Copyright 2009 Year IEEE. Reprinted from IEEE TRANSACTIONS ON ADVANCED PACKAGING. Such permission of the IEEE does not in any way imply IEEE

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1 Copyright 2009 Year IEEE. Reprinted from IEEE TRANSACTIONS ON ADVANCED PACKAGING. Such permission of the IEEE does not in any way imply IEEE endorsement of any of Institute of Microelectronics products or services. Internal of personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to

2 IEEE TRANSACTIONS ON ADVANCED PACKAGING, VOL. 32, NO. 2, MAY Design, Fabrication, and Assembly of an Optical Biosensor Probe Package for OCT (Optical Coherence Tomography) Application C. S. Premachandran, Senior Member, IEEE, Ahmad Khairyanto, Kelvin Chen Wei Sheng, Janak Singh, Jason Teo, Xu Yingshun, Chen Nanguang, Colin Sheppard, and Malini Olivo Abstract A miniaturized optical bioprobe package is developed using a 3-D micromirror and is tested for bio-imaging application. A silicon optical bench is designed and micromachined to assemble the fiber, lens, and the 3-D micromirror device. A 45 angle trench is used to place the micromirror to achieve larger scanning range. Trace lines are formed on the optical bench and are connected to silicon micromirror using solder. A GRIN lens with lower numerical aperture has been used to focus the optical beam onto the micromirror. The bioprobe is packaged and is tested in a time domain optical coherence tomography (OCT) setup and optical image is obtained for plant tissue. Index Terms Biosensor, micro-electro-mechanical system (MEMS), MEMS packaging, micromirror, optical coherence tomography (OCT), optical probe, silicon optical bench (SiOB), 3-D MEMS. I. INTRODUCTION OPTICAL coherence tomography (OCT) bio-imaging is a new emerging technique for higher resolution biopsies and other medical diagnostic applications as well [1]. OCT imaging can achieve real time cellular scale resolution, which is important to produce high resolution cross-sectional images of the internal microstructure of living tissues [2], [3]. Higher resolution combined with real time mode makes the optical probe OCT imaging an important tool for accurate cancer diagnostics and monitoring to avoid recurring of cancer lesions. OCT with miniaturized probes can be used where excision biopsy is unsafe or not possible. It can also be used in delicate interventional procedures, such as for neural investigations in brain and to reduce sampling errors due to the fact that it is real time. Optical probe is one of the critical elements in OCT imaging, as this makes the OCT imaging real time. The miniaturized optical probe helps Manuscript received May 14, 2007; revised March 15, First published May 08, 2009; current version published May 28, This work was recommended for publication by Associate Editor K. Kurabayashi upon evaluation of the reviewers comments. C. S. Premachandran, A. Khairyanto, K. C. W. Sheng, J. Singh, and J. Teo are with the A*STAR Institute of Microelectronics, Singapore Science Park II, Singapore. X. Yingshun, C. Nanguang, and C. Sheppard are with the Department of Bioengineering, National University of Singapore, Singapore. M. Olivo is with the Division of Medical Sciences, National Cancer Centre, Singapore and also with the Bio-Optical Imaging Group, SBIC (Singapore Bioimaging Consortium), A*STAR (Agency for Science, Technology and Research), Singapore.. Color versions of one or more of the figures in this paper are available online at Digital Object Identifier /TADVP Fig. 1. OCT setup. in reducing patient s trauma by eliminating tissue removal required for biopsy. In its simplest implementation, the bioprobe is miniaturized assemblies of fiber optics, which can deliver (and also collect scattered) light beam and scan in one dimension (lateral) on the target. This scanning can be achieved by actuating the fiber itself. Research has also been reported where scanner micro-electro-mechanical system (MEMS) micromirror is integrated at the outer tip of the probe to add scan flexibility [4] [6]. Micromirror technology adds the dynamism in the selection of cross section (of tissue, lesions, etc.) by real time observations. Main challenge is in increasing dynamic flexibility while keeping the diameter small, which is essential to reduce patient trauma during real time optical biopsy. This paper outlines the details of packaging and integration development of a miniaturized optical bio-probe. A miniaturized package is required to make the probe to use in the OCT setup to have insitu real time imaging of the cells/tissues. II. OPTICAL COHERENCE TOMOGRAPHY TEST METHOD A schematic view of the endoscope OCT imaging system is shown in Fig. 1. A low coherent light source is used to shine the light into the sample. The source is coupled to the OCT system by a splitter so that the input light is split into two, one is coupled to reference optics and another is to a scanning optics. The light /$ IEEE

