摘要
近年来,随着溃疡性肠炎,结肠癌等消化道疾病的发病率的逐年上升,消化道定位药物释放技术成为国际制药领域的一个新技术热点,通过无缆式微型机器人将药物放在特定区域,研究药物在消化道不同区域的吸收特性,对于新药的开发和提高传统药物的有效性都有很大的帮助。
本文分析了微型药物释放机器人的功能要求,提出了系统性的解决方案。在分析了人体消化道生理参数及功能特征的基础上,论证了机器人被动行走方案的可行性。对微型药物释放机器人的主体结构以及密封方案进行了合理的设计。通过对各种驱动方案的分析,选择了合理的驱动机构,对压缩弹簧进行了受力分析。提出通过检测永磁体空间磁场参数的变化从而实现对微型机器人在消化道的定位。探讨了一种基于磁荷模型的圆柱型永磁体空间磁场的数值计算方法。将置于机器人内的圆柱型永磁体等效为磁偶极子,建立了基于磁偶极子模型的磁定位方程。设计了基于HMC1023磁阻传感器的永磁定位信号处理电路。研究了压缩弹簧驱动机构的触发释放方式,提出了基于磁场触发的干簧管熔断电路与纯磁力机构两种触发方式。
搭建药物驱动装置的压缩弹簧刚度测试试验台,得到了较为精确的弹簧刚度值。在定性分析干簧管导通磁场的基础上,通过实验测试了干簧管管脚的长短与弯曲程度对其导通磁场的影响,并提出了导通磁场的最佳设置方向。为了确认药物是否释放,设计了反馈信号电路,并应用电路仿真软件Multisim对西勒振荡电路进行了模拟仿真,制作了插板电路,用小型信号接收电视机进行了信号测试,结果表明,信号发射电路是完全可行的。用纯磁力机构的压缩弹簧释放方式成功模拟了药物释放试验。
In recent years, as the incidence of ulcerative enteritis,colon cancer and other gastrointestinal diseases are increasing year by year, the site—specific drug delivery technology (SSDDT) has become a focus areas of international pharmaceutical drugs. Releasing drugs to specific areas in alimentary Canal by non-cable-type micro-robot and studying absorption characteristics of drugs at different regions, which are very helpful for development of new drugs and improving the effectiveness of traditional medicines.
Based on analyzing the functional requirements of micro drug release robot, a systemic solution was proposed. The functional characteristics and physiological parameters of the human digestive tract were analyzed. The passive walking micro-robot program’s feasibility was demonstrated. The micro-robot’s main structure and sealing system were designed reasonably. A reasonable drive mechanism was selected through the analysis of the various options. The force analysis of the compression springs was done. A location mode to achieve the positioning of the micro-robot in alimentary Canal by detecting spatial magnetic field parameters was proposed. A numerical calculation of magnetic charge model based on cylindrical permanent’s magnet magnetic field was studied. The cylindrical permanent magnet inside micro-robot was equivalent to magnetic dipole. The magnetic orientation equation based on magnetic dipole model was established. The permanent-magnet positioning signal processing circuit was designed based on HMC1023 magnetoresistive sensors. The triggering means of the compression spring drive mechanism was studied. Two trigger ways were proposed based on magnetic reed switch fuse circuit and pure magnetic mechanism respectively.
Stiffness test platform of drug drive compression spring was built and the relative accurate stiffness value was got. Conduction magnetic field of reed switch was analyzed qualitatively. The experiment for testing influence of the reed switch length of reed-pin and bending to its triggering magnetic field was done. The best on-field direction setting was proposed. A feedback signal circuits was designed in order to confirm whether the drugs is released. The circuit simulation software Multisim was applied to simulate a Hilary oscillator circuit. A small TV signal reception was used to test the signal of the flapper circuit. The result demonstrated that the signal transmission circuit is completely feasible. The drug release experiment of compression spring model with pure magnetic mechanism trigger was successful.
引文
[1]温诗铸.关于微机电系统的研究[J].中国机械工程,2003,14(2):159-163.
[2]王立鼎,刘冲.微机电系统科学与技术发展趋势[J].大连理工大学学报,2000,40(5):505-508.
[3]刘莹,温诗铸.微机电系统中微摩擦特性及控制研究[J].机械工程学报,2002,38(3):1-5.
