Minimally Invasive Diagnostics And Treatment Using Micro .
Minimally Invasive Therapy. 2006; 15:4; 218–225ORIGINAL ARTICLEMinimally invasive diagnostics and treatment using micro/nanomachiningYOICHI HAGA1, TADAO MATSUNAGA1, WATARU MAKISHI1, KENTARO TOTSU2,TAKASHI MINETA3 & MASAYOSHI ESASHI31Tohoku University Biomedical Engineering Research Organization (TUBERO), Sendai, Japan, 2Hirosaki UniversityFaculty of Science and Technology, Aomori, Japan, and 3Graduate School of Engineering, Tohoku University, Sendai, JapanAbstractSeveral medical tools with various functions have been developed for minimally invasive diagnostics and treatment.Microfabrication techniques such as MEMS technology are useful for the realization of high-performance multifunctionalminimally invasive medical tools with small sizes. An ultra-miniature pressure sensor and an intravascular ultrasonicforward-viewing imager have been developed as microsensors for use in the human body. Active bending catheters havebeen developed for steering catheter tips without using traction of wires from outside the body. An ultrasonic therapeutictool for sonodynamic therapy and sonoporation, and a micro scanner for precise laser treatment have been developed astherapeutic tools for use in the human body. High-functionalized endoscopic tools and catheters will enable more preciseand safe diagnostics and therapy, as well as novel diagnostics and treatment which have been impossible to date.Key words: Minimally invasive treatment, micromachining, MEMS, catheter, endoscopeIntroductionMedical tools for use in the human body, such ascatheters and endoscopic tools, need to be thin orsmall. With the progress of minimally invasivediagnostics and treatment techniques and theincreasing number of their applications, thesemedical tools must not only be thin or small, butmust also be capable of performing several functions. To meet these demands, microfabricationtechniques such as MEMS (Micro ElectroMechanical Systems) technology, in addition tonew material technology, are effective. MEMS is atechnology which deals with the fabrication ofmechanical structures on silicon wafers using integrated circuit (IC) processing techniques, such asphotolithography and silicon etching. A MEMSdevice can incorporate several functions, such assensor, actuator, and microelectronics. We havedeveloped several microsensors and microactuation systems for mounting in intravascular andendoscopic medical tools for the realization ofhigh-performance and multifunctional minimallyinvasive medical tools.Active catheter and active guide wireActive catheterActive catheters and active guide wires whichincorporate microactuators at their tips and arecontrolled from outside the body have been developed (1). These actuators, which incorporate Ti–NiShape memory alloy (SMA) microcoils, are capableof several motions such as torsional and extendingmotions. The actuation method and actuatormechanism design are relatively simple, since whenthe wire diameter of the coil is small (e.g. 50–100 mm), the coils can be actuated by the direct flowof electrical current through the SMA with no heateror cooler. A bias spring made of metal such asstainless steel restores the catheter shape and enablesrepeatable motion. By keeping the SMA microcoilCorrespondence: Y. Haga, Tohoku University Biomedical Engineering Research Organization (TUBERO), 6-6-01, Aza-Aoba Aramaki, Aoba-ku, Sendai,Japan 980-8579. E-mail: haga@cc.mech.tohoku.ac.jpISSN 1364-5706 print/ISSN 1365-2931 online # 2006 Taylor & FrancisDOI: 10.1080/13645700600836224