418 IEEE TRANSACTIONS ON ADVANCED PACKAGING, VOL. 32, NO. 2, MAY 2009 Fig. 3. Schematic view of the package with silicon optical bench (SiOB) approach. Fig. 2. (a) Three-dimensional MEMS micromirror with thermal actuators.

The light from the reference optics also traverse back to the detector. Reflected light from the reference optics and the scattered light from the sample will create an interference signal.

3 418 IEEE TRANSACTIONS ON ADVANCED PACKAGING, VOL. 32, NO. 2, MAY 2009 Fig. 3. Schematic view of the package with silicon optical bench (SiOB) approach. Fig. 2. (a) Three-dimensional MEMS micromirror with thermal actuators. (b) Actuator in close view. from the scanning optics fall onto the sample of interest and is scattered back to the scanning optics and couple back to the detector. The light from the reference optics also traverse back to the detector. Reflected light from the reference optics and the scattered light from the sample will create an interference signal. The interference signal provides information about the sample. The interference signal is detected and demodulated based on the backscattered light from the tissue. The depth of probing on sample can be changed by moving the reference mirror back and forth. By moving probe optics on the sample different areas of the sample can be scanned. III. PACKAGE DESIGN Advantage in OCT is using a short coherence length of broad band light source in order to achieve cross sectional images with micrometer resolution. With the advantage of silicon micromachining and using miniaturized micromechanical devices the OCT systems can be achieved with high speed and high resolution images. Since optical components made using MEMS has smaller physical size, it enhances in speed and lower operating power. In the OCT setup a miniaturized probe is required to obtain a real time imaging. A real time imaging can provide instant tissue information during the surgery. Limitation on current technique is on the scanning range of the beam. Using a 3-D micromirror the beam can be steered based on the mirror rotational angle [Fig. 2(a)]. Earlier results have shown that 3-D scanning can be achieved with a 2-D mirror with an external motor driven to further rotate the mirror. In this design no external motor is required and the mirror it self can rotate and scan the beam in larger angle to capture the scattered light from the tissue. Using silicon MEMS process a miniaturized 3-D mirror is fabricated. The mirror size is about 500 m in a 1.5 mm square chip. The mirror is suspended in four springs and is connected to actuators [Fig. 2(b)]. Thermal actuation is used to move the mirror. Since the actuators are very thin, 2 m thick and the heating of the actuator require only a very small voltage, the outside temperature variation will not affect the overall temperature of the actuator. Also a feed back control circuit controls the mirror rotation and if the angle of rotation does not meet additional voltage will be supplied to meet the required angle of rotation. The maximum angle the mirror can rotate is about 16 ; the scanning rate is 21 fps. A schematic view of the probe is shown below (Fig. 3). The assembly of the probe starts with attaching the mirror, Grin lens, optical fiber on to silicon optical bench (SiOB) fabricated by KoH process. The micromirror is attached on to the lower substrate and the metal traces are formed on the substrate. Grin lens and fiber are attached onto the top substrate. The two substrates are bonded together in an optical bench after aligning the grin lens to the micromirror. IV. OPTICAL DESIGN The micro-optical components are required to collect the light and focus the beam on to the mirror. Design of the package depends on the on the selection of micro-optical components. The dimension and shape of the optical components will determine the final package size. The optical component s physical properties are determined based on the optical resolution and image quality requirement. The axial resolution of the OCT system depends on the light source. The advantage in using the optical probe is to increase the lateral resolution of the system. The lateral resolution of the

PREMACHANDRAN et al.: DESIGN, FABRICATION, AND ASSEMBLY OF AN OPTICAL BIOSENSOR PROBE PACKAGE FOR OCT 419 TABLE I POWER DISTRIBUTION ALONG THE OPTICAL PATH INSIDE THE PROBE Fig. 4. Optical simulation to study the beam size and coupling efficient.

system depend on optical parameters such as the size of the lens, geometry, and scan angle of the MEMS mirror, beam diameter and the focal length of the lens.

