WO2023155753A1 - 一种复合水溶胶及其制备方法与应用 - Google Patents
一种复合水溶胶及其制备方法与应用 Download PDFInfo
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- WO2023155753A1 WO2023155753A1 PCT/CN2023/075694 CN2023075694W WO2023155753A1 WO 2023155753 A1 WO2023155753 A1 WO 2023155753A1 CN 2023075694 W CN2023075694 W CN 2023075694W WO 2023155753 A1 WO2023155753 A1 WO 2023155753A1
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- WIPO (PCT)
- Prior art keywords
- lipoic acid
- composite
- composite hydrosol
- hydrosol
- glue
- Prior art date
Links
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Classifications
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the carboxyl group and/or carboxylate of lipoic acid and/or lipoic acid salt in the composite hydrosol can be functionally grafted or modified, thereby changing the composition of the composite hydrosol. performance.
- the composite hydrosol prepared by the present invention can also be used as a carrier of other biologically active ingredients, which has more abundant biological functions after loading other biologically active ingredients, and better meets the needs of clinical applications.
- Figure 1 shows the basic properties of the composite hydrosol.
- Tyndall phenomenon of composite hydrosols (a) Adhesion of the composite hydrosol to fingers.
- Injectable properties of the composite hydrosol (c) Injectable properties of the composite hydrosol.
- Flow properties of the composite hydrosol (d)
- Figure 4 shows the hemostasis of the liver defect by the composite hydrosol through adhesion.
- Step A Disperse 93 mg of lipoic acid and 327 mg of sodium lipoate in 1 mL of aqueous solution to prepare a dispersion of lipoic acid and sodium lipoate.
- LA-Glue showed a gradual degradation trend, and some LA-Glue remained undegraded after soaking for 1800min, indicating that the introduction of lipoic acid can regulate the degradation rate of the composite hydrogel, so that it can better meet the clinical application needs.
- the skin defect healing rate of the LA-Glue group was significantly faster than that of the blank control (Control) group, the surgical thread suture group and the 3M-Glue group.
- the Control group, the surgical suture group, and the 3M-Glue treatment group all had obvious scars, while the scars in the LA-Glue treatment group disappeared completely.
- the quality of the regenerated skin tissue was further analyzed by H&E and Masson staining of the repaired skin tissue (Fig. 8). The experimental results showed that obvious tissue defects could be observed in the slices of the surgical thread suture group and the 3M-Glue group, while there was no obvious tissue defect in the slices of the Control group but the new tissue was immature.
- the fluid viscous composite hydrosol loaded with tannic acid obtained in this example is close to the composite hydrosol obtained in Example 1 in terms of adhesion, degradation and anti-inflammatory activity.
- Example 1 was obtained The composite hydrosol and the composite hydrosol loaded with tannic acid were co-cultured with Escherichia coli and Staphylococcus aureus respectively, and the research results showed that the composite hydrosol loaded with tannic acid had better performance than the composite hydrosol obtained in Example 1. Antibacterial activity, can effectively kill Escherichia coli and Staphylococcus aureus.
- the composite hydrosol loaded with hydroxyapatite has lower adhesion, slower degradation rate and similar anti-inflammatory activity.
- the composite hydrosol obtained in Example 1 and the composite hydrosol loaded with hydroxyapatite were co-cultured with bone marrow mesenchymal stem cells, and the research results showed that the composite hydrosol loaded with hydroxyapatite was more than that obtained in Example 1
- the composite hydrosol has a stronger ability to induce bone marrow mesenchymal stem cells to differentiate into osteoblasts.