[4]白杨,张亚历.胶囊内镜的临床应用[J].中华消化内镜杂志,2002,19(5):318-319.
[5]张晗,刘鹏年,崔雷.国外消化性溃疡文献研究热点的分析[J].世界华人消化杂志,2007,15(100):1150-1155.
[6]田丰民,陈向东,李向东.无线内窥镜[J].仪器仪表学报,2003,24(4):212-214.
[7] Lorenzo-Lamosa M.L., Remunan-Lopez C., Vila-Jato J.L., et al. Design of microencapsulated chitosan microspheres for colonic drug delivery [J]. Journal of Controlled Release,1998,52(4):109-118.
[8] Wilding I. Site-specific drug delivery in the gastrointestinal Tract [J]. Critical reviews in therapeutic drug carrier systems, 2000, 17(6): 557-561.
[9]刘洪英,郑小林等.消化道定位药物释放技术及其在新药中的利用[J].中国药学杂志,2006.40(13):970-972.
[10]皮喜田,彭承琳,郑小林,等.用于药物吸收研究的消化道定点释放药丸系统研究进展[J].北京生物医学工程,2005,24(3):230-232.
[11] Hugemann B., Ammain F., Schuster O., et al. Device for the release of substances at defined locations in alimentary tract[P]. US patent: 326 825, Dec.2, 1981.
[12] Lambert A., Vaxman F., Crenner F., et al. Autonomous telemetric capsule to explore the small bowel [J]. Med. & Biol. Eng &Computer, 1991, 29(3):191-196.
[13] Schentag J. J., Andrea E.D. Telemetry capsule and process[P]. US patent: 707 842, May 30, 1991.
[14] Casper R. A., Michael L., Jochem W. J., et al. Medical capsule device actuated by radio-frequency signal[P]. US patent: 591 838, Oct. 2, 1990.
[15] Parr A. F., Sandefer E. P. Wissel P., et al. Evaluation of the Feasibility and use of a Prototype Remote Drug Delivery Capsule for Non-Invasive Regional Drug Absorption Studies in the GI Tract of Man and Beagle Dog[J]. Pharmaceutical Research, 1999, 6(2):266-271.
[16] Houzego P.J., Morgan P.N., Hirst P. H., et al. Ingestible device[P]. US patent:09/742 936,Dec. 20,2000.
[17] Wilding I., Hirst P., Connor A. Development of a new engineering-based capsule for human drug absorption studies [J]. Research focus, 2000, 3(11):385-392.
[18]皮喜田,彭承琳,郑小林,等.用于人体药物吸收研究的定点释放药丸系统研制[J].中国生物医学工程学报,2003,23(6):579-582.
[19]李韪韬,王惠南.胶囊内窥镜的研究进展[J].医疗设备信息,2005,20(2):36-37.
[20] Richert H., Surzhenko O., Wangemann S., et al. Development of a magnetic capsule as a drug release system for future applications in the human GI tract[J].Journal of Magnetism and Magnetic Materials,2005,65(1):497-500.
[21] Gr?ning R., Danco I., Müller R.S. Development of sensor elements to control drug release from capsular drug delivery systems [J]. International Journal of Pharmaceutics,2007,24(3):61-64.
[22] Yang L.B., Chu J.S., Fix J. A. Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation [J]. International Journal of Pharmaceutics,2002,235(1-2):1-15.
[23] Ishibashi T., Hatano H., Kobayashi M., et al. Design and evaluation of a new capsule-type dosage form for colon-targeted delivery of drugs [J]. International Journal of Pharmaceutics,1998,168 (1) :31–40.
[24]胡鸿胜.基于磁力驱动的药物释放微机电系统的研究[D].广州:华南理工大学,2009.
[25] Philips’intelligent pill targets drug development and treatment for digestive tract diseases [EB/OL]. http://www.research.philips.com, 2008-11-11.
[26]张瑞侠.磁控微型机器人驱动控制特性的研究[D].大连:大连理工大学,2005.
[27]皮喜田,彭承琳,郑小林,等.一种消化道定点药物释放工程药丸系统的研制[J].中国医疗器械杂志,2004,28(5):319-321.
