聚合物基MEMS技术在生物医学上的应用研究
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摘要
MEMS技术是近年来随着硅微加工技术发展起来的一种微加工技术,通过光刻等技术,可以在微米甚至纳米尺度上制备元器件。近几年来,在MEMS领域中出现了柔性MEMS和Bio-MEMS技术。柔性MEMS技术在柔性基底上加工出微米尺度的器件,这样制备的器件具有能经受冲击、能够折叠弯曲等优点;而Bio-MEMS技术利用MEMS技术制造体外分析诊断器件和体内植入器件。
随着有机聚合物化学的发展,近年来人们开发出各种聚合物材料,这些聚合物材料具有各种优良的加工性能和生物相容性,在生物医学领域得到了广泛的应用。本论文主要研究在高分子聚合物聚酰亚胺柔性基底上制备生物电极阵列和环氧SU-8胶在乳腺癌细胞培养方面的应用。
视网膜视觉修复是通过对盲人视网膜植入微电极阵列,利用电信号刺激视网膜神经,从而使盲人产生光幻视,修复盲人的视觉的治疗方法。在视网膜视觉修复中,生物电极阵列作为人造器件与生物神经交互作用的桥梁,其性能对生物电刺激的传输起着举足轻重的作用。由于视网膜分辨率为微米尺度,所以可以用MEMS技术来制备生物电极阵列。目前已有制备成功的二维平面生物电极阵列。
随着人们对细胞培养研究的深入,人们发现三维微米或纳米微结构中培养的细胞能够显示出与二维平面上培养的细胞不同的性能。由于MEMS能够制备尺寸很小的器件,在体内植入器件制备方面具有得天独厚的优势
本论文研究的一个内容是视网膜视觉修复三维生物电极阵列的研制。应用MEMS工艺,采用MEMS工艺中通用的溅射、RIE刻蚀、光刻、电铸等方法,结合聚酰亚胺的特性,我们成功的在柔性聚酰亚胺基底上制备成功了一种三维生物电极阵列。我们主要解决了聚酰亚胺与引线间结合力问题、电极生物相容性保护问题和电极的露出问题,以及柔性基底与刚性基片的分离问题。与二维平面电极不同,我们制备的三维电极阵列电极部分能够凸出基底表面,与体液良好接触。由于采用聚酰亚胺柔性基底,我们制备的生物电极阵列具有较好的柔性。阻抗测试结果表明,在频率为20 Hz到10 kHz之间时,在生理盐水中单个电极阻抗为22 kΩ到8 kΩ。我们制备的生物电极阵列具有较小的阻抗,能够减少电刺激信号在电极阵列上的损耗。适合作为研究视网膜神经信号的工具。
本论文研究的另一个内容是我们通过采用MEMS制造技术,利用SU-8光刻胶在微米尺度制造了带有不同深宽比的沟槽、五角星、齿轮,与乳腺癌细胞株MCF-7细胞共同培养,采用形态学观察、MTT分析以及流式细胞仪检测这些微结构对乳腺癌细胞生长的影响,以探讨这些微结构在肿瘤治疗方面的潜在应用前景。
MEMS technology is a kind of micro manufacture technology which developed along with silicon micro manufacture technology. By process such as photolithograph, we can manufacture device of micro or nano dimension. Flexible MEMS and Bio-MEMS have appeared in MEMS domain recent several years. Device of micrometer dimension on flexible substrate can be manufactured by flexible MEMS technology, and these devices have the virtue that they can bear impact and can be curved; in vitro diagnostic device and in vivo device can be manufactured by Bio-MEMS technology.
With developing of organic compound technology, recent year people developed kinds of polymer material, which has good fabrication character and good biocompatibility. These organic compounds are used widely in medical domain. This thesis mainly focuses on fabricating bioelectrode array on organic compound PI substrate and application of epoxy based SU-8 in breast cancer MCF-7 cell culture.
Retinal Prosthesis is a therapy method that through implant micro electrode array on retina of blind people, using electric signal stimulate retina, and cause the blind to see vision. In Retinal Prosthesis, bioelectrode array, as the bridge between artificial instrument and nature neuron, is most important to transmittance of electric signal. We manufacture bioelectrode array using MEMS technology, for the resolution on retina is of micro dimension. Now some two dimensional bioelectrode arrays have been developed.
With further research to cell culture, people find that cell cultured in three dimensional structure of micro or nano dimension differs from ones that cultured in two dimensional structures. Bio - MEMS has the nature advantages in in vivo device manufacture for its small dimension.
First subject of this thesis is that we developed a kind of 3-D bioelectrode array used in retinal prosthesis. Using common MEMS technology such as sputtering, RIE, photolithography, electroforming, etc, combine with character of PI(Polyimide), we manufactured a kind of 3-D bioelectrode array on flexible substrate successfully. We solved the problems in process technology, which include adhesion force between PI and wire, electrode biocompatibility protection, emerge of electrode, and peeling apart of flexible substrate. Differ from two dimensional bioelectrode array, 3-D bioelectrode array electrodes protrude from substrate surface and can contact with tissue more fully. Our bioelectrode array is flexible because we use polyimide as the substrate. Impedance test result indicates that the impedance of single electrode is from 22 kΩto 8 kΩwhen frequencies vary from 20 Hz to 10 kHz. The impedance of our bioelectrode is small, as a result, it consume less energy on bioelectrode array when electric signal pass through it. It is suitable to use three dimensional bioelectrode arrays as a tool of researching retinal neural signals.
