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Wireless Implantable MicroSystems: Coming Breakthroughs in Health Care

K. D. Wise
Engineering Research Center for Wireless Integrated MicroSystems Department of Electrical Engineering and Computer Science The University of Michigan, Ann Arbor, MI 48109-2122

Abstract
This paper reviews recent progress i n implantable microsystems. Electrode arrays of up to 1024 sites now allow direct interfacing with the central nervous system, monitoring neural activity and delivering both electrical and chemical stimulation. Operating at milliwatt levels with site spacings of 100-400fim and communicating wirelessly at up to 100kbls. these arrays form a microelectronic bridge to the cellular world. Combined with embedded processors and wafer-level packaging, these microsystems promise exciting advances in dealing with a variety of neurological disorders during the coming decade.

allowing detection in the outside world. The RF field powers the implant and detects its output. As implant size decreases, so does the intercepted power and allowed coupling distance. Today, implanted pressure sensors measuring a few millimeters on a side with ranges of a few centimeters are possible [ 6 ] , but more progress is needed. For example, molding a pressure sensor into an arterial stent would permit checking for re-stenosis at any time; however, an overall device size less than 0.5mm is required. Substantial progress will likely be seen in this area during the coming decade. Some of the least understood problems in health care are those associated with the nervous system. Deafness, blindness, paralysis, Parkinson's disease, and epilepsy are all major health problems for which few effective treatments are available. However, over the last decade, auditory (cochlear) prostheses have emerged to restore functional hearing to the profoundly deaf [7]. Over 30,000 of these microsystems have been implanted worldwide, and they are reducing some forms of hearing loss to a treatable disorder. Encouraging progress is being made on a retinal prostheses for the blind as well, and the recent use of electrical stimulation to suppress the manifestations of Parkinson's disease [XI has produced results bordering on miraculous. While much more is needed, the coming decade may well see electronics make major contributions in the treatment of these and other disorders.

Introduction In the thirty years since microprocessors first made their debut, microelectronics has made major strides, transforming communications, data processing, and control. However, in other areas, its impact has been muted because of problems in interfacing electronics to the non-electronic world. The development of integrated sensors and microsystems (MEMS)[l] addresses these problems and during the past decade has emerged as a major worldwide activity. Perhaps nowhere are such microsystems needed more than in medical applications, but progress has been slow. The interface between electronics and living tissue is especially difficult. and the demands placed on these systems are particularly challenging. Thirty years ago, medical electronics was the keynote theme at the International Solid-State Circuits Conference [2], and micromachined integrated sensors made their debut there as well [3]. This paper will examine progress made since that time along with continuing challenges.
Implantable devices are driven by a need for very small size and by a corresponding need for very low power. Pacemakers are the oldest and most successful example of implantable microsystems, and they have evolved from simple open-loop devices to complex programmable systems capable of executing stimulation protocols conditioned on physiological responses. But for the most part, their form has remained unchanged. Electrodes form the biological interface, and the electronic system is protected inside a welded titanium package. Beyond pacemakers, progress has been slow, and yet today we seem poised for substantial progress. For example, considerable work is being directed at wireless pressure sensors for intracranial, intraocular, and intra-arterial use [4]. These devices typically interface over a passive telemetry link [5] in which the sensor modulates the load on an implantable antenna that, in turn, loads an external coil,

Toward Closed-Loop Neural Prostheses

Any microsystem intended for use in the nervous system must be capable of working unattended for decades and must be biocompatible in terms of its interface with living tissue. I t must be able to deliver appropriate stimulation to the biological system, conditioning that stimulation on physiological responses. Thus, such microsystems should be closed-loop, employing transducers, embedded micropower control, a wireless interface, and chip-level hermetic packaging. Figure 1 shows an example of such as system. In principle, it could deliver electrical stimulation to tissue, record biological responses, and deliver drugs at the cellular level. Such a system might be used to electronically replace defective input portions of the auditory or visual systems, restoring functional sight to the blind and hearing to the deaf. It might also capture motor control signals from the cortex to restore movement to paralyzed limbs. And it might detect the onset of an epileptic seizure, applying electrical a n d o r chemical stimulation to prevent the seizure from developing. Five important aspects of this microsystem will be considered here: microelectrodes, microfluidics, embedded microprocessors, wireless interfaces, and micropackaging. They are generic to many implants.

