CN115536833A - 一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂及应用 - Google Patents
一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂及应用 Download PDFInfo
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- CN115536833A CN115536833A CN202210921559.2A CN202210921559A CN115536833A CN 115536833 A CN115536833 A CN 115536833A CN 202210921559 A CN202210921559 A CN 202210921559A CN 115536833 A CN115536833 A CN 115536833A
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- poloxamer
- acrylate
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- injectable hydrogel
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Abstract
本发明公开了一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂及应用,该可注射水凝胶粘合剂以质量百分数计,包含如下组分:末端生物降解泊洛沙姆5%‑20%,粘附功能小分子0.1%‑5%,光引发剂0.1%‑0.5%,溶解量的溶解液,末端生物降解泊洛沙姆通过将末端修饰结构引入到泊洛沙姆的两个末端得到;所述末端修饰结构的分子量小于300,含有可生物降解的酯键或酰胺键,且最末端为碳碳双键。该可注射水凝胶粘合剂具有快速粘附和抗溶胀双重性能,在紫外光照射后的数秒内实现针对潮湿组织的粘附,可用于伤口封闭和快速止血,特别适用于神经外科手术的伤口处理,避免术后粘合剂体积膨胀压迫神经组织的风险,保证患者术后的安全性。
Description
技术领域
本发明属于生物医用材料技术领域,具体涉及一种兼具快速固化和抗溶胀的可注射水凝 胶粘合剂及应用。
背景技术
在处理意外创伤或外科手术造成的损伤时,伤口闭合和快速止血是必须的,常用的方法 包括缝合线、吻合钉或绷带。但是,这些技术不适合封闭易碎组织或伴随有液体或气体泄漏 的伤口,原因在于会造成组织的二次损伤,以及不理想的气体或液体密封性。近些年来,随 着生物材料科学的发展,研究人员开发出了一系列可注射水凝胶粘合剂,用于伤口封闭和创 面止血,比如纤维蛋白胶和高分子水凝胶等,它们易于使用,对柔软的组织损伤小,具有良 好的水密性和气密性,受到临床治疗的广泛关注。
目前的可注射水凝胶组织粘合剂存在固化速度慢的问题,注射后还未形成凝胶的前体溶 液易被血液或体液冲走,产生渗漏和流失,无法实现伤口封闭和快速止血,不宜于封闭有持 续液体流出的伤口或者止血。另外,这类可注射水凝胶组织粘合剂大多数在水环境中吸水会 发生体积溶胀,有造成周围组织压迫损伤的风险,尤其是神经组织(脑和脊髓)。此外,体 积溶胀还会导致水凝胶组织粘合剂力学性能和组织粘附性减弱,造成伤口二次开裂或再次出 血,危及患者生命健康。因此,开发一种兼具快速固化和抗溶胀双重性能的可注射水凝胶具 有重要意义。
发明内容
为了解决现有可注射水凝胶粘合剂固化过程不可控且速度较慢以及大多数水凝胶粘合剂 在体内水环境中会吸水体积膨胀导致粘附性能下降而脱落的技术问题,本发明旨在提供一种 兼具快速固化和抗溶胀的可注射水凝胶粘合剂及应用。
本发明兼具快速固化和抗溶胀的可注射水凝胶粘合剂,主要由末端生物降解的泊洛沙姆、 粘附功能小分子、光引发剂和溶解液组成,在光照条件下快速固化成型。本发明利用具有热 敏收缩性能的泊洛沙姆纳米胶束作为凝胶因子和交联剂制备水凝胶,其中热敏收缩纳米胶束 增强了水凝胶的内聚力并赋予其水环境抗溶胀特性。光引发交联特性保证水凝胶的快速可控 固化,粘附功能小分子可以在光交联过程中整合到水凝胶网络中,通过与组织表面氨基发生 共价键连接提供持久稳定的组织粘附性。此外,利用末端生物降解泊洛沙姆的末端可降解设 计,通过改变泊洛沙姆的化学结构以及水凝胶的组份调控降解时间,满足不同使用场景对不 同降解时间的需求。