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Abstract
本发明公开了一种复合水溶胶及其制备方法与应用，属于生物材料技术领域。所述复合水溶胶是通过加热溶解含有硫辛酸和硫辛酸盐的混合分散液并冷却获得，具有良好的生物相容性、生物降解性和抗炎活性。所述复合水溶胶不仅能作为组织粘合剂用于多种组织的缺损粘合而且能作为组织填充物修复不规整的组织缺损。此外，所述复合水溶胶还能作为载体材料负载各种生物活性成分，在药物递送等方面具有应用前景。
Description
本发明属于生物材料技术领域，具体涉及一种复合水溶胶及其制备方法与应用。
溶胶作为一类由聚合物和水形成的流动状粘性液体，其在组织缺损粘合、填充以及药物递送方面显示出巨大的应用潜力。譬如，氰基丙烯酸酯生物胶水是目前临床广泛使用的一类溶胶产品，其可替代传统的组织缝合，以规避组织缝合的繁琐过程及其给患者带来的不适/疼痛。然而，目前水溶胶仍然存在许多缺陷，包括生物相容性较差、可降解性差、与软组织的力学相容性差，以及缺乏生物活性等，难以满足临床应用的需求。
发明内容
针对以上问题，本发明提供了一种新型复合水溶胶及其制备方法与应用。所述复合水溶胶由含有硫辛酸和硫辛酸盐的原料制备且在制备过程中不掺入任何有机溶剂和共价交联剂，具有良好的生物相容性。所述复合水溶胶通过动态二硫键交联形成，在机体内具有良好的生物降解性；所述复合水溶胶的降解产物为硫辛酸/硫辛酸盐小分子，具有优异的抗炎活性，其不仅能促进组织缺损的愈合且能有效地避免愈合后疤痕的出现；所述复合水溶胶能在干燥或湿润条件下粘附各种组织和脏器，用于多种组织缺损粘合；所述复合水溶胶还能作为组织填充物填充各种不规整的组织缺损并促进其快速愈合；所述复合水溶胶能高效负载各种生物活性成分，在药物递送方面具有较大的应用价值。
本发明包含以下技术方案∶
一种复合水溶胶，是由含有硫辛酸和硫辛酸盐的原料制备而成的流动状粘性液体。单一硫辛酸由于难溶于水不能制备成水溶胶，而单一硫辛酸盐形成的流动状液体降解快，无法满足生物医学应用的需求。本发明通过将硫辛酸和硫辛酸盐复合，成功制备出具有良好生物相容性、生物降解性和生物活性的复合水溶胶。所述复合水溶胶能在不使用任何有机溶剂和共价交联剂的条件下制备，具有良好的生物相容性；所述复合水溶胶能在机体内生物降解，且降解产物为具有抗炎活性的硫辛酸/硫辛酸盐小分子，有利于加速组织缺损愈合并能避免疤痕的生成；
同时，该复合水溶胶能在干燥或湿润条件下粘附各种组织和脏器，用于多种组织缺损粘合；此外，一定条件下该复合水溶胶可转变成凝胶，能作为组织填充物以加速组织的修复和再生；该复合水溶胶还能高效负载各种生物活性成分，在药物递送方面也具有较大的应用价值。
本发明中所述硫辛酸为广义的硫辛酸概念，其既可以是硫辛酸分子，也可以是硫辛酸衍生物或两者的混合物，所述硫辛酸衍生物包括对硫辛酸进行的不影响其核心作用发挥的非实质性改性而获得的改性物(包括但不限于在硫辛酸分子上接枝官能团)。
作为可选方式，在上述复合水溶胶中，所述硫辛酸盐为硫辛酸钠、硫辛酸钾、硫辛酸锂。所述方案中选用的硫辛酸盐中所含金属离子均为正一价，这些正一价金属离子可以作为羧酸根的抗衡离子又不会与硫辛酸发生螯合作用。