Minimally invasive diagnostics and treatment using micro/nano machiningactuator, which generates heat, separated from thecatheter surface, the catheter can be actuated with asufficiently low surface temperature to be safe in thehuman body. One application of the active bendingmechanism is the bending of a long intestinal tube.Intestinal obstruction (ileus) is a serious passagedisorder in the intestines, which is often treatednonoperatively by the insertion of a long intestinaltube made of silicone rubber into the intestine,followed by depressurization by continuous suctionfrom outside the body. A doctor inserts the tube intothe patient’s nasal cavity and pushes it forward fromoutside the body, while monitoring its position using xray fluoroscopy. It is difficult to maneuver the tubethrough the lower opening of the stomach (pylorus)due to its narrowness. For precise manipulation of thetip of the tube, a 40 mm long unidirectional activebending mechanism using an SMA microcoil actuatoris mounted in the tube for easy passage through thepylorus as shown in Figure 1. This tube can also utilizegravity to facilitate manipulation of the tip byincorporating stainless steel weights at the tip as aconventional manipulation method. The externaldiameter of the bending part is approximately 6 mm.Its bending angle is controlled by changing the dutyratio by pulse width modulation (PWM). Bendingcharacteristics are shown in Figure 2. The maximumbending angle is 110 and the radius of curvature is20 mm (2). An active bending electric endoscopeusing SMA microcoil actuators has also been developed not only for intestinal use but also for inspectionwithin the abdominal cavity as shown in Figure 3. ACCD (charge-coupled device) imager (410,000 pixels)is mounted at the end of the endoscope, and the tip hasan omni-directional bending mechanism using threeSMA coil actuators (3).Microfabrication technology of shape memory alloy(SMA)A new batch fabrication process for the creationof flat meandering SMA microactuators fromFigure 1. Active bending long intestinal tube.219Figure 2. Bending characteristics.Figure 3. Active bending electric endoscope using SMA microcoilactuators.40–50 mm thick Ti-Ni alloy sheets or small diameterTi-Ni alloy tubes using electrochemical pulsedetching has been developed (4). An active bendingguide wire 0.5 mm in outer diameter (describedbelow) uses a microactuator fabricated by thismethod. To simplify the assembly process of theSMA actuators, three meandering actuators areformed from an SMA tube using photolithographicresist patterning and electrochemical etching asshown in Figure 4. Alternatively, the use of femtosecond laser ablation allows micromachining ofmemorized SMA with no deterioration of its shapememory effect, since the laser pulse width is veryshort (10215 s), such that heat generation is sufficiently reduced during laser machining. Severaldesigns of SMA microactuators can be realized withlaser machining (5).
220Haga et al.Figure 6. Hydraulic active bending catheter.Figure 4. SMA actuator fabricated from Ni-Ti tube usingphotolithography and etching (external diameter: 0.5 mm).Active bending guide wireAn active bending guide wire 0.5 mm in outerdiameter has been developed. This device incorporates a Ti-Ni meandering SMA actuator, whichbends unidirectionally by supplying electrical current to the SMA as shown in Figure 5 (6). Severalapplications for this device are expected, such as therecanalization of chronic total occlusion in bloodvessels. Although the tip of the guide wire bends inunidirectionally, omnidirectional insertion can beperformed by rotating the wire from outside thebody. It is preferable that the external diameter ofthe tool be v0.35 mm (0.014 inch) for severalintravascular surgical procedures.Hydraulic active bending catheterA small diameter active bending catheter, with abending motion controlled by suction of liquid in thecatheter, has been developed (Figure 6) (7). Thecatheter is made of a Ti-Ni super elastic alloy (SEA)tube which is processed by laser micromachining,and a silicone rubber tube which covers the outsideof the SEA tube. The active catheter is filled withwater and its bending angle is controlled fromoutside the body by suction of the water. The tipof the silicone rubber tube functions as a valve andcloses by initial suction of the water, and the catheteris bent by subsequent suction. The bending anglecan be controlled by regulation of suction. In theprocessed SEA tube, a line of rings is connected withmeandering beams to allow a large bending angle.Figure 5. Active bending guide wire (external diameter: 0.5 mm) (a) tube type, (b) without external membrane.