4 PREMACHANDRAN et al.: DESIGN, FABRICATION, AND ASSEMBLY OF AN OPTICAL BIOSENSOR PROBE PACKAGE FOR OCT 419 TABLE I POWER DISTRIBUTION ALONG THE OPTICAL PATH INSIDE THE PROBE Fig. 4. Optical simulation to study the beam size and coupling efficient. Fig. 6. Light path of the beam based on the optical model of the probe. Fig. 5. Design of grin lens dimensions to meet the beam diameter requirements. (Grintech GmbH). system depend on optical parameters such as the size of the lens, geometry, and scan angle of the MEMS mirror, beam diameter and the focal length of the lens. In the current design the transverse resolution refers to the smallest resolvable dimension on the sample that the optical device is capable of, in the direction perpendicular to the optical axis. In the case of this probe, the transverse resolution, w, can be defined as the spot diameter at the beam waist (focal point). Transverse resolution can be obtained from the following formula: An optical simulation is performed to study the beam diameter and the coupling efficiency after scattering from the sample (Fig. 4). In the initial setup, a reflective surface is used to study the coupling efficiency and subsequently modified the reflective surface to more rough for scattering. Optical design is done to make sure that the light will be focused at the sample (tissue) side. A grin lens is selected to get the maximum working distance and at the same time to achieve a smaller beam diameter (BD) at the mirror side (Fig. 5). Beam diameter at the mirror side should be at least 50% smaller than the mirror diameter so that most of the light falls into the mirror even there is a small shift in beam due to optical components misalignment. Efficiency of the light collection at the MEMS mirror after scattering from the sample is calculated in the simulation. It is found that about 70% of the light could be collected at the mirror provided the sample is a reflective surface (Table I). The collection efficiency will be degraded if the sample is rough and scattering nature (Fig. 6). V. FABRICATION OF SIOB The driving factor in developing a probe is to miniaturize the over all dimension. This is a challenge for the packaging of the probe. The optical components and the mirror need to be packaged in a miniaturized format and at the same time the packaging material must be transparent to infrared (IR) light. In the current design wavelength of 1300 nm is used in shining the light on to the sample. Selection of substrate for packaging should meet both optical and miniaturization requirements. Silicon is a good material for micromachining to create smaller dimension to meet miniaturization and is transparent to IR wavelength. The targeted diameter of the probe is 2 mm. An 8-in wafer is used to fabricate the SiOB structures. Since KOH etching can not make 45 angle trenches, the structures are made on wafer with 45 shift. The structure is rotated at 45 angle and the trenches are made. While singulating the devices the wafer has to be mounted carefully to offset the 45 angle trench. The Si wafer is micromachined to form a slot to attach the 3-D micromirror. Depth of the trench is calculated to make sure that the mirror pads are aligned to metal traces to form interconnection (Fig. 7).

420 IEEE TRANSACTIONS ON ADVANCED PACKAGING, VOL. 32, NO. 2, MAY 2009 Fig. 7. Silicon optical bench for 3-D micromirror attachment. Fig. 9.

The UBM Cr Au are deposited on the silicon wafer by sputtering method. The sputtered metal is patterned by lithographic technique. The pitch of the metal traces is about 150 m with width of 125 m.

The metal traces are formed on the trenches and is extended to the end of the silicon optical bench to connect to the external world. GRIN lens and the fiber are attached to a silicon optical bench.

Probe Assembly Assembly of the probe starts with attachment of grin lens and fiber into the silicon optical bench (Fig. 8).