作为可选方式，在上述复合水溶胶中，所述硫辛酸与硫辛酸盐的摩尔比为1∶(2～100)，含水量为55～90％。当硫辛酸与硫辛酸盐的摩尔比高于1∶2时无法形成水溶胶；当硫辛酸与硫辛酸盐的摩尔比为1∶2时，只形成了含水量为80％的复合水溶胶溶胶；当硫辛酸与硫辛酸盐的摩尔比为1∶100时能形成含水量为55～90％的复合水溶胶；当硫辛酸与硫辛酸盐的摩尔比低于1∶100时，形成的溶胶降解快，难以满足临床应用的要求。此外，所述复合水溶胶中硫辛酸与硫辛酸盐的摩尔比越大，复合水溶胶的含水量范围越窄；所述复合水溶胶中硫辛酸与硫辛酸盐的摩尔比越小，复合水溶胶的含水量范围越宽。
作为可选方式，在上述复合水溶胶中，所述复合水溶胶的粘性大于等于3kPa。有利于与生物组织形成有效粘附。
作为可选方式，在上述复合水溶胶中，所述复合水溶胶是一种流动状的粘性液体，所述复合水溶胶中的硫辛酸分子上的羧基使其能与生物组织发生界面相互作用，进而实现组织粘附。所述复合水溶胶在用作粘合剂时，特别在用于粘接生物组织类的湿润界面时，能够通过硫辛酸的疏水作用排除湿润界面水分的不利影响，大幅提升粘接效果，还能够有效克服现有粘接剂(如氰基丙烯酸酯)存在的生物降解性差、粘合过程放热且粘合后软组织固化等问题。所述复合水溶胶在用作填充材料被植入预定组织部位后，一方面能够有效填充形状不规则空隙部位，另一方面能够与周围组织有效粘连锚定，避免流动扩散到非目标区域。所述复合水
溶胶在用作载体材料时，一方面由于良好的流动性能有利于被负载的物质的均匀分散，并顺利达到目标部位，另一方面可以利用其成胶潜能和粘性实现与目标部位周围组织的固定，实现靶向输送。
作为可选方式，在上述复合水溶胶中，通过将硫辛酸与硫辛酸盐的复合分散液加热使硫辛酸与硫辛酸盐溶解，然后冷却形成流动状的复合水溶胶。通过加热交联制备溶胶的方法简单且不需要额外引入交联剂，确保溶胶良好的生物相容性和生物安全性。
作为可选方式，在上述复合水溶胶中，所述复合水溶胶在大于60℃下反应制备。
作为可选方式，在上述复合水溶胶中，可对所述复合水溶胶中硫辛酸和/或硫辛酸盐的羧基和/或羧酸根进行功能化接枝或修饰，进而改变复合水溶胶的性能。
作为可选方式，在上述复合水溶胶中还含有其它生物活性成分。进一步的，所述生物活性成分具体为生长因子、抗菌剂、药物活性成分、止血剂等，生物活性成分的引入能赋予溶胶更丰富的生物学功能，使其更好的满足临床应用的需求。
本发明还提供了一种上述的复合水溶胶的制备方法，在不使用任何有机溶剂和共价交联剂的条件下，加热溶解硫辛酸和硫辛酸盐的分散液并冷却获得一种硫辛酸/硫辛酸盐复合水溶胶。
作为可选方式，在上述制备方法中，具体包括以下步骤∶
步骤A：将硫辛酸和硫辛酸盐分散于水中制得均匀的硫辛酸和硫辛酸盐分散液。
步骤B：将步骤A中的硫辛酸和硫辛酸盐分散液加热溶解，并冷却至室温即可获得硫辛酸/硫辛酸盐复合水溶胶。
作为可选方式，在上述制备方法中，在所述步骤A中加入其它生物活性成分。
作为可选方式，在上述制备方法中，具体包括以下步骤∶
步骤1：将生物活性成分、硫辛酸和硫辛酸盐分散于水中制得均匀的硫辛酸和硫辛酸盐分散液。
步骤2：将步骤1中的生物活性成分、硫辛酸和硫辛酸盐分散液加热溶解，并冷却至室温即可获得负载有生物活性成分的硫辛酸/硫辛酸盐复合水溶胶。
本发明还提供了一种上述复合水溶胶的应用，其特征在于，将其用作组织缺损粘合剂，组织缺损填充物和药物递送载体。
本发明还提供了一种上述硫辛酸/硫辛酸盐复合水溶胶制成的粘合剂、填充剂或载体材料。
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。
本发明的有益效果：
1.本发明制备的复合水溶胶主要成分是内源性小分子硫辛酸且未使任何有机溶剂和共价交联剂，具有良好的生物安全性和生物相容性。