本发明的技术方案具体如下:
本发明第一方面提供一种末端生物降解泊洛沙姆,所述末端生物降解泊洛沙姆通过将末 端修饰结构引入到泊洛沙姆的两个末端得到;
所述末端修饰结构的分子量小于300,末端修饰结构中含有可生物降解的酯键或酰胺键, 且末端修饰结构的最末端为碳碳双键;
所述末端生物降解泊洛沙姆可通过光照引发交联反应。
进一步地,所述末端生物降解泊洛沙姆的化学结构式如下式I或式II所示;
式I和式II中x和y根据泊洛沙姆的型号进行确定。
进一步地,所述末端生物降解泊洛沙姆为泊洛沙姆二乙酰丙烯酸酯、泊洛沙姆二丙酰丙 烯酸酯、泊洛沙姆二丁酰丙烯酸酯、泊洛沙姆二甘氨酸丙烯酸酯、泊洛沙姆二丙氨酸丙烯酸 酯或泊洛沙姆二β-丙氨酸丙烯酸酯;
所述泊洛沙姆二乙酰丙烯酸酯的化学结构式如下式1所示;
所述泊洛沙姆二丙酰丙烯酸酯的化学结构式如下式2所示;
所述泊洛沙姆二丁酰丙烯酸酯的化学结构式如下式3所示;
所述泊洛沙姆二甘氨酸丙烯酸酯的化学结构式如下式4所示;
所述泊洛沙姆二丙氨酸丙烯酸酯的化学结构式如下式5所示;
所述泊洛沙姆二β-丙氨酸丙烯酸酯的化学结构式如下式6所示;
进一步地,上述末端生物降解泊洛沙姆中,所述泊洛沙姆优选为泊洛沙姆407、泊洛沙姆 188、泊洛沙姆237或泊洛沙姆338。
本发明第二方面提供一种末端生物降解泊洛沙姆的合成方法,包括如下步骤:
将泊洛沙姆溶于二氯甲烷中,加入三乙胺和氯烷基酰氯进行反应,反应完成后,用乙醚 沉淀,离心收集后真空干燥得到泊洛沙姆二氯烷基酸酯;将泊洛沙姆二氯乙酸酯溶于DMF中, 加入丙烯酸钠进行反应,反应完成后滴加到乙醚沉淀,离心收集后真空干燥得到泊洛沙姆二 烷基酰丙烯酸酯;
所述氯烷基酰氯的化学结构式如下式a所示,n≤10;
所述泊洛沙姆二氯烷基酸酯的化学结构式如下式b所示,n≤10;
所述泊洛沙姆二烷基酰丙烯酸酯的化学结构式如下式c所示,n≤10;
或,将泊洛沙姆溶于甲苯中,加入对甲苯磺酸和氨基酸进行反应,反应完成后,用乙醚 沉淀,离心收集后真空干燥得到泊洛沙姆二氨基酸;将泊洛沙姆二甘氨酸溶于二氯甲烷中, 加入三乙胺和丙烯酰氯进行反应,反应完成后滴加到乙醚沉淀,离心收集后真空干燥得到泊 洛沙姆二氨基酸丙烯酸酯;
所述氨基酸的化学结构式如下式d所示,R为侧基;
所述泊洛沙姆二氨基酸的化学结构式如下式e所示,R为侧基;
所述泊洛沙姆二氨基酸丙烯酸酯的化学结构式如下式f所示,R为侧基;
进一步地,所述泊洛沙姆在反应过程中,与氯烷基酰氯、氨基酸、丙烯酸钠和丙烯酰氯 摩尔比为均为1:2。
本发明第三方面提供所述末端生物降解泊洛沙姆在制备可注射水凝胶粘合剂中的应用。
本发明第四方面提供一种兼具快速固化和抗溶胀的可注射水凝胶粘合剂,以质量百分数 计,所述可注射水凝胶包含如下组分:
所述粘附功能小分子具备与氨基反应能力并且可以通过光引发双键交联整合到水凝胶网 络中;
所述末端生物降解泊洛沙姆选自任一项上述末端生物降解泊洛沙姆中的一种或几种。
进一步地,所述末端生物降解泊洛沙姆选自泊洛沙姆407二乙酰丙烯酸酯(PF127-bis-AA)、 泊洛沙姆407二丙酰丙烯酸酯(PF127-bis-PA)、泊洛沙姆407二丁酰丙烯酸酯(PF127-bis-BA)、 泊洛沙姆407二甘氨酸丙烯酸酯(PF127-bis-GA)、泊洛沙姆407二丙氨酸丙烯酸酯 (PF127-bis-AlA)和泊洛沙姆407二β-丙氨酸丙烯酸酯(PF127-bis-β-AlA)中的一种或几种。
进一步地,所述粘附功能小分子选自N-羟基琥珀酰亚胺丙烯酸酯(AA-NHS)、3-甲基 丙烯酰多巴胺(DA-MA)和4-乙烯基苯甲醛(EBA)中的一种或多种。
进一步地,所述光引发剂选自2-羟基-4′-(2-羟乙氧基)-2-甲基苯丙酮(I2959)、2-羟基-2-甲 基-1-苯基-1-丙酮(I1173)和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂(LAP)中的一种或多种。
