液(醇溶性)染色10~30s;
6)95%乙醇I、II中各调色约10s;
7)无水乙醇I、II中各脱水1~2min,二甲苯I、II中各透明1~2min;
8)封片,镜检。
8.3.2、Masson染色
1)切片常规脱蜡至水;
2)用配好的Weigert铁苏木素染色液染色5~10min;
3)酸性乙醇分化液分化5~15s,水洗;
4)Masson蓝化液返蓝3~5min,水洗;
5)蒸馏水洗1min;
6)丽春红酸性品红染色液染色5~10min;
7)在上述操作过程中按蒸馏水:弱酸溶液=2:1比例配置弱酸工作液,用弱酸工作液洗1min;
8)磷钼酸溶液洗1~2min;
9)用配置好的弱酸工作液洗1min;
10)直接放入苯胺蓝染色液中染色1~2min;
11)用配置好的弱酸工作液洗1min;
12)95%乙醇快速脱水;
13)无水乙醇脱水3次,每次5~10s;
14)二甲苯透明3次,每次1~2min;
15)中性树胶封固。
HE和Masson染色结果分别如图9和图10所示,由图9和图10均可见,与Control组相比,Gel组血管狭窄程度明显降低(P<0.05);与Control组相比,BS-gel组血管狭窄程度也明显降低(P<0.05);移植静脉在术后30天内膜和中膜增厚,血管平滑肌细胞在内膜和中膜中迁移增殖,导致血管狭窄;血管再狭窄病变中,平滑肌细胞增殖并向内膜迁移,血管为同心或者偏心性狭窄。
为了评估移植静脉的狭窄程度,我们还计算了血管腔面积与总血管面积的比值(血管腔面积/总血管面积),结果如图11所示,可见,与Control组相比,Gel组和BS-gel组的血管狭窄程度明显降低(P<0.05)。
综上,本发明的凝胶外支架和载药凝胶外支架(包载预防/抑制/治疗血管病变的药物的凝胶外支架)均可抑制静脉移植血管的再狭窄,提高其通畅率。另外,载药凝胶外支架可抑制静脉桥血管内平滑肌细胞的增殖和迁移,对于抑制血管病变的效果增加,可用于治疗心脏外科冠心病,肾内科透析患者动静脉瘘,神经内外科颈动脉狭窄等各种血管疾病。
以上仅是本发明的优选实施方式,本发明的保护范围并不仅局限于上述实施例,凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理前提下的若干改进和润饰,应视为本发明的保护范围。
Claims (6)
1.一种树脂凝胶,其特征在于,所述树脂凝胶的制备方法包括如下步骤:
向10mmol/L的pH为8.5±1.5的三(羟甲基)氨基甲烷盐酸盐溶液中,分别按0.1mg/ml的浓度和1.2mg/ml的浓度加入儿茶酚胺(CA)和乳液聚合引发剂,得缓冲液;
将三级胺共引发剂以10%~90%的质量比率加入上述缓冲液中,并将所得混合液振荡至缓冲液层变为棕黑色;
振荡后的混合液经脱水处理,获得深棕色胶状物,即复合材料A;
在甲基丙烯酸酯类化合物中,按1.5%的质量分数加入自由基型光引发剂,按0.1%的质量分数加入紫外线吸收剂,按0.1%~10%的质量分数加入光稳定剂,得到混合物B;
将复合材料A与混合物B在80℃下进行混合,至固体完全溶解,得到树脂凝胶,所述复合材料A与混合物B的混合质量比为1:5~5:1。
2.根据权利要求1所述的树脂凝胶,其特征在于:所述振荡后的混合液进行脱水处理的条件为:将振荡后的混合液在1500~3000转/分的高速搅拌条件下加热至100℃~300℃进行脱水。
3.根据权利要求1所述的树脂凝胶,其特征在于:所述儿茶酚胺为多巴胺、盐酸多巴胺、酪氨酸、左旋多巴胺、去甲肾上腺素中的任一种或多种;
所述乳液聚合引发剂可选用过硫酸铵、过硫酸氢铵、过硫酸钠、过硫酸钾中的任一种或多种;
所述三级胺共引发剂为三甲胺、三(3-氨丙基)胺、三异丙胺、三正丁胺、三乙醇胺、四甲基乙二胺、乙醇胺衍生物、二乙基乙醇胺、N-乙基二乙醇胺、N-二苯甲基氮杂环丁烷、N-甲基氮杂环戊烷、N-甲基哌啶、N,N二甲基环己胺、2-甲基哌嗪、N,N-二甲基苯胺中的任一种或多种;
所述甲基丙烯酸酯类化合物为甲基丙烯酸羟乙酯、2-羟甲基丙烯酸乙酯、丙烯酸羟丙酯、丙烯酸羟乙酯、甲基丙烯酸羟丙酯中的任一种或多种。
4.一种凝胶外支架,其特征在于,以权利要求1-3任一项所述的树脂凝胶为原料,通过紫外光固化而成。
5.一种载药凝胶外支架,其特征在于,由载药凝胶通过紫外光固化而成,具体包括以下步骤:
将药物直接混入权利要求1-3任一项所述树脂凝胶中或将药物混入脂溶剂中后再混入权利要求1-3任一项所述树脂凝胶中,获得载药凝胶;
将载药凝胶通过紫外线固化成型,得到载药凝胶外支架。
6.权利要求1-3任一项所述的树脂凝胶或权利要求4所述的凝胶外支架或权利要求5所述的载药凝胶外支架在制备治疗血管疾病药物中的应用。
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