[28]皮喜田彭承琳郑小林,等.一种体内微型医疗装置磁标记定位系统的人机操作平台设计[J].医疗卫生设备,2008(8):10-11.
[29]唐伟,陈科,彭承琳,等.基于MEMS药物释放技术的试验研究[J].华南国防医学杂志,2008,22(3):6-9.
[30]刘洪英,皮喜田,周承文,等.基于MEMS的消化道定点释药微系统研究[J].传感技术学报,2008,21(3):381-384.
[31] Liu H.Y., Pi X.T., Zhou C.G., et al. Design of Site Specific Delivery Capsule based on MEMS [C]. Proceedings of the 3rd IEEE Int. Conf. on Nano/Micro Engineered and Molecular Systems, 2008: 498-501.
[32]姜萍萍,颜国正,王文兴.人体消化道微型介入式诊疗系统的研制[J].机器人技术与应用,2003(4):33-35.
[33]姜萍萍,颜国正,郭旭东,等.用于体内胶囊式遥测系统的电磁跟踪定位方法[J].光学精密工程,2007,15(8):1247-1252.
[34]姜萍萍,颜国正,田社平,等.人体全消化道生理参数遥测胶囊体外连续跟踪定位方法[J].上海交通大学学报,2005,39(6):864-868.
[35]郭旭东,颜国正,何文辉.全消化道微型诊查胶囊的遥测定位[J].航天医学与医学工程,2007,20(4):294-298.
[36]郭旭东,颜国正,何文辉.介入式微型医疗装置连续定位系统的建模[J].系统仿真学报,2007,19(15):3582-3585.
[37]郭旭东,颜国正,何文辉.交流励磁三维定位系统中磁传感器设计[J].仪器仪表学报,2007,28(7):1211-1216.
[38]郭旭东,颜国正,何文辉,等.基于电磁感应的遥测式三维定位系统[J].上海交通大学学报,2007,41(11):1753-1757.
[39]马官营,颜国正,何秀.基于电磁感应的消化道内微系统的无线供能[J].上海交通大学学报,2008,42(5):1753-1757.
[40]马官营,颜国正.基于电磁感应的消化道内微系统无线能量传输问题研究[J].生物医学工程学杂志2008,25(1):61-64.
[41]梁浩,朱文坚,黄平.体内胶囊式药物释放微机电系统机构设计研究[J].现代制造工程,2004(2):19-21.
[42]梁浩,朱文坚,黄平.基于MEMS的体内药物释放微机构的研制与改进[J].机电工程技术,2006,35(8):66-67.
[43]王亚珍,朱文坚,黄平.胶囊式胃肠道取样微机电系统的设计研究[J].现代制造工程,2004(5):16-18.
[44]王亚珍,朱文坚.新型胶囊式胃肠道取样微机电系统的设计与试验研究[J].机电工程技术,2006,35(8):79-80.
[45]陈扬枝,魏劲松,肖剑.一种超声触发控制方法及装置[ P ].中国专利:200810029211, 2008-07-03.
[46]陈扬枝,魏劲松,肖剑.利用超声触发控制的化学反应气压式肠胃道药物释放装置[ P ].中国专利: 200810029085,2008-11-12.
[47]陈扬枝,魏劲松,肖剑.消化道定点药物释放系统研究进展[J].现代制造工程,2009(1):136-141.
[48]荣东平.人体胃肠道给药机器人微型化的研究[D].广州:华南理工大学, 2008.
[49]罗海堤,李洁,黄平.微机器人在消化道内摩擦行为的研究[J].世界华人消化杂志,2005,13(17):2115-2118.
[50]王亚珍.人体胃肠道取样微机器人的设计与研究[D].广州:华南理工大学, 2005.
[51]李洁,黄平,罗海堤.体内微机构与动物肠道摩擦实验研究[J].润滑与密封,2006(3):119-122.
[52]梁浩.胃肠道用微胶囊药物释放微机电系统的设计与研究[D].广州:华南理工大学,2004.
[53]何文辉,颜国正,郭旭东.人体消化道无创检测胶囊定位系统的研究进展[J].生物医学工程学杂志,2008,25(1):196-199.
[54]王泽忠,全玉生,卢斌先.工程电磁场[M].北京:清华大学出版社, 2004.