5 420 IEEE TRANSACTIONS ON ADVANCED PACKAGING, VOL. 32, NO. 2, MAY 2009 Fig. 7. Silicon optical bench for 3-D micromirror attachment. Fig. 9. Three-dimensional micromirror is interconnected to SiOB with solder balls. Fig. 8. GRIN lens and fiber attached to the SioB substrate. The UBM Cr Au are deposited on the silicon wafer by sputtering method. The sputtered metal is patterned by lithographic technique. The pitch of the metal traces is about 150 m with width of 125 m. The tight dimensions are required to meet the probe size of 2 mm diameter. The metal traces are formed on the trenches and is extended to the end of the silicon optical bench to connect to the external world. GRIN lens and the fiber are attached to a silicon optical bench. Placement of GRIN lens is such a way that the optical axis is in line with the centre of the MEMS 3-D micromirror. A. Probe Assembly Assembly of the probe starts with attachment of grin lens and fiber into the silicon optical bench (Fig. 8). In this development an integrated grin lens with fiber is used and hence there is no need to do align the fiber and lens separately. A UV cure epoxy is used to attach the GRIN lens and the fiber to the bench. The 3-D micromirror is attached to another SiOB which has got a 45 trench to place the mirror. Solder balls are attached to the mirror device and is subjected to reflow (Fig. 9). A pick and place machine picks the mirror device and attached to the silicon substrate. The solder balls on the mirror device get contact with the metal traces on the bench. The solder interconnected mirror device with the silicon substrate is reflowed again to form the final interconnection to the external world. Fig. 10. GRIN lens and fiber attached to silicon substrate bonded with mirror SiOB. The integrated GRIN lens and fiber attached silicon substrate is sandwich bonded with the mirror attached silicon substrate (Fig. 10). The final assembly is encapsulated into a plastic injection molded tube suitable to meet endoscope requirements. VI. TESTING OF THE OPTICAL PROBE IN OCT SETUP Test setup of the probe in the OCT system is shown in Fig. 11(a). A time domain OCT system is used to scan the sample. Reflected light from the reference mirror and the sample are made to interfere and the interference signal is detected at the detector. A sample is kept at a distance of 2.5 mm away from the mirror which is to be scanned. The reflected signal from the probe mirror is scanned and is detected. The detected signal is showed in Fig. 11(b). A plant tissue has been used as a bio-sample for imaging. The working distance from the probe mirror is about 2.5 mm. A-line signal is obtained from the time domain OCT and it detects the envelope of interference signals generated from sample through the micromirror in the optical probe and the reference signal reflected by the reference mirror (reference beam) which one we used here is a rotary mirror array (RMA) (Fig. 11). The axial scanning rang of illumination is almost 4 mm in tissue sample. The useful signal range is about 2.5 mm. This line scan results are initial results and is to prove the

assembly of micromirror with Grin lens, micromirror in a silicon optical bench (SiOB) concept that the light can be collected from the scattered sample (Fig. 12).

6 PREMACHANDRAN et al.: DESIGN, FABRICATION, AND ASSEMBLY OF AN OPTICAL BIOSENSOR PROBE PACKAGE FOR OCT 421 Fig. 12. Line signal from OCT system. Fig. 13. Complete probe in a biocompatible housing material. Fig. 11. (a) OCT setup for probe testing. (b) Interference signal from the sample at a distance of 2.5 mm from the MEMS mirror. assembly of micromirror with Grin lens, micromirror in a silicon optical bench (SiOB) concept that the light can be collected from the scattered sample (Fig. 12). Signal-to-noise ratio is measured and found to be more than 70 db and which can be evaluated from A-line signal. A completed probe enclosed in biocompatible housing is shown in Fig. 13. The spatial (axial) resolution of the image is depend on the band width of the light source at full-width half-maximum (FWHM) (power level). The band width of the light source used is about 110 nm and the achieved resolution is about 6.8 m. VII. CONCLUSION A miniaturized optical bio-probe has been developed using a 3-D MEMS micromirror. A miniaturized package is developed for the bio-probe using Silicon optical bench. Micro-optical components such as GRIN lens and fiber is used for optical coupling and geometrical simulation study showed that beam diameter is with in the MEMS mirror. A silicon optical bench with a 45 slant trench is developed for attaching the mirror. Interconnection of MEMS mirror to the outside world is made through the solder bumps interconnection and good continuity has been achieved. Bio-probe package developed has been tested in the OCT setup and demonstrated the interference signal for sample signal at a distance of 2.5 mm form the probe mirror. Subsequently an onion tissue has been used for optical scanning and good depth of image has been produced. Imaging of cancer tissue with the developed probe is being studied and will be reported later. ACKNOWLEDGMENT The authors would also like to thank K. Ramakrishna, P. V. Ramana, and C. T. Kuan (NTU) for their support in this project.