2.本发明制备的复合水溶胶由动态二硫键交联形成，在机体内具有良好的生物降解性。
3.本发明制备的复合水溶胶在机体内的降解产物为硫辛酸，具有优异的抗炎活性，能抑制炎性通路NF-κB以防止胶原蛋白过度沉积，进而避免组织缺损修复期间疤痕的形成。
4.本发明制备的复合水溶胶在粘合组织时不会引起组织固化，具有良好的力学相容性。
5.本发明制备的复合水溶胶还可以作为其它生物活性成分的载体，其在负载其它生物活性成分后具有更丰富的生物学功能，更好地满足临床应用的需求。
图1为复合水溶胶的基本性质。(a)复合水溶胶的丁达尔现象。(b)复合水溶胶对手指的粘附性。(c)复合水溶胶的可注射特性。(d)复合水溶胶的流动特性。
图2为复合水溶胶的降解性能。(a)复合水溶胶浸提液的紫外图谱。(b)复合水溶胶和仅由硫辛酸钠构成的液体在PBS中降解曲线。
图3为复合水溶胶的粘附性。(a)复合水溶胶的粘附机理图。(b)复合水溶胶对不同物体的粘附性。(c)复合水溶胶通过粘附悬挂起装有超纯水的广口瓶(300g)。(d)复合水溶胶粘附心、肝、脾、肺和肾等生物组织的实物图。
图4为复合水溶胶通过粘合对肝脏缺损进行止血。(a)不同材料粘合肝脏后失
血情况的实物图。(b)不同实验组的失血量的定量分析。
图5为复合水溶胶的体外抗炎活性。
图6为复合水溶胶粘合缺损皮肤组织后的实物图。
图7为不同材料(不处理、手术缝合、3M-Glue和LA-Glue)处理伤口后不同时间点伤口的愈合情况。
图8为不同材料处理伤口7天后伤口部位组织切片的H&E染色和Masson染色。
图9为在不同硫辛酸与硫辛酸钠摩尔比以及不同含水量下制备的复合水溶胶的实物图。
以下通过实施例的具体实施方式再对本发明的上述内容作进一步的详细说明。但不应当将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明的精神和原则之内做的任何修改，以及根据本领域普通技术知识和惯用手段做出的等同替换或者改进，均应包括在本发明的保护范围内。
实施例1：
(1)硫辛酸/硫辛酸钠复合水溶胶的制备。
步骤A：将93mg硫辛酸和327mg硫辛酸钠分散于1mL水溶液中，制得硫辛酸和硫辛酸钠分散液。
步骤B：将步骤A所得分散液在90℃下溶解，冷却后即可获得硫辛酸/硫辛酸钠复合水溶胶(命名为LA-Glue)。
(2)硫辛酸/硫辛酸钠复合水溶胶的性能表征及结果分析。
LA-Glue的基本性质。如图1a所示本实施例制备出的LA-Glue为流动状液体，具有明显的丁达尔现象。如图1b所示LA-Glue被涂覆到拇指和食指中后能将其粘附到一起，表明LA-Glue良好的皮肤粘附性能。图1c和d展示了LA-Glue被装载于注射器中并涂覆成不同的形态，表明LA-Glue良好的流动性。上述所示实验结果表明LA-Glue是一种流动状的粘性液体。
LA-Glue的体外降解性能。利用紫外分光光度计法测定LA-Glue的体外降解性能。步骤如下：将LA-Glue(50mg)黏附在两块猪皮之间，然后将整个材料浸泡到1mL的PBS溶液；最后，将浸提1h后的浸提液用PBS稀释3倍，并用紫外分光光度测定其紫外吸收图谱。如图2a所示，LA-Glue的浸提液在330nm处具
有明显的紫外吸收峰，与文献硫辛酸小分子在330nm处的特征紫外吸收峰一致，表明LA-Glue具有良好的体外降解性且降解产物为硫辛酸。此外，图2b对比了LA-Glue和在相同条件下制备的仅由硫辛酸钠构成的液体(LaNa-Liquid)在PBS中的降解曲线。结果显示LaNa-Liquid在PBS中浸泡10min后完全降解。相比之下，LA-Glue呈逐渐降解的趋势，其浸泡1800min后仍有部分LA-Glue未被降解，表明硫辛酸的引入能调控复合水凝胶的降解速率，使其能更好地满足临床应用的需求。