[55] Harrold W.J. Calculation of equipotentials and flux Lines in axially symmetrical permanent magnet assemblies by computer [J]. IEEE Transactions on magnetics, 1972, 8(1):23-29.
[56] Kalimov A.G., Svedentsov M.L. Three-dimensional magnetostatic field calculation using integro- differential equation for scalar potential [J]. IEEE Transactions on magnetics, 1996,32(3):667-670.
[57] Morisue T., Fukumi M. 3-D magnetostatic field calculation using the magnetic vector potential and boundary integral equation method [J]. IEEE Transactions on magnetics,1987, 23(5): 3311-3313.
[58]孙雨施.关于永磁的计算模型[J].电子学报,1982(5):86-89.
[59]汤双清,沈洁,陈习坤,等.基于磁荷模型的永磁体空间磁场的有限元分析与计算[J].三峡大学学报,2003,25(5):452-455.
[60]夏平畴.永磁机构[M].北京:北京工业大学出版社,2000.
[61]雷银照.电磁场[M].北京:高等教育出版社.
[62]侯文生,郑小林,彭承琳,等.体内微型诊疗装置磁定位简化模型的实验研究[J].仪器仪表学报,2005,26(9):895-901.
[63]郭旭东,颜国正,何文辉.胶囊状全消化道介入诊查装置的三维磁定位[J].北京生物医学工程,2007,26(3):225-259.
[64]李金,郑小林,侯文生,等.消化道诊疗胶囊三维磁定位系统的误差修正[J].传感器与微系统,2008,27(11):93-99.
[65]裴轶,虞南方,刘奇,等.各向异性磁阻传感器的原理及其应用[J].仪表技术与传感器, 2004(8): 26-28.
[66]周勋,梁冰清,唐文俊,等.磁电阻效应的研究进展[J].物理实验,2000,20(9): 13-16.
[67]王利容.胃肠道取样微机电系统及其定位技术的研究[D].广州:华南理工大学, 2005.
[68] Dibbern U. Magnetic field sensors using the magnetoresistive effect [J].Sensors and Actuators, 1986, 10(2):127-140 .
[69]姚学标,郑万鎏,柳宗英,等.铁磁金属薄膜磁阻传感器的研制[J].安徽大学学报, 1995, 15 (1): 40-44.
[70]何文辉,颜国正,郭旭东.基于磁阻传感器的消化道诊查胶囊的位置检测[J].仪器仪表学报,2006,27(10):1187-1190.
[71]磁阻传感器HMC/HMR系列介绍[EB/OL]. http:www.sensor-ic.com, 2010-1-6.
[72]磁阻传感器三维磁阻微电路芯片(HMC1023)[EB/OL]. http://www.honeywell- sensor.com.cn, 2010-1-6.
[73]昝鹏,颜国正,何文辉,等.一种人体消化道无创诊查胶囊磁定位系统的设计[J].测试技术,2006,25(9):58-60.
[74]彭小燕,彭承琳,侯文生,等.一种用于体内微型诊疗装置定位的磁场检测电路设计[J].医疗卫生设备,2003(12):7-8.
[75]侯文生,郑小林,彭承琳,等.基于永磁体空间磁场检测的体内微型诊疗装置定位系统的研究[J].北京生物医学工程,2004,23(2):81-87.
[76]曾昭旺,朱文坚.药物释放微胶囊控制电路的设计与研究[J].现代制造工程,2009(8):37-41.
[77]佟为明,翟国富,张文义,等.低压电器继电器及其控制系统[M].哈尔滨:哈尔滨工业大学出版社, 2000.
[78]李丽云.干簧继电器研究现状与进展[J].中国水运,2007,7(3):62-64.
[79]张文义,刘茂恺.永久磁铁在干簧继电器中的应用[J].机电元件,2001,21(1):11-12.
[80]栾华东.高频电子线路[M].西安,西北工业大学出版社,2003.
[81]童诗白,华成英.模拟电子技术基础[M].北京:高等教育出版社,2000.
[82]刘福太,张立民,修建华,等.电子线路学习指导与习题详解[M].北京,国防工业出版社,2002.
[83]唐赣,吴翔,苏建峰.Multisim 10 & Ultiboard 10原理图仿真与PCB设计[M].北京,电子工业出版社,2008.
