【摘要】：作為交叉學(xué)科,生物醫(yī)學(xué)工程領(lǐng)域所研究的問題較為復(fù)雜,結(jié)構(gòu)功能單一的材料往往無法滿足研究者的需求。同時(shí)研究者們也發(fā)現(xiàn)將多種具有不同性質(zhì)的材料進(jìn)行復(fù)合,往往能為材料賦予新的結(jié)構(gòu)或者功能,而這些具有新功能的材料能更好的解決生物醫(yī)學(xué)領(lǐng)域所面臨的一些復(fù)雜問題,因此通過復(fù)合的方法制備具有新結(jié)構(gòu)或者功能的材料成為生物醫(yī)用材料的研究熱點(diǎn)之一。作為納米材料的分支之一,磁性納米材料因其較好的生物相容性和響應(yīng)外加磁場的特性受到研究者們的持續(xù)關(guān)注。近些年基于磁性納米材料的復(fù)合材料發(fā)展勢頭迅猛,而在與其復(fù)合的眾多材料中,水凝膠因其各方面的優(yōu)秀特性受到研究者們的普遍親睞。這兩種特性迥異的材料復(fù)合后產(chǎn)生了具有磁響應(yīng)功能的水凝膠復(fù)合材料。在此基礎(chǔ)上進(jìn)一步復(fù)合過程中外加磁場,可以使得復(fù)合材料獲得單一材料不具備的新結(jié)構(gòu)與功能。本文利用外加磁場輔助調(diào)控制備了一系列具有各向異性結(jié)構(gòu)和特性的磁性納米材料-水凝膠復(fù)合材料,研究了磁各向異性水凝膠的各向異性結(jié)構(gòu)與特性之間的相互關(guān)系,初步探究了其作為體外三維細(xì)胞培養(yǎng)基質(zhì)的應(yīng)用。論文的具體內(nèi)容包含以下幾個(gè)部分:1.結(jié)合靜磁場輔助組裝、磁性納米材料和水凝膠,制備了一種具有特殊取向結(jié)構(gòu)的新型磁各向異性水凝膠,該方法簡便易行,具有較好的普適性。根據(jù)模擬計(jì)算結(jié)合實(shí)驗(yàn),探究了用于制備磁各向異性水凝膠的磁性納米材料和水凝膠體系的基本要求;研究了磁性納米材料的種類、尺寸及濃度;水凝膠單體濃度及交聯(lián)劑濃度;外加磁場強(qiáng)度及組裝時(shí)間對磁各向異性水凝膠結(jié)構(gòu)的影響,并首次使用高分辨顯微CT原位表征并重建了磁各向異性水凝膠中磁性納米材料組裝結(jié)構(gòu)在空間中的分布。2.對基于靜磁場制備的磁各向異性水凝膠的力學(xué),光學(xué),磁學(xué)和在交變磁場中的發(fā)熱特性進(jìn)行了研究。具有特定取向的磁性納米材料組裝結(jié)構(gòu)對磁各向異性水凝膠在不同方向上的彈性模量有不同程度的影響,其在空間中的分布方式使得復(fù)合材料具有類似三維光柵的衍射能力。首次發(fā)現(xiàn)并報(bào)道了具有磁各向異性水凝膠在交變磁場中的可控發(fā)熱增強(qiáng)效應(yīng),并對通過研究磁各向異性水凝膠的磁學(xué)效應(yīng)對其機(jī)制進(jìn)行了初步闡釋,結(jié)果顯示這種獨(dú)特的發(fā)熱性質(zhì)可能是由磁性納米顆粒之間的相互作用引起的。這種可以通過改變磁各向異性水凝膠與外加交變磁場交角進(jìn)行控制的發(fā)熱方式使得其可以作為具有藥物控制釋放能力的載體等,結(jié)合磁各向異性水凝膠的發(fā)熱特性在腫瘤熱/化療協(xié)助作用方面具有較好的潛在應(yīng)用前景。3.首次利用交變磁場/旋轉(zhuǎn)磁場輔助制備磁各向異性水凝膠。初步探究了交變磁場/旋轉(zhuǎn)磁場對磁各向異性水凝膠結(jié)構(gòu)和特性的影響,研究了交變磁場頻率、旋轉(zhuǎn)磁場轉(zhuǎn)速等因素對磁各向異性水凝膠的影響。結(jié)果顯示交變磁場組裝可能有助于提高磁性納米材料間的相互作用;旋轉(zhuǎn)磁場能在水凝膠內(nèi)部形成類似圓餅狀的磁性納米材料組裝結(jié)構(gòu),具有這種特別結(jié)構(gòu)的磁各向異性水凝膠同樣在交變磁場中具有各向異性的發(fā)熱特性;增大旋轉(zhuǎn)磁場的轉(zhuǎn)速能提高旋轉(zhuǎn)磁場輔助制備的磁各向異性水凝膠在交變磁場中的發(fā)熱能力。4.首次利用抗細(xì)胞粘附的水凝膠和細(xì)胞粘附的磁性納米材料結(jié)合制備磁各向異性水凝膠,利用物理切割的方法將磁性納米材料組裝結(jié)構(gòu)暴露在界面上,細(xì)胞可以粘附在復(fù)合材料的表面上,通過粘附、增殖、遷移和聚集,自主形成多細(xì)胞聚集體,多細(xì)胞聚集體進(jìn)一步通過增殖和融合形成具有緊實(shí)結(jié)構(gòu)的多細(xì)胞球。細(xì)胞增殖結(jié)果顯示在此模型上生長的細(xì)胞其增殖速度遠(yuǎn)低于在細(xì)胞孔板上生長的細(xì)胞,與細(xì)胞在體內(nèi)生長的速率更接近;活\死細(xì)胞染色顯示培養(yǎng)一段時(shí)間后在多細(xì)胞球的中心部分有初步形成的死核,抗藥性測試結(jié)果顯示具有這種結(jié)構(gòu)的多細(xì)胞球可以有效的被用于腫瘤細(xì)胞體外藥物和治療手段的評價(jià);不同細(xì)胞株(正常細(xì)胞或腫瘤細(xì)胞)在磁各向異性水凝膠表面形成多細(xì)胞球的效率存在一定差異,而且可以促使一些無法在傳統(tǒng)三維細(xì)胞培養(yǎng)系統(tǒng)中形成多細(xì)胞球的細(xì)胞株形成多細(xì)胞球。這種促進(jìn)腫瘤細(xì)胞自發(fā)形成多細(xì)胞球的功能使得磁各向異性水凝膠在腫瘤體外診斷上具有良好的應(yīng)用前景。
[Abstract]:As a cross-discipline, the problems in the field of biomedical engineering are complex and the material with a single structural function is often unable to meet the needs of the researchers. At the same time, the researchers have also found that a variety of materials with different properties can be compounded, and new structures or functions can be imparted to the material, and the materials with the new function can better solve the complex problems of the biomedical field, so that the preparation of the material with the new structure or function by the composite method becomes one of the research hotspots of the biomedical materials. As one of the branch of the nano-material, the