进一步地,所述溶解液选自去离子水、生理盐水、PBS缓冲液或SPF模拟体液等常用的医 用液体。
进一步地,可注射水凝胶的各组分在365-405nm光照下交联形成所述可注射水凝胶粘合 剂。
进一步地,所述可注射水凝胶还包含可光交联的天然多糖高分子衍生物,所述可光交联 的天然多糖高分子衍生物的质量百分数含量为0.1%-10%。
优选地,所述可光交联的天然多糖高分子衍生物选自双键改性明胶(Gel-MA)、双键改 性透明质酸(HA-MA)、双键改性壳聚糖(CS-MA)、双键改性海藻酸钠(SA-MA)、双 键改性丝素蛋白(SF-MA)、双键改性纤维素(MA-C)和双键改性葡聚糖(MA-Glu)中的 一种或多种,可以提供所需的生物学功能。
本发明第五方面提供所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂在人体或动物 体意外创伤或手术伤口的封闭和/或快速止血中的应用;
优选地,所述手术伤口包括神经外科手术伤口。
本发明第六方面提供所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂的应用方法, 将可注射水凝胶粘合剂各组分加入到溶解液中充分溶解,注射到使用部位,光源照射后引发 光交联反应,使所述可注射水凝胶发生固化;
优选地,所述光源波长范围是365-405nm;
优选地,所述光源照射的时间为5-20s。
本发明的有益效果为:
本发明提供的可注射水凝胶粘合剂具有快速光固化的能力,良好的生物安全性和可控的 生物降解速度,优秀的组织粘附性和力学性能,以及水环境抗溶胀特性。临床使用该水凝胶 时,可快速封闭伤口和止血,术后可避免因体积变化导致的压迫损伤周围组织或伤口封闭失 效,并且可以随着伤口的愈合逐渐降解。本发明可注射水凝胶在紫外光照射后的数秒内可实 现针对潮湿组织的粘附,可用于伤口封闭和快速止血,特别适用于神经外科手术的伤口处理, 比如脑颅或脊柱手术,避免术后粘合剂体积膨胀压迫神经组织的风险,保证患者术后的安全 性。
附图说明
图1PF127-bis-AA、PF127-bis-PA、PF127-bis-BA、PF127-bis-GA、PF127-bis-AlA和 PF127-bis-β-AlA的化学结构式。
图2为兼具快速光照固化和抗溶胀的可注射水凝胶粘合剂的外观图。
图3为本发明水凝胶粘合剂的快速光照固化性能。A:凝胶时间的流变学测试;B:水凝 胶的光固。
图4为本发明水凝胶粘合剂的抗溶胀特性,与常见的聚乙二醇溶胀水凝胶进行对比。A: 水凝胶浸泡在PBS中不同时间点的外观图;B:水凝胶浸泡在PBS中不同时间点的溶胀率。
图5为本发明水凝胶粘合剂的压力爆破组织粘附性。A:压力爆破测试实验装置;B:压 力爆破粘附性数据。
图6为水凝胶粘合剂进行大鼠和兔子心脏紧急出血的快速止血效果图。(a)暴露大鼠心 脏并制造穿透出血模型;(b)出血行为展示;(c)注射水凝胶粘合剂并进行光照固化,封 闭伤口止血;(d)干净纱布擦拭出血部位;(e)纱布上没有血迹,说明止血成功。(1)暴 露兔心脏并制造穿透出血模型;(2)出血行为展示;(3)注射水凝胶粘合剂并进行光照固 化,封闭伤口止血;(4)干净纱布擦拭出血部位;(5)纱布上没有血迹,说明止血成功。
图7为水凝胶粘合剂进行大兔子硬脊膜损伤封闭的效果图。(1)暴露硬脊膜;(2)制造硬脊 膜损伤模型;(3)成功封闭硬脊膜,避免脑脊液漏。
具体实施方式
为了更清楚地理解本发明,现参照下列实施例及附图进一步描述本发明。实施例仅用于 解释而不以任何方式限制本发明。实施例中,各原始试剂材料均可商购获得,未注明具体条 件的实验方法为所属领域熟知的常规方法和常规条件,或按照仪器制造商所建议的条件。
实施例1
PF127-bis-AA、PF127-bis-PA、PF127-bis-BA、PF127-bis-GA、PF127-bis-AlA和PF127-bis-β-AlA的合成:
1)末端生物降解的光交联PF127高分子(PF127-bis-AA)的合成:
第一步:首先将12.6g PF127溶于100mL二氯甲烷中,然后加入1mL三乙胺和230mg氯 乙酰氯。反应完成后,反应液乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二氯乙酸酯 (PF127-bis-CA)。