LA-Glue的粘附性。得益于硫辛酸分子中的羧基能与多种生物组织发生界面相互作用，LA-Glue展示出优异的粘附性(图3a)。如图3b和c所示，LA-Glue不仅能粘附塑料、玻璃、金属、木材、树叶和石头等基材，甚至能通过粘附提升起超过300g的广口瓶。此外，LA-Glue能牢固地粘附到大鼠的心、肝、脾、肺和肾等多种脏器组织表面，并将其悬挂在空中(图3d)。上述结果表明LA-Glue能粘附到多种生物组织表面，具有较大的生物应用潜力。
LA-Glue的止血性能。利用Sprague Dawley大鼠肝脏止血模型来进一步评价LA-Glue的粘附性能。首先，在Sprague Dawley大鼠肝脏处构建组织缺损。然后，利用LA-Glue和3M-Glue粘合肝脏缺损。最后，记录肝脏缺损处的失血情况和失血量。如图4a所示，未进行任何处理的肝脏缺损处有大量的血液流出。相比之下，利用LA-Glue粘合后的肝脏缺损处只有少量的血液流出，表明3M-Glue能粘合肝脏缺损进而对其进行止血。此外，失血量的定量结果(图4b)显示3M-Glue组和LA-Glue组的失血量相近，明显低于未进行任何处理的肝脏缺损组的失血量。综上所述，LA-Glue能快速粘合肝脏缺损进而对其止血，且其止血性能接近于商用的3M-Glue。
LA-Glue的体外抗炎活性。将LA-Glue浸提液与脂多糖(LPS)刺激的小鼠巨噬细胞(RAW 264.7)共培养后，通过检测RAW 264.7细胞中炎性基因的相对表达水平来评价LA-Glue的体外抗炎活性，具体实验步骤如下：首先，利用LPS(1.5μg/mL)与RAW 264.7细胞共孵育12h。然后，利用LA-Glue浸提液与LPS刺激后的RAW 264.7细胞共孵育24h。最后，利用PCR检测RAW 264.7细胞内促炎基因(TNF-α,IL-1β,IL-6和TGF-β1)的表达情况。如图5所示LPS刺激后的细胞呈现较高的炎性反应，TNF-α,IL-1β,IL-6和TGF-β1的表达明显高于未进行
LPS刺激的细胞。与LA-Glue作用后TNF-α,IL-1β,IL-6和TGF-β1的表达显著下降，甚至接近于未进行LPS刺激的细胞。上述实验结果表明LA-Glue具有优异的体外抗炎活性，主要原因是其降解释放出的硫辛酸能抑制炎性通路NF-κB。
LA-Glue的力学相容性。通过观察LA-Glue粘合皮肤组织缺损后皮肤组织的柔韧性来评价LA-Glue的力学相容性。首先，在Sprague Dawley大鼠背部构建皮肤组织缺损。然后，分别利用手术线缝合以及LA-Glue和3M-Glue粘合皮肤组织缺损。最后，通过观察皮肤组织的柔韧性等指标来评价材料与皮肤组织的力学相容性。如图6所示，3M-Glue虽然能取代传统手术缝合将缺损的皮肤组织粘合在一起，但3M-Glue粘合后皮肤组织明显变硬，表明3M-Glue与皮肤组织具有差的力学相容性。相比之下，LA-Glue不仅能达到与3M-Glue相似的粘合效果且粘合后的皮肤组织仍然具有柔韧性。上述结果表明，相比较与3M-Glue，LA-Glue与皮肤组织具有更好的力学相容性，使用过程中不会对皮肤组织带来明显的副作用，显示出良好的临床应用潜力。