Minimally invasive diagnostics and treatment using micro/nano machining221The external diameter of the fabricated activebending catheter is 0.94 mm, with an internaldiameter of 0.85 mm. The maximum bending angleof 160 and curvature radius of 1.4 mm wereobtained with a 9 mm long bending part. The activecatheter is effective for navigating difficult bloodvessel branches with highly acute angles, and theselective embolization of arteries for treatment oftumors, such as myoma of the uterus.Microsensors for diagnostics and treatment inthe human bodyUltra-miniature fiber-optic pressure sensorA fiber-optic pressure sensor 125 mm in diameter isshown in Fig. 7 (8). A 0.7 mm thick SiO2 diaphragmis formed at the end of an optical fiber using MEMStechnology. Deformation of the diaphragm inducedby pressure, such as blood pressure, is detected byinterferometric spectrum change of white light.Experiments on animals have been carried out andthe monitored blood pressure in the left ventricle of agoat is shown in Figure 8. Because of the ultraminiature sensor head, this sensor can be used in asmall-diameter blood vessel or a stenosed vessel. Itcan also be utilized for simultaneous multi-pointmeasurement by incorporating more than one sensorin a tool, such as a catheter or a guide wire.Furthermore, this sensor is expected to be useful inmultifunctional interventional tools. The siliconcolumn sensing element is batch fabricated on asilicon wafer by MEMS process, and is then bondedto the half-mirror coated optical fiber end. Afterbonding, unnecessary silicon column parts areremoved by xenon difluoride (XeF2) etching. Asthe diameter of the silicon column is 120 mm,approximately 100,000 sensor elements can beFigure 8. Continuous display of blood pressure in left ventricle ofgoat.fabricated from a 4 inch silicon wafer. In animalexperiments using a rat, dynamic blood pressurechanges in the carotid artery have been successfullymonitored.Intravascular forward-viewing ultrasonic imagerAn intravascular forward-viewing ultrasonic probe atthe tip of a catheter has been developed (9). Threedimensional visual information can be acquiredwithout touching lesions in a blood vessel, such asstenosed lesions or occlusions. The system isexpected to enable safer and more precise intravascular treatment. The ultrasonic probe has eightseparated ring array 1–3 composite transceivers,which consist of PZT rod arrays in a polymer matrix.To obtain sufficiently low ultrasound beam directivityto be suitable for image construction algorithms, each1–3 composite transducer has a convex shape, createdby pressing between a polymer base and a metal moldwhich was fabricated using a high-speed millingmachine (Figure 9) (10). Image construction isperformed by computerized ultrasonic time-of-flightprocessing. A preliminary image construction test hasbeen successfully performed using the fabricatedforward-viewing ultrasonic probe, with a diameterof 3 mm and a working channel of 0.5 mm.Micro treatment tools for use in the human bodyUltrasonic therapeutic tool for sonodynamic therapy andsonoporationFigure 7. Ultra-miniature fiber-optic pressure sensor.In recent years, sonodynamic therapy, which usesa synergistic combination of ultrasound and a
222Haga et al.intensity distribution of the fabricated probe, andpeak intensity was 25 W/cm2. GFP plasmid DNA asa reporter gene that expresses green fluorescenceprotein was transferred in Chinese hamster ovary(CHO) cells, and green fluorescence was observed.Microbubble Optison, an ultrasound contrast agent,was simultaneously administered to enhance ultrasound-induced transfer. Injection of drugs, plasmidDNA, and ultrasound transmission gel will beperformed via a through hole 500 mm in diameter.2D micro scanner for precise laser treatmentFigure 9. Intravascular forward-viewing ultrasonic imager.chemical compound for treatment of conditionssuch as cancer, and sonoporation, which inducestransient increases in cell membrane permeabilityand delivers macromolecules such as plasmid DNA,have been developed