第二步:首先将12.6g PF127-bis-CA和190mg丙烯酸钠溶于50mL DMF中。反应完成后, 反应液滴加到乙醚中沉淀,离心收集后真空干燥得到洛沙姆407二乙酰丙烯酸酯(PF127-bis-AA)。
2)末端生物降解的光交联PF127高分子(PF127-bis-PA)的合成:
第一步:首先将12.6g PF127溶于100mL二氯甲烷中,然后加入1mL三乙胺和250mg氯 丙酰氯。反应完成后,反应液乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二氯丙酸酯 (PF127-bis-CP)。
第二步:首先将12.6g PF127-bis-CP和190mg丙烯酸钠溶于50mL DMF中。反应完成后, 反应液滴加到乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二丙酰丙烯酸酯(PF127-bis-PA)。
3)末端生物降解的光交联PF127高分子(PF127-bis-BA)的合成:
第一步:首先将12.6g PF127溶于100mL二氯甲烷中,然后加入1mL三乙胺和280mg氯 丁酰氯。反应完成后,反应液乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二氯丁酸酯 (PF127-bis-CB)。
第二步:首先将12.6g PF127-bis-CB和190mg丙烯酸钠溶于50mL DMF中。反应完成后, 反应液滴加到乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二丁酰丙烯酸酯(PF127-bis-BA)。
4)末端生物降解的光交联PF127高分子(PF127-bis-GA)的合成:
第一步:首先将12.6g PF127溶于100mL甲苯中,然后加入345mg对甲苯磺酸和150mg 甘氨酸。反应完成后,反应液乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二甘氨酸 (PF127-bis-Gly)。
第二步:首先将12.6g PF127-bis-Gly溶于100mL二氯甲烷中,然后加入1mL三乙胺和181 mg丙烯酰氯。反应完成后,反应液滴加到乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆 407二甘氨酸丙烯酸酯(PF127-bis-GA)。
5)末端生物降解的光交联PF127高分子(PF127-bis-AlA)的合成:
第一步:首先将12.6g PF127溶于100mL甲苯中,然后加入345mg对甲苯磺酸和180mg 丙氨酸。反应完成后,反应液乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二丙氨酸 (PF127-bis-Ala)。
第二步:首先将12.6g PF127-bis-Ala溶于100mL二氯甲烷中,然后加入1mL三乙胺和181 mg丙烯酰氯。反应完成后,反应液滴加到乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆 407二丙氨酸丙烯酸酯(PF127-bis-AlA)。
6)末端生物降解的光交联PF127高分子(PF127-bis-β-AlA)的合成:
第一步:首先将12.6g PF127溶于100mL甲苯中,然后加入345mg对甲苯磺酸和180mgβ- 丙氨酸。反应完成后,反应液乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆407二β-甘氨酸 (PF127-bis-β-Ala)。
第二步:首先将12.6g PF127-bis-Ala溶于100mL二氯甲烷中,然后加入1mL三乙胺和181 mg丙烯酰氯。反应完成后,反应液滴加到乙醚中沉淀,离心收集后真空干燥得到泊洛沙姆 407二β-丙氨酸丙烯酸酯(PF127-bis-β-AlA)。
实施例2