magnetic nano-material is subject to the constant attention of the researchers because of its good biocompatibility and response to the characteristics of the applied magnetic field. In recent years, the development of the composite material based on the magnetic nano-materials has developed rapidly, and in the many materials compounded with it, the water-gel is subject to the general affinity of the researchers because of the excellent characteristics of its various aspects. The two types of materials with different characteristics result in a hydrogel composite with a magnetic response function. on the basis of which, a magnetic field is added to the composite material, so that the composite material can obtain a new structure and a function that a single material does not have. In this paper, a series of magnetic nano-material-hydrogel composites with anisotropic structure and properties were prepared by external magnetic field-assisted regulation, and the relationship between the anisotropic structure and the properties of the magnetic anisotropic hydrogel was studied. The application of it as a three-dimensional cell culture matrix in vitro was studied. The specific contents of the thesis include the following parts: 1. The novel magnetic anisotropic hydrogel with special orientation structure is prepared by combining the static magnetic field auxiliary assembly, the magnetic nano material and the hydrogel, and the method is simple and convenient, and has good universality. In this paper, the basic requirements of the magnetic nano-materials and the hydrogel system for preparing the magnetic anisotropic hydrogel are investigated, and the species, the size and the concentration of the magnetic nano-materials, the concentration of the water-gel monomer and the concentration of the cross-linking agent are studied. The influence of the magnetic field strength and the time of assembly on the structure of the magnetic anisotropic hydrogel was studied, and the distribution of the magnetic nano-material in the space was reconstructed in situ by using the high-resolution micro-CT in-situ and the distribution of the magnetic nano-material in the space was reconstructed. The mechanical, optical, magnetic and heat-generating properties of the magnetic anisotropic hydrogel prepared based on the static magnetic field are studied. The magnetic nano-material assembly structure with specific orientation has different influence on the elastic modulus of the magnetic anisotropic hydrogel in different directions, and the distribution mode of the magnetic nano-material in the space makes the composite material have the diffraction capability similar to the three-dimensional grating. The controllable heating enhancement effect of the magnetic anisotropic hydrogel in the alternating magnetic field was first found and reported, and the mechanism of the magnetic anisotropic hydrogel was initially explained. The results show that this unique heating property may be caused by the interaction between the magnetic nanoparticles. this can be controlled by changing the angle between the