醛基化透明质酸/羟丙基壳聚糖自愈合水凝胶的制备与性能

王艺璇; 曲萌菲; 张杭; 李征征

醛基化透明质酸/羟丙基壳聚糖自愈合水凝胶的制备与性能

王艺璇¹,
曲萌菲¹,
张杭¹,
李征征^{1, 2, ,}

1.
天津科技大学　化工与材料学院, 天津 300457
2.
复旦大学　聚合物分子工程国家重点实验室, 上海200433

基金项目: 天津市海洋资源与化学重点实验室(201706)、2018 年度天津市教委科研计划项目(2018KJ110)和天津市制浆造纸重点实验室开放基金资助项目(201809)

详细信息

通讯作者:
李征征，博士，副研究员，硕士生导师，研究方向为智能高分子水凝胶及其生物医用研究　E-mail: li.z.z@tust.edu.cn

中图分类号: O63
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- 文章访问数: 464
- HTML全文浏览量: 235
- 被引次数: 0
出版历程
- 收稿日期: 2022-10-31
- 修回日期: 2023-01-17
- 录用日期: 2023-01-18
- 网络出版日期: 2023-02-13

Preparation and properties of oxidized hyaluronic acid-hydroxypropyl chitosan self-healing hydrogel

1.
School of Chemical Engineering and Materials, Tianjin University of Science and Technology, Tianjin 300457, China
2.
Fudan University, State Key Laboratory of Molecular Engineering of Polymers, Shanghai 200433, China

Funds: Tianjin Key Laboratory of Marine Resources and Chemistry (No.201706)、2018Tianjin Education Commission Scientific Research Program Project (2018KJ110) and Tianjin Key Laboratory of Pulp and Paper Open Fund Project (No.201809)

摘要

摘要: 目的近年来，研究人员对自愈合水凝胶在生物医学工程领域如生物组织工程支架及药物载体等领域进行了广泛研究。透明质酸 (HA) 和羟丙基壳聚糖 (HPCS) 因具有良好的生物可降解性和生物相容性等优点在生物医药领域备受关注。本文通过将HA进行氧化改性，以醛基化透明质酸 (OHA) 和HPCS为原料，制备OHA/HPCS自愈合水凝胶。方法以透明质酸 (HA) 和羟丙基壳聚糖(HPCS) 为原料，通过对透明质酸进行改性，制备了醛基化透明质酸 (OHA)。以OHA和HPCS为原料，利用醛基和氨基形成席夫碱的反应，OHA上的醛基与HPCS的氨基发生反应，生成动态亚胺键，制备了OHA/HPCS自愈合水凝胶。通过傅里叶变换红外光谱 (FT-IR) 和核磁共振氢谱 (H NMR) 表征OHA/HPCS自愈合水凝胶的结构并考察了OHA和HPCS的用量对OHA/HPCS水凝胶的微观形态、粘弹性、溶胀性能、自愈合性能和药物释放性能的影响。结果 (1) OHA的红外谱图在1730 cm出现醛基的特征峰，证明OHA制备成功。在3000~3750 cm和2930 cm处分别对应—OH (羟基) 和—CH— (次甲基) 伸缩振动，在1657cm处为HPCS的羰基峰。在1730cm处醛基的特征峰消失，1640cm处为C=N伸缩振动峰，表明OHA的醛基与HPCS的氨基发生席夫碱反应生成亚胺键，说明OHA/HPCS水凝胶制备成功。(2) 在OHA的核磁共振氢谱图中，4.9~5.0 ppm 处出现新的化学位移，这表明由OHA上的醛基与相邻羟基形成半缩醛质子，说明OHA制备成功。(3) OHA/HPCS水凝胶孔隙与孔隙之间相互贯通。OHA/HPCS水凝胶的孔径范围在70~200 μm之间。由于OHA的浓度增大，交联度增大，同时OHA/HPCS水凝胶中聚合物的质量分数增加，OHA/HPCS水凝胶的内部三维空间的孔隙结构变小。 (4)对OHA/HPCS水凝胶进行拉伸，发现拼接处未发生断裂，表明OHA/HPCS水凝胶的断裂面在拼接后产生化学反应，进一步证明OHA/HPCS水凝胶可以实现自愈合。(5) OHA/HPCS水凝胶的均大于，表明OHA/HPCS水凝胶具有良好的弹性。由于随着OHA的用量增加，醛基与氨基所形成的亚胺键数量增多，交联密度增大，OHA/HPCS水凝胶逐渐增大，OHA/HPCS水凝胶的弹性逐渐提高。表明OHA的用量能够影响OHA/HPCS水凝胶的弹性。(6) OHA/HPCS水凝胶具备一定程度的吸水和储水能力。OHA/HPCS水凝胶最大溶胀比为29~35。随着OHA用量增加，OHA/HPCS水凝胶的最大溶胀比呈现逐渐减小的趋势。(7) OHA/HPCS水凝胶能够被溶菌酶所降解。提高OHA的用量，醛基数量增加，生成的动态亚胺键增多，提高了交联程度，并增加了OHA/HPCS水凝胶内部的空间位阻效应，延长降解时间。 (8) OHA/HPCS水凝胶对吉西他滨具有缓慢释放的作用。OHA/HPCS水凝胶对吉西他滨的药物释放率达到70%~84%，释放时间为12天。随着OHA的用量增大，吉西他滨分子链上的氨基与OHA的醛基可能存在一定的席夫碱反应，吉西他滨与OHA之间发生反应性吸收， OHA/HPCS水凝胶的交联度增大阻碍分子链运动，使得药物释放受到阻碍，释放速率减小。OHA/HPCS水凝胶内外环境的药物浓度差逐渐缩小直至平衡，药物释放速率逐渐趋缓直至平衡。结论 (1) 通过氧化透明质酸 (HA) 制备醛基化透明质酸 (OHA) ，以OHA和羟丙基壳聚糖 (HPCS) 为原料，通过席夫碱的生成反应，制备具有动态亚胺键的OHA/HPCS水凝胶。(2) 通过控制OHA的用量，OHA/HPCS水凝胶在无外界条件刺激的作用下4 h可实现自愈合。OHA/HPCS水凝胶具有多孔结构且孔隙之间相互贯通的特点，孔径范围在70~200 μm之间。OHA/HPCS水凝胶在30 min达到溶胀平衡，溶胀比为25~29。(3) OHA/HPCS水凝胶对吉西他滨的药物释放率达到70%~84%，释放时间为12天。因此OHA/HPCS水凝胶具有缓慢释放吉西他滨的性能，OHA/HPCS水凝胶在药物递送领域具有较好的应用前景。
- 醛基化透明质酸 /
- 羟丙基壳聚糖 /
- 自愈合 /
- 水凝胶 /
- 药物释放
Abstract: In this paper, oxidized hyaluronic acid (OHA) was synthesized by oxidizing hydroxyl groups on hyaluronic acid (HA) with sodium periodate. OHA/HPCS self-healing hydrogel was prepared by using OHA and hydroxypropyl chitosan (HPCS) as raw materials. The aldehyde group on OHA reacted with the amino group of HPCS to form dynamic imine bond through Schiff base reaction. In this paper, the microscopic morphology and properties of OHA/HPCS self-healing hydrogel was characterized by Fourier Transform infrared spectroscopy (FT-IR), UV-Vis spectrophotometer (UV-Vis), scanning electron microscopy (SEM), rheology and ¹H NMR. OHA/HPCS hydrogels have a porous structure, and the results showed that the pore size ranged from 70 to 200 μm by changing the amount of OHA. With the increase of the dosage of OHA, the pores in the OHA/HPCS hydrogels increased, the pore size became smaller, the swelling ratio of OHA/HPCS became smaller, and the degradation rate became slower. OHA/HPCS hydrogel could self-heal within 4 h at room temperature without external stimulation. OHA/HPCS hydrogel can release anticancer drug of gemcitabine in sustained way, with a cumulative release percent of 70%-84% in 12 days. OHA/HPCS hydrogels have the properties of sustained release gemcitabine, indicating that OHA/HPCS hydrogels have potential application prospects in the field of drug release.
- oxidized hyaluronic acid /
- hydroxypropyl chitosan /
- self-healing /
- hydrogels /
- sustained drug release