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将100mg PF127-bis-AA,1mg AA-NHS,2.5mg LAP加入900微升PBS缓冲液中,旋涡震荡至充分溶解;然后,将溶液加入 模具中,用365nm紫外光照射5秒,固化形成水凝胶。
实施例3
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将100mg PF127-bis-AA,1mg AA-NHS,10mg Gel-MA,2.5mg LAP加入890微升PBS缓冲液中,旋涡震荡至充分溶解;然 后,将溶液加入模具中,用365nm光源光照射5秒,固化形成水凝胶。
实施例4
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将50mg PF127-bis-AA,50mg PF127-bis-PA,1mg DA-MA,2.5mg LAP加入900微升PBS缓冲液中,旋涡震荡至充分溶解; 然后,将溶液加入模具中,用365nm光源光照射10秒,固化形成水凝胶。
实施例5
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将50mg PF127-bis-AA,50mg PF127-bis-PA,1mg DA-MA,10mg HA-MA,2.5mg LAP加入890微升PBS缓冲液中,旋涡 震荡至充分溶解;然后,将溶液加入模具中,用405nm光源光照射10秒,固化形成水凝胶。
实施例6
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将30mg PF127-bis-AA,30mg PF127-bis-PA,40mg PF127-bis-BA,1mg EBA,2.5mg LAP加入900微升PBS缓冲液中,旋 涡震荡至充分溶解;然后,将溶液加入模具中,用405nm光源光照射20秒,固化形成水凝胶。
实施例7
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将30mg PF127-bis-AA,30mg PF127-bis-PA,40mg PF127-bis-BA,1mg EBA,10mg CS-MA,2.5mg LAP加入890微升PBS 缓冲液中,旋涡震荡至充分溶解;然后,将溶液加入模具中,用365nm光源光照射10秒,固 化形成水凝胶。
实施例8
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将100mg PF127-bis-GA,1mg AA-NHS,2.5mg LAP加入900微升PBS缓冲液中,旋涡震荡至充分溶解;然后,将溶液加入 模具中,用365nm紫外光照射5秒,固化形成水凝胶。
实施例9
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将100mg PF127-bis-GA,1mg AA-NHS,10mg Gel-MA,2.5mg LAP加入890微升PBS缓冲液中,旋涡震荡至充分溶解;然 后,将溶液加入模具中,用365nm光源光照射5秒,固化形成水凝胶。
实施例10
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将50mg PF127-bis-GA,50mg PF127-bis-AlA,1mg DA-MA,2.5mg LAP加入900微升PBS缓冲液中,旋涡震荡至充分溶解; 然后,将溶液加入模具中,用365nm光源光照射10秒,固化形成水凝胶。
实施例11
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将50mg PF127-bis-GA,50mg PF127-bis-AlA,1mg DA-MA,10mg HA-MA,2.5mg LAP加入890微升PBS缓冲液中,旋涡 震荡至充分溶解;然后,将溶液加入模具中,用405nm光源光照射10秒,固化形成水凝胶。
实施例12