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A boron predep is used to define the overall probe shape. The etch-stop drive-in is done simultaneously with the p-well drive-in of the subsequent CMOS process. An n-epi psubstrate p-well process allows positive and negative site drive, with the electronics surrounded by a grounded p-type silicon shell. The CMOS process itself is standard up through circuit interconnect, which is done in aluminum. The aluminum is buried under I p m of LTO and PECVD silicon nitride. Above that a metal cap prevents the dielectrics from being directly exposed to the extracellular fluid. These dielectric-metal structures have been soaked under bias for up to four years, maintaining sub-nanoamp leakage. For still longer implant periods, additional coatings may be needed. For 3D structures (Fig. l), however, the upper area of the probe will be potted and could be hermetically sealed with an anodically-bonded glass cap.
OUTPUT LEADY
RIBBONCABLE

Fig. 1: Diagram of a generic neural prosthesis and electronic interface to the nervous system.
INTERCONNECTlNG PROCESSING

. . . .

Microelecrrodes Work to apply silicon micromachining technology to probes able to interface at the cellular level. has been underway since the mid-1960s [ 2 ] , and today much of the technology for doing what is required by the above system is in place. Figure 2 shows a diagram of a typical silicon probe. Recording andlor stimulating sites are positioned along a shank defined using a boron etch-stop. Site conductors are insulated above and below using stress-relieved silicon dioxidelsilicon nitride dielectrics, a n d on-chip circuitry amplifies and multiplexes the recorded signals to a platform holding an array of such probes (Fig. 1) 191. Since the exact position of the probe with respect to neurons of interest is not known a priori, a front-end selector is used to pick sites of interest, compensating for any position changes over time. On the button-size platform, the recorded neural spike potentials are digitized and relayed to an embedded processor and a wireless interface to the outside world.
Figure 3 shows a 1024-site 64-channel 3D multiplexed microelectrode array [IO]. Sites are located on 400pm centers, and any site can be programmed for stimulation or recording. On some versions of this probe, on-chip currentoutput DACs generate 0 to 2128pA stimulus currents with a resolution of *IPA, and extensive self-test circuitry is provided. The circuitry is realized in 3pm I W 2 P CMOS technology. For cortical applications, it is important that the array protrude no more than Imm above the surface to ensure that the implant remains free to move with the brain in-vivo. The sites on such probes are generally IrO, with polysilicon or silicide conductors on the shanks. Orthogonal connections between the probes and the surface platform are formed using ultrasonically-bonded plated-gold lead tabs on the probes. These tabs permit an interconnect pitch of less than 100pm. The array in Fig. 3 displaces less than one percent of the penetrated tissue volume.

REC
T!NG SUBSTRATE

Fig. 2: Diagram of a silicon micromachined neural probe Typical neural signals range from about 20pV to perhaps 400pV, with a frequency content extending to about IOkHz. Thus, recording bandwidths from lOHz to lOkHz are needed along with an overall gain of about 60dB. Amplifiers must be very small and low power. Local heating limits power consumption for the implant to a few milliwatts, and some mechanism for stabilizing the dc input levels in the face of drift in the electrochemical site potential and optically-induced input current must be provided. Stabilization can be achieved using implanted polysilicon shunt resistors or using shunt transistors operating in the subthreshold regime. For a lower frequency cutoff of IOHz, this requires a shunt input resistance between about 75MQ and 500MQ. The use of a subthreshold transistor allows the lower cutoff to be programmable. A second approach to meeting the input stabilization needs is to ac couple the recording amplifier itself [ I l l . Figure 4 shows such a configuration. Here, a lOpF input capacitor and a IOOtF feedback capacitor set the midband gain at 40dB. A diode-connected subthreshold nMOS transistor in the feedback loop sets the lower bandpass corner at less than IOHz, while a Miller capacitor in the opamp sets the highfrequency limit. A dc baseline rejection of more than t5OOmW is achieved. The amplifier dissipates less than 1OOpW from + I S V supplies with a layout area in IW2P 3pm CMOS of 0.08mm. Such amplifiers appear fully capable of meeting the needs for the electrode front-end. Symposium On VLSl Circuits Digest of Technical Papers