The other subject of this thesis is that we manufactured SU-8 grooves, pentacle and gear structures of micro dimension with different deep wide ratio using MEMS technology. We cultured breast cancer MCF-7 cells in micro structures. Configuration observation, MTT check and flow cytometry were used to check effect of microstructures on breast cancer MCF-7 cells to research potential application in tumor therapy of micro structures.
随着有机聚合物化学的发展,近年来人们开发出各种聚合物材料,这些聚合物材料具有各种优良的加工性能和生物相容性,在生物医学领域得到了广泛的应用。本论文主要研究在高分子聚合物聚酰亚胺柔性基底上制备生物电极阵列和环氧SU-8胶在乳腺癌细胞培养方面的应用。
视网膜视觉修复是通过对盲人视网膜植入微电极阵列,利用电信号刺激视网膜神经,从而使盲人产生光幻视,修复盲人的视觉的治疗方法。在视网膜视觉修复中,生物电极阵列作为人造器件与生物神经交互作用的桥梁,其性能对生物电刺激的传输起着举足轻重的作用。由于视网膜分辨率为微米尺度,所以可以用MEMS技术来制备生物电极阵列。目前已有制备成功的二维平面生物电极阵列。
随着人们对细胞培养研究的深入,人们发现三维微米或纳米微结构中培养的细胞能够显示出与二维平面上培养的细胞不同的性能。由于MEMS能够制备尺寸很小的器件,在体内植入器件制备方面具有得天独厚的优势
本论文研究的一个内容是视网膜视觉修复三维生物电极阵列的研制。应用MEMS工艺,采用MEMS工艺中通用的溅射、RIE刻蚀、光刻、电铸等方法,结合聚酰亚胺的特性,我们成功的在柔性聚酰亚胺基底上制备成功了一种三维生物电极阵列。我们主要解决了聚酰亚胺与引线间结合力问题、电极生物相容性保护问题和电极的露出问题,以及柔性基底与刚性基片的分离问题。与二维平面电极不同,我们制备的三维电极阵列电极部分能够凸出基底表面,与体液良好接触。由于采用聚酰亚胺柔性基底,我们制备的生物电极阵列具有较好的柔性。阻抗测试结果表明,在频率为20 Hz到10 kHz之间时,在生理盐水中单个电极阻抗为22 kΩ到8 kΩ。我们制备的生物电极阵列具有较小的阻抗,能够减少电刺激信号在电极阵列上的损耗。适合作为研究视网膜神经信号的工具。
本论文研究的另一个内容是我们通过采用MEMS制造技术,利用SU-8光刻胶在微米尺度制造了带有不同深宽比的沟槽、五角星、齿轮,与乳腺癌细胞株MCF-7细胞共同培养,采用形态学观察、MTT分析以及流式细胞仪检测这些微结构对乳腺癌细胞生长的影响,以探讨这些微结构在肿瘤治疗方面的潜在应用前景。
MEMS technology is a kind of micro manufacture technology which developed along with silicon micro manufacture technology. By process such as photolithograph, we can manufacture device of micro or nano dimension. Flexible MEMS and Bio-MEMS have appeared in MEMS domain recent several years. Device of micrometer dimension on flexible substrate can be manufactured by flexible MEMS technology, and these devices have the virtue that they can bear impact and can be curved; in vitro diagnostic device and in vivo device can be manufactured by Bio-MEMS technology.
With developing of organic compound technology, recent year people developed kinds of polymer material, which has good fabrication character and good biocompatibility. These organic compounds are used widely in medical domain. This thesis mainly focuses on fabricating bioelectrode array on organic compound PI substrate and application of epoxy based SU-8 in breast cancer MCF-7 cell culture.
Retinal Prosthesis is a therapy method that through implant micro electrode array on retina of blind people, using electric signal stimulate retina, and cause the blind to see vision. In Retinal Prosthesis, bioelectrode array, as the bridge between artificial instrument and nature neuron, is most important to transmittance of electric signal. We manufacture bioelectrode array using MEMS technology, for the resolution on retina is of micro dimension. Now some two dimensional bioelectrode arrays have been developed.
With further research to cell culture, people find that cell cultured in three dimensional structure of micro or nano dimension differs from ones that cultured in two dimensional structures. Bio - MEMS has the nature advantages in in vivo device manufacture for its small dimension.
First subject of this thesis is that we developed a kind of 3-D bioelectrode array used in retinal prosthesis. Using common MEMS technology such as sputtering, RIE, photolithography, electroforming, etc, combine with character of PI(Polyimide), we manufactured a kind of 3-D bioelectrode array on flexible substrate successfully. We solved the problems in process technology, which include adhesion force between PI and wire, electrode biocompatibility protection, emerge of electrode, and peeling apart of flexible substrate. Differ from two dimensional bioelectrode array, 3-D bioelectrode array electrodes protrude from substrate surface and can contact with tissue more fully. Our bioelectrode array is flexible because we use polyimide as the substrate. Impedance test result indicates that the impedance of single electrode is from 22 kΩto 8 kΩwhen frequencies vary from 20 Hz to 10 kHz. The impedance of our bioelectrode is small, as a result, it consume less energy on bioelectrode array when electric signal pass through it. It is suitable to use three dimensional bioelectrode arrays as a tool of researching retinal neural signals.
The other subject of this thesis is that we manufactured SU-8 grooves, pentacle and gear structures of micro dimension with different deep wide ratio using MEMS technology. We cultured breast cancer MCF-7 cells in micro structures. Configuration observation, MTT check and flow cytometry were used to check effect of microstructures on breast cancer MCF-7 cells to research potential application in tumor therapy of micro structures.
引文
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