422 IEEE TRANSACTIONS ON ADVANCED PACKAGING, VOL. 32, NO. 2, MAY 2009 REFERENCES [1] J. G. Fujimoto, Optical coherence tomography C. R. Acad. Sic. Paris t.2, Applied Physics (Biophysics), 2001, pp.

Fujimoto, Optical coherence tomography, Science, vol. 254, pp. 1178 1181, 1991. [3] B. E. Bouma, S. H. Yun, W. Y. Oh, M. Shishkov, J. F. de Boer, and G. T.

en, and N. C. Tien, 3-D MEMS based minimally invasive optical coherence tomography, in Transducers 05, Jun. 5 9, 2005, pp. 1644 1648. [5] T. Xie, H. Xie, G. K. Fedder, and Y.

P. Chen, Three- dimensional endoscopic optical coherence tomography by use of a two axis microelectromechanical scanning mirror, Appl. Phys. Lett., vol. 88, p. 163901, 2006. [7] P. H. Tan, D. S.

Ayers, W. C. Tang, and Z. Chen, 60 degree rotating micromirror for transmitting and sensing optical coherence tomography signals, in Proc. Sensors, Oct. 2004, vol. 1, pp. 497 500.

degree in MEMS from Indian Institute of Technology, Delhi, India, in 1998, and the MBA degree from the Business School, National University of Singapore, in 2008 He joined the MEMS group at Institute

His recent interests include MEMS applications for biomedical applications, nano technology, and silicon photonics.