HTML全文

图 1 醛基化透明质酸 (OHA)/ 羟丙基壳聚糖 (HPCS)自愈合水凝胶合成路线示意图

Figure 1. Schematic diagram of oxidized hyaluronic acid (OHA)/ hydroxypropyl chitosan (HPCS) self-healing hydrogels synthesis route

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图 2 HA和OHA的红外光谱图

Figure 2. FT-IR spectra of HA and OHA

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图 3 HPCS、HA、OHA和OHA/HPCS水凝胶的红外光谱图

Figure 3. FT-IR spectra of HPCS, HA, OHA, and OHA/HPCS hydrogels

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图 4 OHA和HA的核磁共振氢谱图

Figure 4. ¹H NMR spectra of OHA and HA

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图 5 OHA₁/HPCS(a), OHA₂/HPCS(b)和OHA₃/HPCS(c)水凝胶的SEM图

(a~c:放大150倍)

Figure 5. SEM images of OHA₁/HPCS (a), OHA₂/HPCS (b)and OHA₃/HPCS (c) hydrogels

(a ~ c: 150 times magnification)

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图 6 OHA/HPCS水凝胶自愈合图示

Figure 6. Self-healing diagram of OHA/HPCS hydrogels

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图 7 OHA/HPCS 水凝胶的粘弹性能:G'和 G''随应变变化曲线

Figure 7. Viscoelastic properties of OHA/HPCS hydrogels G' and G" curves with strain

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图 8 OHA/HPCS自愈合水凝胶的溶胀性能曲线

Figure 8. Swelling performance curves of OHA/HPCS self-healing hydrogels

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图 9 OHA/HPCS水凝胶的体外降解

Figure 9. In vitro degradation of OHA/HPCS hydrogels

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图 10 OHA/HPCS自愈合水凝胶的药物释放曲线

Figure 10. Drug release curves of OHA/HPCS self-healing hydrogels

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表 1 OHA/HPCS水凝胶的实验配比

Table 1. Experimental ratio of OHA/HPCS hydrogel

Samples OHA/g HPCS/g PBS/mL

OHA₁/HPCS 0.03 0.07 1
OHA₂/HPCS 0.05 0.07 1
OHA₃/HPCS 0.07 0.07 1

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