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synchronizes it with the recovered data, and performs parity checks. It then communicates with the probe electronics. Fabricated in a 1 W 2 P 3pm BiCMOS process, the circuitry has 1100 transistors, occupies an area of 10mm2, and dissipates less than 10mW. Bidirectional systems are also being developed.
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Vout

C1 l O O f F

I Fig. 3: Two views of a 1024-site neuroelecvonic interface

Microfluidics The ability to deliver drugs to specific locations in-vivo is an important feature for some prosthetic systems. Significant work today is oriented toward percutaneous drug delivery and toward drug delivery at the cellular level (121. Microchannels for drug delivery can be included in the above probes using only one additional mask and are formed by undercutting p+ silicon ribs to form a continuous channel. The channels are sealed using deposited dielectrics, are typically 20-30pm wide, and can inject doses of 100-2OOpL in about a second with a drive pressure of about 50 Torr. On-chip flowmeters can be formed by adding a second mask [13]. These flowmeters have thermal time constants of less than 200psec and hence can be operated in pulsed mode, minimizing any temperature rise in the surrounding tissue. Such temperature rises should be kept less than 1C. For a fully-integrated microsystem, on-chip pumps and valves are also needed and are a special challenge since high actuation voltages are precluded and high temperatures are similarly not allowed. Such devices are currently under development and appear feasible using simple extensions of the above process. Wireless interfaces Wireless interfaces have been developed to supply power and control signals to implanted microsystems such as that shown in Fig. 1. An example is shown in Fig. 5 [14]. The chip receives data and power from an amplitude-modulated 4MHz RF carrier. It generates regulated +5V supplies capable of providing up to 50mW. generates a 4MHz internal clock from the carrier, and recovers input data at up to 100kblsec. T h e chip generates a user-programmable internal clock,

Fig. 4: An ac-coupled probe recording amplifier and an 8channel probe using such devices. (Shown on a US nickel) Microprocessors The development of low-power microprocessors for use in implanted microsystems is an important area for work. RF links can supply the. power and voltage needed and allow complex signal processing to be done externally, as in present cochlear implants, but cosmetic and reliability considerations are driving toward fully-implantable systems. In these cases, the RF link is used only for occasional reprogramming and for periodically recharging the implanted power source. Milliwatt and sub-milliwatt power dissipation levels are then needed in the circuitry. Although low-voltage processors are attractive, higher drive voltages for electrodes and other peripheral devices may still be required, some delivering substantial current. Power considerations may well limit the feasibility of fully-implanted microsystems for some time to come, especially when the rate of information delivery to the physiological system is high (auditory and visual prostheses). Micropackaging T h e packaging of implantable devices is a maJor challenge. Although exposed silicon etches slowly in-vivo, boron-doping produces a near etch-stop in the body, Just as it does in faster silicon etchants. Silicon oxynitride dielectrics
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are sufficient for a few years in-vivo hut for decades their integrity must still be proven. Additional coatings being explored include diamond and polymeric materials. The use of barrier films (e.g., metals) can extend the life of implanted devices significantly by blocking ionic access to dielectric films. Furthermore, glass-silicon packages, which can be formed at wafer level, can provide hermetic encapsulation for times estimated at more than 100 years [15]. Hermetic feedthroughs using polysilicon lead transfers have been developed that are capable of providing sensor access to such packages, which can incorporate the microprocessors and wireless links necessary for the system described in Fig. 1.

Acknowledgments

The author wishes to thank Professors K. Najafi and D. J. Anderson for their many contributions to the work reported here. Drs. M. Gingerich and J. F. Hetke also made many contributions along with M. Ghovanloo, M. N. Gulari, A. DeHennis, and R. H. Olsson. This work was sponsored by the Neural Prosthesis Program (NINDS) and the National Center for Research Resources (NCRR) of the National Institutes of Health, and by the Engineering Research Centers Program of the National Science Foundation under Award Number EEC9986866.