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将30mg PF127-bis-GA,30mg PF127-bis-AlA,40mg PF127-bis-β-AlA,1mg EBA,2.5mg LAP加入900微升PBS缓冲液中, 旋涡震荡至充分溶解;然后,将溶液加入模具中,用405nm光源光照射20秒,固化形成水凝 胶。
实施例13
兼具快速光照固化和抗溶胀的可注射水凝胶的制备:首先,将30mg PF127-bis-GA,30mg PF127-bis-AlA,40mg PF127-bis-β-AlA,1mg EBA,10mg CS-MA,2.5mg LAP加入890微升 PBS缓冲液中,旋涡震荡至充分溶解;然后,将溶液加入模具中,用365nm光源光照射10秒, 固化形成水凝胶。
使用实施例3水凝胶进行下列测试
1.水凝胶的外观
水凝胶外观为无色高透明弹性固体,见附图2,图左为实施例2水凝胶,图右为实施例3 水凝胶。在处理伤口或止血过程中,可以方便观察创伤的情况,及时进行治疗方案的改进。
2.凝胶的固化速度
利用流变学测试检测水凝胶的光固化时间:测试温度25℃,将水凝剂前体溶液填充测试 平台(直径40mm平板,间隙1mm),形变量为1%,频率为1Hz,光源(365nm,100mW cm-2) 开始照射时间设定为0秒,收集水凝胶的储能模量(G′)和损耗模量(G″)数值随时间的变化曲线。 二者交叉的时间点即为水凝胶的光固化时间。结果见附图3A。
利用称重法检测水凝胶的光固化效率:将接受不同光照时间的水凝胶冷冻干燥后称取质 量Wp,根据水凝胶中组份含量可计算出初始组份质量Wo。二者比例即为水凝胶的光固化效 率:光固化效率%=(Wp/Wo)×100。结果见附图3B。结果表明,水凝胶的凝胶时间小于2秒, 完全光固化时间小于5秒。
3.水凝胶的溶胀行为
将水凝胶浸泡在PBS缓冲液中,保持37℃。在1、3、5天进行湿重的测量(Ws),并与初始的水凝胶(Wi)进行对比,计算溶胀率,评价其溶胀形变能力:溶胀率%=((Ws-Wi)/Wi)×100。 利用相同分子量的聚乙二醇二丙烯酸酯替代PF127-bis-AA,其他组份相同,制备对照组聚乙 二醇水凝胶。结果见附图4。结果表明,水凝胶在5天内表现出优秀的抗溶胀行为。
4.水凝胶的组织粘附性
利用压力爆破实验测试水凝胶的组织粘附性,实验装置见附图5。首先,在圆形猪皮表面 制造一个直径为2mm的孔状伤口,然后在伤口表面滴加水凝胶前体溶液,紫外照射5秒固化, 最后推动注射观察水凝胶破裂时气压计的读数,即水凝胶的粘附强度,结果见附图5。结果表 明,水凝胶的爆破强度可以达到200mm Hg,远强于人体血压的120mm Hg,适用于紧急出血 的快速止血,并且水环境中强度不下降,保持稳定。利用相同分子量的聚乙二醇二丙烯酸酯 替代PF127-bis-AA,其他组份相同,制备对照组聚乙二醇水凝胶。相比之下,聚乙二醇水凝 胶的粘附强度在水环境中明显下降。
5.水凝胶的快速止血效果
以大鼠和兔子为模型动物,用注射器针头在心脏部位制造穿刺伤害,模拟紧急出血。利 用水凝胶粘合剂进行止血,效果见附图6。结果表明,只需将可注射水凝胶粘合剂注射到出血 部位并进行紫外照射,就可以有效止血,具备针对急性出血快速止血的功能。
6.水凝胶在神经外科手术中的应用
以兔子为模型动物,进行脊柱手术制造硬脊膜损伤模型。利用水凝胶粘合剂封闭硬脊膜 损伤避免脑脊液漏,效果见附图7。结果表明,只需将可注射水凝胶粘合剂注射到硬脊膜损伤 部位并进行紫外照射,就可以有效封闭硬脊膜伤口,使用于神经外科手术中的紧急伤口处理。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所 属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。 这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处 于本发明创造的保护范围之中。
Claims (10)
1.一种末端生物降解泊洛沙姆,其特征在于,所述末端生物降解泊洛沙姆通过将末端修饰结构引入到泊洛沙姆的两个末端得到;
所述末端修饰结构的分子量小于300,末端修饰结构中含有可生物降解的酯键或酰胺键,且末端修饰结构的最末端为碳碳双键;
