Application of intelligent hydrogel in the tissue engineering

doi:10.3969/j.issn.2095-4344.2014.12.023

Abstract

Abstract:

BACKGROUND: Compared with traditional hydrogels, intelligent hydrogels can appear to exhibit different responses to different stimuli such as temperature, pH value, light, and magnetic field, produce two-stage structure and alter chemical structure to generate the ordered supramolecular structure by self-assembling, and ultimately cause the formation of the gel with three-dimensional structure.
OBJECTIVE: To review the research status of intelligent hydrogels and its application in tissue engineering.
METHODS: A computer-based search of CNKI and PubMed databases was performed to retrieve articles addressing intelligent hydrogels in tissue engineering published before 2014. The keywords were “hydrogel, tissue engineering” in Chinese and English.
RESULTS AND CONCLUSION: Intelligent hydrogels are classified into temperature sensitivity, pH sensitivity, photosensitivity, magnetic susceptibility and temperature/pH dual responsive hydrogels. The change of the external environment can be automatically detected and responded. Intelligent hydrogels exhibit a series of outstanding performances in drug delivery systems, drug delivery, repair and improvement of defected tissues, which are not possessed by traditional materials. In particular, the intelligent hydrogels show considerable superiorities in tissue engineering, including low immunogenicity that reducing inflammation and rejection, biodegradability, realizing the three-dimensional scale simulation of cell microenvironment that is conducive to cell adhesion, growth, migration and differentiation.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

全文链接：

Key words: biocompatible materials, hydrogel, tissue engineering, review

CLC Number:

R318

Zhang Ding-wen, Liu Yan-fei, Qi Peng, Liu Jian-guo. Application of intelligent hydrogel in the tissue engineering[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(12): 1944-1950.

Figures/Tables 4

Ho等[11]以N-异丙基丙烯酰胺接枝聚合反应制备了两种温敏性的可注入型水凝胶，所得到理化性质表明，其在34 ℃水溶液中时具有低临界溶液温度。Pochan等[12]设计了一种双亲性的多肽(VKVKVKTKVDPPTKVKVKVKV- NH2)，当升高温度时，在疏水作用和氢键的推动下，赖氨酸残基形成亲水面，缬氨酸残基形成疏水面，从而折叠形成双层夹心结构，最终自助装成纳米纤维凝胶；当低温的时候，赖氨酸静电排斥使得自组装的凝胶溶解，此体系是一种典型的温度敏感热可逆水凝胶。 2.1.2 pH敏感性水凝胶 1980年，Tanaka等[13]首次报道陈化后的丙烯酰胺凝胶，因具有pH值敏感性而引起了人们极大的兴趣，随后有关pH值敏感性水凝胶的报道越来越多。pH敏感性实验表明，凝胶的溶胀率在pH=1.0的介质中较大，在pH=4.0的介质中次之，在中性或pH=9.0的碱性介质中较低，表明凝胶具有明显的pH敏感性。王芳平等[14]用自由基交联共聚法合成了具有pH敏感性的聚丙烯酸-co-甲基丙烯酸辛基酚聚氧乙烯醚酯水凝胶(图3)，发现在不同pH缓冲溶液中的溶胀性、溶胀动力学和退溶胀动力学单体配比不相同。通过浸泡法在水凝胶中载入L-抗坏血酸，初步研究了模拟胃肠液中凝胶对L-抗坏血酸的释放行为，结果表明凝胶兼具快速的溶胀和退溶胀速率，良好的pH敏感性等特征。另有学者采用溶液共聚法合成了聚(N-异丙基丙烯酰胺-co-衣康酸)pH敏感性阴离子型水凝胶。图4为聚(N-异丙基丙烯酰胺-co-衣康酸)凝胶的红外光谱图。通过正交设计实验发现pH对凝胶溶胀率的影响十分显著，当pH在1-13之间变化时溶胀率可快速地从34 g/g变化到760 g/g[15]。郑施施等[16]研制一种新型羧甲基壳聚糖基pH敏感性水凝胶(图5)，发现其具有明显的孔洞结构和良好的pH响应性能，在中性磷酸盐缓冲溶液(pH=7.4)中吸水率显著大于在酸性溶液(pH=2)中的吸水率。载有磺胺嘧啶钠的羧甲基壳聚糖水凝胶在中性磷酸盐缓冲溶液(pH=7.4)中的4 h药物累计释放率可达到95%，而在酸性溶液(pH=2)中的4 h药物累计释放率却只有50%，在口服药物传输体系中有一定的应用前景。Park等[17]制备口服可控的壳聚糖交联γ-PGA合成水凝胶，其吸水率在pH=3-6之间有显著的变化，通过可溶于水的四唑实验证明：水凝胶具有良好生物相容性，并且在结肠中药物扩散速率主要依赖于pH，具有显著pH敏感性。 2.1.3 光敏感性水凝胶光敏感性水凝胶可分为可见光敏感性水凝胶与紫外光敏感性水凝胶两种，含有光敏发色团的PNIAAm水凝胶具有可见光敏感性，另外紫外光敏感性水凝胶可以通过含有二(4-二甲氨基)苯基甲烷氰化物的聚合物网状结构制得。张海璇[18]利用曲酸二棕榈酸酯为模型药物、偶氮苯-Ⅳ-琥珀酰壳聚糖聚合物和偶氮苯、壳聚糖聚合物为主要光敏感性智能载体，研究曲酸二棕榈酸酯光敏感性水凝胶智能给药系统，采用离子胶凝化法、电镜扫描法观察优选凝胶小球的表面，形态结构表征及凝胶小球的包封率、载药量、溶胀度、光敏感性等，发现在紫外光存在的条件下，该凝胶小球吸收一定波长的紫外光后释放药物，从而抑制酪氨酸酶的活性，阻断皮肤黑色素的形成，达到防治紫外线对皮肤损伤的目的。Yamamoto等[19]报道了一种光交联的聚(L-赖氨酸)多肽，此多肽的部分L-赖氨酸残基中光敏基团可以发生光交联反应获得凝胶。他们进一步报道了含有光敏基团的聚(L-鸟氨酸)多肽通过光交联反应制备凝胶[20]。"