LA-Glue促进伤口愈合的能力。利用Sprague Dawley大鼠背部皮肤缺损修复实验来验证LA-Glue促进伤口愈合的能力，大致实验步骤如下：首先，在Sprague Dawley大鼠背部构建线型皮肤组织缺损。其次，利用手术线缝合以及LA-Glue和3M-Glue粘合皮肤组织缺损，以不做处理的组织缺损作为实验的空白对照组。最后，通过观察皮肤缺损在不同时间点的修复情况及其组织学切片(H&E和Masson染色)来评价材料促进伤口愈合的能力。如图7所示，LA-Glue组的皮肤缺损愈合速率明显快于空白对照(Control)组、手术线缝合组和3M-Glue组。特别地，植入7天后，Control组、手术线缝合组和3M-Glue治疗组都还有明显的疤痕，相比之下，LA-Glue治疗组的疤痕完全消失。通过对修复后的皮肤组织进行H&E和Masson染色进一步分析再生皮肤组织的质量(图8)。实验结果显示手术线缝合组和3M-Glue组的切片中都有明显的组织缺损能被观察到，而Control组的切片中无明显的组织缺损但新生组织还未成熟。相比之下，LA-Glue组的组织切片中无明显的组织缺损且再生组织中出现毛囊等结构(与正常皮肤组织类似)，表明再生组织已逐渐成熟。上述所有实验结果表明LA-Glue不仅能粘合组织缺损而且能加速这些组织缺损的修复。
实施例2：
本实施例操作与实施例1基本相同，只是改变实施例1步骤A中硫辛酸、硫辛酸钠和水的量，制备不同含水量和不同硫辛酸和硫辛酸钠摩尔比的复合材料(图9)。通过本实施例制备出的复合材料的成分、含水量和粘性见表1。
表1：不同硫辛酸、硫辛酸钠和水的量制备出的复合材料的成分、含水量和粘性。
如图9所示，当步骤A中硫辛酸与硫辛酸钠的摩尔比为1∶0时，生成的复合材料均呈现固液分离状态，未形成水溶胶。当步骤A中硫辛酸与硫辛酸钠的摩尔比为1∶1时，生成的复合材料状态为固液分离或固态，同样未形成水溶胶。当步骤A中硫辛酸与硫辛酸钠的摩尔为1∶2，含水量为90％时形成复合材料固液分离，含水量为77％、67％和50％时形成的复合材料为固态，只有含水量为83％时形成了水溶胶(粘性：15.2kPa)。当步骤A中硫辛酸与硫辛酸钠的摩尔为1∶4，含水量为90％时形成的复合材料固液分离，含水量为67％和50％时形成的复合材料为固态，含水量为83％和77％时形成溶胶(粘性分别为：10.4kPa和16.2kPa)。当步骤A中硫辛酸与硫辛酸钠的摩尔为1∶10，含水量为90％时形成的复合材料固液分离，含水量为50％时形成的复合材料为固态，含水量为83％、77％和67％时形成溶胶(粘性分别为：7.9kPa、9.3kPa和14.7kPa)。当步骤A中硫辛酸与硫辛酸钠的摩尔为1∶100，含水量为50％时形成的复合材料为固态，含水量为90％、83％、77％和67％时形成溶胶(粘性分别为：3.0kPa、4.2kPa、5.6kPa和11.9kPa)。上述结果表明当硫辛酸与硫辛酸盐的摩尔比越大，形成的复合水溶胶含水量范围越窄；硫辛酸与硫辛酸盐的摩尔比越小，形成的复合水溶胶含水量范围越宽。当硫辛酸与硫辛酸钠的摩尔小于1∶100时制备出的复合水溶胶降解速率快，难以满足临床应用的需求。
实施例3：
复合水溶胶的含水量还可以通过控制加热时间挥发复合水溶胶的水分来控制。将实施例2中硫辛酸和硫辛酸钠摩尔比为1∶100，含水量90％形成的复合水溶胶持续加热除去部分水分可获得含水量低至55％的复合水溶胶。当含水量进一步降低时，材料变成固态。
实施例4：
本实施例的操作与实施例1基本相同，只是将实施例1中温度从90℃调整为100℃。
通过本实施例获得的流动状粘性复合水溶胶，其粘附性、降解性以及抗炎活性都与实施例1获得的复合水溶胶接近。
实施例5：