as new therapeutic methods. Itis difficult to transmit ultrasound from an externaltransducer to points deep within the human body atadequate intensity and position, due to the attenuation of ultrasound by air, bone and tissue, and thedeflection of ultrasound. A probe, which includes afocused ultrasonic transducer made of PZT at its tip,has been developed for ultrasonic treatment in thehuman body (Figure 10) (11). The probe will beinserted into the human body using a catheter or anendoscope. Sonoporation experiments in vitro havebeen successfully performed using a probe 5.5 mmin diameter with concave PZT elements. Theconcave PZT transducers were fabricated frombulk PZT using a high-speed micro-millingmachine. Figure 11 shows measured ultrasonicLaser treatments in the human body have beenperformed by transmitting a laser beam through anoptical fiber. To realize precise laser treatment in thehuman body, a two-dimensional (2D) laser microscanner has been developed (12). The fabricatedscanner is shown in Figure 12. A laser beam istransmitted through an optical fiber and a micro rodlens. The laser is reflected and scanned by ascanning Si thick mirror 1 mm in diameter and200 mm thick, which was fabricated using a MEMSprocess. The laser is then focused on an objectivearea. The scanning mirror is actuated by threepiezoelectric unimorph cantilevers. Each cantileverhas a ball fixed at its tip in contact with the mirror,acting as a ball joint. The mirror is supported by apivot under the mirror. The maximum inclinationangle of the scanning mirror is 26 . Using potasiumtitanyl-phosphate (KTP) laser, the laser positioningfunction was confirmed. By arranging the piezoelectric unimorph cantilevers parallel to each other, alarge mirror inclination angle was obtained, whileretaining the ability for the device to be packaged ina small diameter tube, suitable for insertion into achannel of an endoscope.MEMS process for high performance andmulti-functional medical toolsFigure 10. Ultrasonic therapeutic tool for sonodynamic therapyand sonoporation.As mentioned before, it is preferable that medicaltools inserted temporarily or implanted in thehuman body, such as endoscopic tools andcatheters, be small, thin, multifunctional, and highperformance. Tubular lumens, which are requiredfor insertion of medical tools and for injection ofdrugs, are necessary for endoscopes and catheters.MEMS processes on cylindrical substrates can meetthese demands. However, it is difficult to applyconventional planar micro-fabrication techniques tonon-planar surfaces and three-dimensional objectssuch as tubes. Fabrication techniques for multilayercircuits using metallization and patterning, andsurface mounting of components on cylindrical
Minimally invasive diagnostics and treatment using micro/nano machining223Figure 11. Ultrasonic intensity distribution: (a) Measurement setup of acoustic filed of fabricated probe using ultrasonic hydrophone, (b)ultrasonic intensity distribution on vertical plane (Z50) at 1.83 MHz.substrates have been developed for tubular highperformance micro medical tools with small diameters (13). A maskless exposure system forcylindrical substrates incorporating a DigitalMicromirror Device (DMD) has been developedfor the exposure of complex patterns. The DMDFigure 12. 2D micro scanner for precise laser treatment.line exposure system can also realize several threedimensional patterns using gray-scale (half-tone)lithography by precise control of the profile ofexposure dose at each point, as shown in Figure 13a. Smoothly sloped resist patterns (feature height20 mm) were obtained on a glass tube with a