References
VDD
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CLK

Data

1Recovery I IGenerator ]--I

Strobe

Fig. 5 : Block diagram and chip photograph of a wireless interface

for implanted stimulating electrode arrays. Cunclusiuris Implantable microsystems are being developed for a number of important medical applications. In the nervous system, electrode arrays are now capable of interfacing with virtually every cell in a three-dimensional block of tissue. Onchip circuitry performs site selection, amplification, and multiplexing of the recorded data as well as the delivery of stimulating currents at the cellular level. Wireless interfaces can provide power and data to such systems while maintaining the overall system power dissipation in the range of a few milliwatts. Low-power microprocessors are needed to provide in-vivo signal analysis to eliminate the need for extemallyworn signal processors, and additional work on packaging is needed to ensure system lifetimes that will reach decades. Such systems should make a significant impact on health care in the coming decade.

D. Wise, ed., Special Issue on Integrated Sensors, Microactuators, and Microsystems. Proc. IEEE, August 1998. [2] D. W. Hill, Impact of Solid-Slate Circuitry Technology on Biomedical Electronics, Digesr Inf. Solid-Srate Circuirs Con/, pp. 33, February 1971 [3] K. D. Wise and 1. B. Angell, A Microprobe with Integrated Amplifiers for Neurophysiology, Digesr Inr. Solid-Stare Circuits Con/.pp. 100-102, February 1971. [4] K. Stangel, S. Kolnsberg, D. Hmerschmidt, B. 1. Hosticka, H. K. Trieu, and W. Mokwa, A Programmable Intraocular CMOS Pressure Sensor System Implant, IEEE J. Solid-Stare Circuirr, pp. 1094-1 100, July 2001. [5] C. C. Collins, Miniature Passive Pressure Trasnsensor for Implanting in the Eye, IEEE Trans. Biomed. Engr. April 1967. [6] A. DeHennis and K. D. Wise, A Double-Sided Single-Chip Wireless Pressure Sensor, Digest IEEE MEMS Cont. Las Vegas, pp. 252.255, January 2002. [7] F. A. Spelman, The Past, Present, and Future of Cochlear Prostheses. IEEE Engr. in Med. B i d . Mag., pp. 27-33, May 1999. [SI P. Limousin, P. Krack, P. Pollack, A. Benazzouz, C. Ardouin. D. Hoffmann, and A. Benabid. Electrical Stimulation of the Subthalamic Nucleus in Advanced Parkinsons Disease, New England Journal ofMedicine, 339, pp. 1105-1 1 1 I, 1998. [9] Q. Bai and K. D. Wise, Single-Unit Recording with Active Microelectrode Arrays, IEEE Trans. Biomed. Engr., pp. 91 I920, August 2001. [IO] M. D. Gingerich, J. F. Hetke, D. 1. Anderson, and K. D. Wise, A 256-Site 3D CMOS Microelectrode Array for Multipoint Stimulation and Recording in the Central Nervous System, Inr. Con/ on Solid-Stale Sensors and Acruators, Munich, June 2001. [ I I]R. H. Olsson 111, M. N. Gulai. and K. D. Wise, Silicon Neural Recording Arrays with On-Chip Electronics for In-Vivo Data Acquisition, IEEE-EMBS Inr. Conf on Microtechn. in Med. andBiol., Madison, May 2002. 1121 J. . _ Chen. K. D. Wise. 1. F. Hetke. and S . C. Bledsoe. Jr.. A Multichannel Neural Probe for Selective Chemical Delivery at the Cellular Level, IEEE Trans. Biomed. Engr., pp. 760-769, August 1997. [I31 D. Papageorgiou. S. C. Blcdsoe, M. Gulari, J. F. Hetke, D. 1. Anderson, and K. D. Wise, A Shuttered Probe with In-line Flowmeters for Chronic In-Vivo Drug Delivery, IEEE MEMS Con/, Interlaken. pp. 212-215. January 2001. [I41 M Ghovanloo, K. Beach, K. D. Wise, and K. Najafri, A BiCMOS Wireless Interface Chip for Micromachined Stimulating Microprobes, IEEE-EMBS I n t . Con/. o n Microrechn. In Med. and Bioi., Madison, May 2002. [ I S ] T. J. Harpster and K. Najafi, Long-Term Testing Of Hermetic Anodically Bonded Glass-Silicon Packages, Digcsr, IEEE Inr. MEMS Con/ (MEMS 2002). Las Vegas. pp. 423-426, January
[I] K .

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