所述末端生物降解泊洛沙姆可通过光照引发交联反应。
2.根据权利要求1所述的末端生物降解泊洛沙姆,其特征在于,所述末端生物降解泊洛沙姆的化学结构式如下式I或式II所示;
优选地,所述末端生物降解泊洛沙姆为泊洛沙姆二乙酰丙烯酸酯、泊洛沙姆二丙酰丙烯酸酯、泊洛沙姆二丁酰丙烯酸酯、泊洛沙姆二甘氨酸丙烯酸酯、泊洛沙姆二丙氨酸丙烯酸酯或泊洛沙姆二β-丙氨酸丙烯酸酯;
所述泊洛沙姆二乙酰丙烯酸酯的化学结构式如下式1所示;
所述泊洛沙姆二丙酰丙烯酸酯的化学结构式如下式2所示;
所述泊洛沙姆二丁酰丙烯酸酯的化学结构式如下式3所示;
所述泊洛沙姆二甘氨酸丙烯酸酯的化学结构式如下式4所示;
所述泊洛沙姆二丙氨酸丙烯酸酯的化学结构式如下式5所示;
所述泊洛沙姆二β-丙氨酸丙烯酸酯的化学结构式如下式6所示;
优选地,所述泊洛沙姆为泊洛沙姆407、泊洛沙姆188、泊洛沙姆237或泊洛沙姆338。
3.一种末端生物降解泊洛沙姆的合成方法,其特征在于,包括如下步骤:
将泊洛沙姆溶于二氯甲烷中,加入三乙胺和氯烷基酰氯进行反应,反应完成后,用乙醚沉淀,离心收集后真空干燥得到泊洛沙姆二氯烷基酸酯;将泊洛沙姆二氯乙酸酯溶于DMF中,加入丙烯酸钠进行反应,反应完成后滴加到乙醚沉淀,离心收集后真空干燥得到泊洛沙姆二烷基酰丙烯酸酯;
所述氯烷基酰氯的化学结构式如下式a所示,n≤10;
所述泊洛沙姆二氯烷基酸酯的化学结构式如下式b所示,n≤10;
所述泊洛沙姆二烷基酰丙烯酸酯的化学结构式如下式c所示,n≤10;
或,将泊洛沙姆溶于甲苯中,加入对甲苯磺酸和氨基酸进行反应,反应完成后,用乙醚沉淀,离心收集后真空干燥得到泊洛沙姆二氨基酸;将泊洛沙姆二甘氨酸溶于二氯甲烷中,加入三乙胺和丙烯酰氯进行反应,反应完成后滴加到乙醚沉淀,离心收集后真空干燥得到泊洛沙姆二氨基酸丙烯酸酯;
所述氨基酸的化学结构式如下式d所示,R为侧基;
所述泊洛沙姆二氨基酸的化学结构式如下式e所示,R为侧基;
所述泊洛沙姆二氨基酸丙烯酸酯的化学结构式如下式f所示,R为侧基;
4.根据权利要求3所述的合成方法,其特征在于,所述泊洛沙姆在反应过程中,与氯烷基酰氯、氨基酸、丙烯酸钠和丙烯酰氯摩尔比为均为1:2。
5.权利要求1或2所述末端生物降解泊洛沙姆在制备可注射水凝胶粘合剂中的应用。
7.根据权利要求6所述的可注射水凝胶粘合剂,其特征在于,所述末端生物降解泊洛沙姆选自泊洛沙姆407二乙酰丙烯酸酯、泊洛沙姆407二丙酰丙烯酸酯、泊洛沙姆407二丁酰丙烯酸酯、泊洛沙姆407二甘氨酸丙烯酸酯、泊洛沙姆407二丙氨酸丙烯酸酯和泊洛沙姆407二β-丙氨酸丙烯酸酯中的一种或几种;
优选地,所述粘附功能小分子选自N-羟基琥珀酰亚胺丙烯酸酯、3-甲基丙烯酰多巴胺和4-乙烯基苯甲醛中的一种或多种;
优选地,所述光引发剂选自2-羟基-4′-(2-羟乙氧基)-2-甲基苯丙酮、2-羟基-2-甲基-1-苯基-1-丙酮和苯基-2,4,6-三甲基苯甲酰基亚磷酸锂中的一种或多种;
优选地,所述溶解液选自去离子水、生理盐水、PBS缓冲液或SPF模拟体液;
优选地,可注射水凝胶的各组分在365-405nm光照下交联形成所述可注射水凝胶粘合剂;
优选地,所述可注射水凝胶还包含可光交联的天然多糖高分子衍生物,所述可光交联的天然多糖高分子衍生物的质量百分数含量为0.1%-10%;
优选地,所述可光交联的天然多糖高分子衍生物选自双键改性明胶、双键改性透明质酸、双键改性壳聚糖、双键改性海藻酸钠、双键改性丝素蛋白、双键改性纤维素和双键改性葡聚糖中的一种或多种。
8.权利要求6或7所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂在人体或动物体意外创伤或手术伤口的封闭和/或快速止血中的应用。
9.根据权利要求8所述的应用,其特征在于,所述手术伤口包括神经外科手术伤口。
10.权利要求6或7所述的兼具快速固化和抗溶胀的可注射水凝胶粘合剂的应用方法,其特征在于,将可注射水凝胶粘合剂各组分加入到溶解液中充分溶解,注射到使用部位,光源照射后引发光交联反应,使所述可注射水凝胶发生固化;
优选地,所述光源波长范围是365-405nm。
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