224Haga et al.Figure 13. MEMS process on cylindrical substrates formed on glass tube (O.D./I.D. 3/2 mm): (a) Sloped resist patterns on glass tube(3 mm O.D.), (b) multilayer wiring, (c) mounting components on tube.diameter of 2–3 mm. 7 mm thick single layer metalpatterns, as well as multilayer electrode patterns(Figure 13 b), have also been formed on glass tubes(O.D./I.D. 2/1 mm and 3/2 mm respectively) usingelectroplating in a patterned resist structure. In orderto improve the performance of small-signal microsensors such as ultrasonic transducers, a high-speedOp-Amp has been mounted on multilayer electrodespatterned on the tube (Figure 13 c). These techniques will realize multifunctional and highperformance tube-shaped micro medical tools withsmall diameters.ConclusionThe science fiction movie ‘‘Fantastic Voyage’’,released in 1966, depicts treatment from inside thehuman body by miniaturized men in a miniaturizedsubmarine injected into a blood vessel. Althoughsuch a fantastic scenario is unlikely, precisionexamination and treatment can be performed byextremely small medical devices which have severalfunctions. Using high-performance endoscopes andcatheters, more precise and safe diagnostics andtreatment will be realized, and newer, more precisediagnostics and treatment, which have been impossible to date, can now be realized.References1. Haga Y, Esashi M. Small Diameter Active Catheter UsingShape Memory Alloy Coils, Trans. IEE of Japan. 2000;120E:509–14 (in Japanese).2. Mizushima M, Haga Y, Totsu K, Esashi M. Active CatheterUsing Shape Memory Alloy for Treatment of IntestinalObstruction. JJSCAS. 2004;6:23–9 (in Japanese).3. Makishi W, Esashi M, Matunaga T, Haga Y. Active BendingElectric Endoscope Using Shape Memory Alloy CoilActuators, Proc. of the The first IEEE / RAS-EMBSInternational Conference on Biomedical Robotics andBiomechatronics (BioRob 2006). p.126.4. Mineta T, Mitsui T, Watanabe Y, Kobayashi S, et al. BatchFabricated Flat Meandering Shape Memory Alloy Actuatorfor Active Catheter. Sensors and Actuators A.2001;88:112–20.5. Haga Y, Mizushima M, Matsunaga T, Esashi M. Medical andWelfare Applications of Shape Memory Alloy MicrocoilActuators. Smart Materials and Structures. 2005;14:266–72.6. Mineta T, Mitsui T, Watanabe Y, Kobayashi S, et al. Anactive guide wire with shape memory alloy bendig actuatorfabricated by room temperature process. Sensors andActuators A. 2002; 97–98: 632–7.7. Haga Y, Muyari Y, Mineta T, Matsunaga T, et al. SmallDiameter Hydraulic Active Bending Catheter Using LaserProcessed Super Elastic Alloy and Silicone Rubber Tube, 3rdAnnual International IEEE-EMBS Special Topic Conferenceon Microtechnologies in Medicine & Biology. 2005. pp.245–8.8. Totsu K, Haga Y, Esashi M. Ultra-miniature fiber-opticpressure sensor using white light interferometry. Journal ofMicromechanics and Microengineering. 2005;15:71–5.9. Haga Y, Fujita M, Nakamura K, Kim CJ, et al. Batchfabrication of intravascular forward-looking ultrasonic probeSensors and Actuators A, 2003;104:40–3.10. Chen JJ, Esashi M, Oshiro O, Chihara K, et al. Developmentof a Forward-looking Ultrasound Imager for IntravascularTreatment. Transactions of the Japanese Society for Medicaland Biological Engineering. 2006;43:553–9 (in Japanese).11. Yasui A, Haga Y, Chen JJ, Esashi M, et al. FocusedUltrasonic Transducer for Localized Sonodynamic Therapy.The 13th International Conference on Solid-State Sensors,Actuators and Microsystems (Transducers’05). 2005.pp.1660–3.
Minimally invasive diagnostics and treatment using micro/nano machining12. Akahori H, Wada H, Esashi M, Haga Y. Tube ShapePiezoelectric 2D Microscanner for Minimally Invasive LaserTreatment. Technical Digest of the 18th IEEE InternationalConference on Micro Electro Mechanical Systems (MEMS2005). 2005. pp.76–9.22513. Goto S, Matsunaga T, Totsu K, Makishi W, et al.Photolithography on Cylindrical Substrates for Realizationof High-Functional Tube-Shaped Micro-Tools. Proceedingsof the 22nd Sensor Symposium on Sensors, Micromachines,and Applied Systems. 2005. pp.112–5.
Key words: Minimally invasive treatment, micromachining, MEMS, catheter, endoscope Introduction Medical tools for use in the human body, such as catheters and endoscopic tools, need to be thin or small. With the progress of minimally invasive diagnostics and treatment techniques and the increasing number of their applications, these
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