2.1.5 温度/pH双重敏感性水凝胶同时对两种或两种以上外界刺激产生反应的智能凝胶已成为高分子缓释载体的发展方向，因pH和温度是生理生化系统中的两个重要因素，研究具有pH和温度双重敏感的水凝胶作为新型高分子材料已备受关注。Shim等[24]通过添加pH/温度敏感部分嵌段共聚物制备了一种新型的pH/温度双重敏感水凝胶，pH值在7.4-8.0变化。该溶液在pH=7.4(人体)、37 ℃形成凝胶时，可作为疏水性药物和蛋白注射的载体，并且可用来作为一个注射输送系统模板技术。陆遥遥等[25]以N-异丙基丙烯酰胺与海藻酸钠为原料，运用水溶液聚合法研制了具有温度和pH值双重敏感性的海藻酸钠/聚(N-异丙基丙烯酰胺)水凝胶。考察了在不同温度和pH值条件下，反应温度、单体浓度、交联剂用量等对该凝胶溶胀度的影响，实验表明凝胶具有良好的温度和pH敏感性能。Sun等[26]将N-异丙基丙烯酰胺和聚乙二醇(相对分子质量2 000)共混制备了具有温度和pH性双重敏感性的水凝胶薄膜，差示扫描量热法研究表明，物理共混膜表现出较低的临界溶液温度及pH值敏感性。余娟等[27]以甲基丙烯酸-2-二甲基胺基乙酯为单体，N,N’-亚甲基双丙烯酰胺为交联剂，过硫酸钾为引发剂，在35 ℃(接近人体温度)条件下，采用自由基水溶液聚合合成了聚甲基丙烯酸-2-二甲基胺基乙酯均聚物水凝胶，所合成的水凝胶具有温度和pH双重敏感性(图7)。Khurma等[28]用壳聚糖水凝胶和聚乙二醇为原料制备pH和温度双重敏感水凝胶，观察温度25，37，45 ℃时在去离子水中水凝胶的溶胀行为，利用差示扫描量热法测定了37 ℃下水凝胶在去离子水中的状态，发现其溶胀率随着凝胶中聚乙二醇浓度的增加而增加。"

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