步骤A：首先，将420mg硫辛酸和63.5mg氢氧化钠分散于1mL水溶液中，制得硫辛酸和硫辛酸钠分散液。
步骤B：将步骤A所得分散液在90℃下溶解，冷却后获得硫辛酸/硫辛酸钠复合水溶胶。
通过本实施例获得的流动状粘性复合水溶胶，其粘附性、降解性以及抗炎活性都与实施例1获得的复合水溶胶接近。
实施例6：
步骤A：将硫辛酸(2.06g)和N-羟基琥珀酰亚胺(1.37g)溶解于四氢呋喃(80mL)并冰浴搅拌反应12h。反应结束后通过旋蒸处理即可获得接枝有活化酯的硫辛酸。
步骤B：将93mg接枝有活化酯的硫辛酸和327mg硫辛酸钠分散于1mL水溶液中，制得接枝活化酯的硫辛酸和硫辛酸钠分散液。
步骤C：将步骤B所得分散液在90℃下溶解，冷却后获得接枝活化酯的硫辛酸/硫辛酸钠复合水溶胶。
通过本实施例获得的接枝活化酯的复合水溶胶，相比于实施例1的复合水溶胶，表现出更强的粘附性，而其降解性以及抗炎活性无显著变化。
实施例7：
步骤1：将93mg硫辛酸、327mg硫辛酸钠和30mg单宁酸分散于1mL水溶液中，制得硫辛酸、硫辛酸钠和单宁酸分散液。
步骤2：将步骤A所得分散液在90℃下溶解，冷却后即可获得即可获得负载有单宁酸的流动状粘性复合水溶胶。
通过本实施例获得的负载有单宁酸的流动状粘性复合水溶胶，其粘附性、降解性以及抗炎活性都与实施例1获得的复合水溶胶接近。此外，将实施例1获得
的复合水溶胶和负载有单宁酸的复合水溶胶分别于大肠杆菌和金黄色葡萄球菌共培养，研究结果显示负载有单宁酸的复合水溶胶比实施例1获得的复合水溶胶具有更优的抗菌活性，能有效地杀死大肠杆菌和金黄色葡萄球菌。
实施例8：
本实施例的操作与实施例7基本相同，只是将实施例7中步骤1中的单宁酸(30mg)分别改为羟基磷灰石(10mg)、阿霉素(1mg)和壳寡糖(10mg)。
通过本实施例制得了三种负载不同生物活性成分的复合水溶胶，包括负载羟基磷灰石的复合水溶胶、负载阿霉素的复合水溶胶和负载壳寡糖的复合水溶胶。
相比于实施例1获得的复合水溶胶，负载羟基磷灰石的复合水溶胶的粘附性降低、降解速度变慢以及抗炎活性相近。此外，将实施例1获得的复合水溶胶和负载有羟基磷灰石的复合水溶胶分别于骨髓间充质干细胞共培养，研究结果显示负载有羟基磷灰石的复合水溶胶比实施例1获得的复合水溶胶具有更强诱导骨髓间充质干细胞向成骨细胞分化的能力。
相比于实施例1获得的复合水溶胶，负载阿霉素的复合水溶胶的粘附性、降解性以及抗炎活性都与实施例1获得的复合水溶胶接近。此外，将实施例1获得的复合水溶胶和负载有阿霉素的复合水溶胶分别与肿瘤细胞(A549细胞、Hela细胞和B16细胞)共培养，实验结果显示负载有阿霉素的复合水溶胶比实施例1获得的复合水溶胶具有更优异的抗肿瘤活性，能高效地杀伤多种肿瘤细胞。
相比于实施例1获得的复合水溶胶，负载壳寡糖的复合水溶胶的粘附性降低、降解速度变慢以及抗炎活性相近。此外，将实施例1获得的复合水溶胶和负载有壳寡糖的复合水溶胶分别与大肠杆菌和金黄色葡萄球菌共培养，研究结果显示负载有壳寡糖的复合水溶胶比实施例1获得的复合水溶胶具有更优的抗菌活性，能有效地杀死大肠杆菌和金黄色葡萄球菌。
实施例9：
步骤A：将110mg硫辛酸和350mg硫辛酸钠分散于1mL水溶液中，制得硫辛酸和硫辛酸钠分散液。
步骤B：将步骤A所得分散液在90℃下溶解，冷却后即可获得硫辛酸/硫辛酸钠复合水溶胶。
通过本实施例获得了一种能用于织缺损填充的复合水溶胶。刚制备的复合水
溶胶呈现出流动状的粘性液体形式，能流动并填充大面积的皮肤组织缺损。填充皮肤组织缺损后，该复合水溶胶会快速固化形成凝胶作为组织修复材料诱导皮肤组织再生。