magnetic anisotropic hydrogel and the applied alternating magnetic field so that it can be used as a carrier with a drug control release capability, etc., The heat-generating property of the combined magnetic anisotropic hydrogel has a better potential application prospect in the treatment of tumor heat/ chemotherapy. the magnetic anisotropic hydrogel is prepared by using an alternating magnetic field/ rotating magnetic field for the first time. The effect of the alternating magnetic field/ rotating magnetic field on the structure and properties of the magnetic anisotropic hydrogel was investigated. The effects of the alternating magnetic field frequency and the rotational speed of the rotating magnetic field on the magnetic anisotropic hydrogel were studied. The result shows that the alternating magnetic field assembly may help to improve the interaction between the magnetic nano-materials, and the rotating magnetic field can form a similar round-cake-like magnetic nano-material assembly structure inside the hydrogel. the magnetic anisotropic hydrogel with the special structure also has an anisotropic heating characteristic in the alternating magnetic field, the rotating speed of the rotating magnetic field is increased, and the heating capacity of the magnetic anisotropic hydrogel in the alternating magnetic field can be improved by increasing the rotating speed of the rotating magnetic field. the magnetic nano-material assembly structure is exposed on the surface of the composite material by physical cutting method for the first time, and the cell can be adhered to the surface of the composite material, and the magnetic nano-material assembly structure can be adhered and proliferated through adhesion and proliferation, migration and aggregation, self-forming multi-cell aggregates, and multi-cell aggregates further forming a multi-cell ball with a compact structure by proliferation and fusion. The cell proliferation results show that the cells grown on this model are far below the cells grown on the cell-well plates, closer to the rate at which the cells grow in vivo, and the live dead cell staining shows a preliminarily formed dead core in the central portion of the multi-cell ball after a period of incubation, the drug resistance test results show that the multi-cell ball with such a structure can be effectively used for the evaluation of the in-vitro drug and treatment means of the tumor cells; the efficiency of forming the multi-cell ball on the surface of the magnetic anisotropic hydrogel by different cell lines (normal cells or tumor cells) is different, but also a number of cell lines that are not able to form multicell spheres in a conventional three-dimensional cell culture system can be promoted to form a multi-cell ball. The function of promoting the spontaneous formation of the multi-cell ball of the tumor cell enables the magnetic anisotropic hydrogel to have a good application prospect in the in vitro diagnosis of the tumor.
【學(xué)位授予單位】：東南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：O648.17;R73-3

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