7 422 IEEE TRANSACTIONS ON ADVANCED PACKAGING, VOL. 32, NO. 2, MAY 2009 REFERENCES [1] J. G. Fujimoto, Optical coherence tomography C. R. Acad. Sic. Paris t.2, Applied Physics (Biophysics), 2001, pp [2] D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and G. Fujimoto, Optical coherence tomography, Science, vol. 254, pp , [3] B. E. Bouma, S. H. Yun, W. Y. Oh, M. Shishkov, J. F. de Boer, and G. T. Tearney, Latest developments in optical coherence tomography, in Proc. 17th Annu. Meeting IEEELasers Electro-Optics Soc., 2004, pp [4] D. T. McCormick, W. Jung, Z. Chen, and N. C. Tien, 3-D MEMS based minimally invasive optical coherence tomography, in Transducers 05, Jun. 5 9, 2005, pp [5] T. Xie, H. Xie, G. K. Fedder, and Y. Pan, Endoscopic optical coherence tomography with new MEMS mirror, Electron. Lett., vol. 39, no. 21, pp , Oct. 16th, [6] W. Jung, D. T. McCormick, J. Zhang, L. Wang, N. C. Tien, and Z. P. Chen, Three- dimensional endoscopic optical coherence tomography by use of a two axis microelectromechanical scanning mirror, Appl. Phys. Lett., vol. 88, p , [7] P. H. Tan, D. S. Mukai, M. Brenner, and Z. Chen, In vivo endoscopic optical coherence tomography by use of a rotational micro electro mechanical system probe, Opt. Lett., vol. 29, no. 11, Jun. 1, [8] J. A. Ayers, W. C. Tang, and Z. Chen, 60 degree rotating micromirror for transmitting and sensing optical coherence tomography signals, in Proc. Sensors, Oct. 2004, vol. 1, pp Janak Singh received the Ph.D. degree in MEMS from Indian Institute of Technology, Delhi, India, in 1998, and the MBA degree from the Business School, National University of Singapore, in 2008 He joined the MEMS group at Institute of Microelectronics Singapore in 1999 and since then has been working in this area. He worked in BioMEMS fluidic devices, micro-relay, MOEMS, and inertial sensors. His recent interests include MEMS applications for biomedical applications, nano technology, and silicon photonics. He currently holds the position of Industry Development Manager for MEMS, Nanoelectronics, and Photonics at the Institute of Microelectronics, Singapore. Jason Teo, photograph and biography not available at the time of publication. Xu Yingshun received the B.Eng. degree in biomedical engineering from Tianjin University, Tianjin, China, in He is currently working toward the Ph.D. degree from the National University of Singapore and Institute of Microelectronics, A*STAR, Singapore. His research interests involve development of optical MEMS and endoscopic imaging. C. S. Premachandran (SM 02) received the M.Tech. degree in solid state technology from Indian Institute of Technology, Madras, India. His research focuses are on the MEMS, bio, and advanced packaging technologies. He is currently a Member of Technical Staff in Institute of Microelectronics, Singapore. Chen Nanguang received the B.S. in electrical engineering from Hunan University, in 1988, the M.S. degree in physics from Peking University, in 1994, and the Ph.D. degree in biomedical engineering from Tsinghua University, in He joined the Optical and Ultrasound Imaging Laboratory at the University of Connecticut in 2000 as a postdoctoral fellow and then became an Assistant Research Professor in Since 2004, he has been an Assistant Professor of Bioengineering and Electrical Engineering with the National University of Singapore. His research interests include diffuse optical tomography, optical coherence tomography, and novel microscopic imaging methods. Ahmad Khairyanto received the B.Eng. (mechanical and production engineering) degree and the M.Eng. (mechanical and aerospace engineering) degree from the from Nanyang Technological University, Singapore, in 2003 and 2008, respectively. He is currently a Research Officer with the A-Star Institute of Microelectronics. His current research interests are in the areas of MEMS packaging, optics, and generalized optimization theory. Kelvin Chen Wei Sheng received the Diploma in electronics and communications, specializing in photonics technology from Nanyang Polytechnic, in He is currently with Singapore A*STAR Institute of Microelectronics. He has published technical papers on MEMS in international conferences. Colin Sheppard received the Ph.D. degree from the University of Cambridge and the D.Sc. degree from the University of Oxford. Currently, he is Professor and Head of the Division of Bioengineering at the National University of Singapore. His main area of research is in confocal and multiphoton microscopy, including instrument development and investigation of novel techniques. Malini Olivo received the Ph.D. degree in bio-medical physics. She is currently Head of Bio-optical Imaging at the Singapore Bioimaging Consortium and she also holds an Adjunct Associate Professor appointment in the Department of Pharmacy at the National University of Singapore. She is also Principal Investigator of the Photodynamic Treatment and Diagnosis and Biophotonics Laboratories in the Singapore National Cancer Centre and SingHealth Research Facilities. She has pioneered the area of clinical application of photodynamic diagnosis and treatment in cancer in Singapore and has spearheaded several collaborative projects in biophotonics and nanophotonics for in vivo optical bio-imaging applications in biomedical research in Singapore. Her research interests include bio-nanophotonics and photomedicine.

A THREE DIMENSIONAL REAL-TIME MEMS BASED OPTICAL BIOPSY SYSTEM FOR IN-VIVO CLINICAL IMAGING

A THREE DIMENSIONAL REAL-TIME MEMS BASED OPTICAL BIOPSY SYSTEM FOR IN-VIVO CLINICAL IMAGING Daniel T. McCormick 1, Woonggyu Jung 2,3, Yeh-Chan Ahn 2, Zhongping Chen 2,3 and Norman C. Tien 4 1 Advanced