Claims (9)
- 一种复合水溶胶，其特征在于，是由含有硫辛酸和硫辛酸盐的原料形成的流动状粘性液体。
- 根据权利要求1所述的复合水溶胶，其特征在于，所述硫辛酸与硫辛酸盐的摩尔比为1∶(2～100)，含水量为55～90％。
- 根据权利要求1所述的复合水溶胶，其特征在于，所述复合水溶胶的粘性大于等于3.0kPa。
- 根据权利要求1所述的复合水溶胶，其特征在于，所述硫辛酸和/或硫辛酸盐的羧基和/或羧酸根经过功能化接枝或修饰。
- 根据权利要求1所述的复合水溶胶，其特征在于，所述复合水溶胶中还含有其它生物活性成分。
- 一种如权利要求1所述的复合水溶胶的制备方法，其特征在于包括以下步骤：步骤A：将硫辛酸和硫辛酸盐分散于水中制得均匀的硫辛酸和硫辛酸盐分散液；步骤B：将步骤A中的分散液加热溶解，并冷却至室温获得流动状的粘性液体。
- 根据权利要求6所述的制备方法，其特征在于，所述步骤A中的硫辛酸和硫辛酸盐分散液，可以是通过在硫辛酸中加入碱性溶液制得。
- 一种如权利要求1所述的复合水溶胶的应用，其特征在于，将其用作组织缺损粘合剂，组织缺损填充物和生物活性成分的递送载体。
- 一种采用权利要求1所述的复合水溶胶制成的粘合剂、填充剂或载体材料。
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| CN113061263A (zh) * | 2021-04-06 | 2021-07-02 | 华东理工大学 | 基于硫辛酸类小分子化合物的光交联动态可逆超分子聚合物粘合剂的制备方法 |
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| CN113621342A (zh) * | 2021-08-27 | 2021-11-09 | 四川大学 | 一种无溶剂粘结剂及其制备方法与应用 |
| CN114010522A (zh) * | 2021-12-22 | 2022-02-08 | 郑州大学 | 一种硫辛酸混合胶束及其制备方法和应用 |
| CN115232329A (zh) * | 2022-08-04 | 2022-10-25 | 广东工业大学 | 一种硫辛酸水凝胶及其制备方法和应用 |
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| JP2015089877A (ja) * | 2013-11-05 | 2015-05-11 | ベアトリクス株式会社 | αリポ酸誘導体含有粘稠性製剤 |
| CN113061263A (zh) * | 2021-04-06 | 2021-07-02 | 华东理工大学 | 基于硫辛酸类小分子化合物的光交联动态可逆超分子聚合物粘合剂的制备方法 |
| CN113583180A (zh) * | 2021-08-11 | 2021-11-02 | 浙江理工大学龙港研究院有限公司 | 一种含硫辛酸阴离子聚离子液体及其制备方法 |
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| CN114010522A (zh) * | 2021-12-22 | 2022-02-08 | 郑州大学 | 一种硫辛酸混合胶束及其制备方法和应用 |
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