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面向生物医疗应用的电刺激集成电路与系统综述
郑昊, 吴家磊, 尹思梦, 秦锦哲, 李紫菡, 陈培栋, 曹康康, 李建业, 潘彦洁, 周怡鑫, 李霞光, 王科平
集成电路与嵌入式系统 ›› 2025, Vol. 25 ›› Issue (2) : 41-54.
PDF(9766 KB)
PDF(9766 KB)
面向生物医疗应用的电刺激集成电路与系统综述
A review of integrated circuits and systems for electrical stimulation in biomedical applications
电刺激技术被广泛应用于多种生物医学领域,包括心脏起搏器、人工耳蜗、肌肉重建、视力恢复和癫痫抑制等。与传统的药物治疗或手术方法相比,电刺激具有更小的侵害性、更高的灵活性和更好的可恢复性,并且消除了药物依赖性与成瘾性的风险。由于集成电路具有功耗低、可靠性高、可编程性强、易于多功能集成和易于大规模生产等优势,能够满足小型化、智能化和经济高效的生物医用需求,近年来已发展成为电刺激器设计的首要选择。然而,高密度电极与刺激产生电路的集成,给电极-组织接口设计带来了很大挑战。本文从电极-组织接口出发,全面概述了植入式电刺激器相关的集成电路设计,包括基础驱动电路拓扑和高性能复杂设计,重点分析了生物医用植入式芯片的可靠性与安全性,并介绍了刺激器与闭环系统中能量收集等模块结合的创新设计。同时结合课题组在电刺激和接口电路方面的工作,讨论了电刺激技术和接口系统的未来方向。
Electrical stimulation technology has been widely applied in various biomedical fields, including cardiac pacemakers, cochlear implants, muscle reconstruction, vision restoration, and epilepsy suppression. Compared to traditional drug therapies or surgical methods, electrical stimulation offers advantages such as reduced invasiveness, greater flexibility, improved recoverability, and the elimination of risks associated with drug dependency and addiction. Due to the advantages of integrated circuits, including low power consumption, high reliability, strong programmability, ease of multifunctional integration, and suitability for mass production, they have recently become the primary choice for designing electrical stimulators, meeting the demands for miniaturized, intelligent, and cost-effective biomedical applications. However, the integration of high-density electrodes with stimulation-generating circuits presents significant challenges in designing electrode-tissue interfaces. This paper begins with the electrode-tissue interface and provides a comprehensive overview of integrated circuit design for implantable electrical stimulators, including fundamental driver circuit topologies and high-performance complex designs. It emphasizes the analysis of the reliability and safety of biomedical implantable chips and introduces innovative designs that integrate stimulators with energy harvesting modules in closed-loop systems. This review also discusses the future directions of electrical stimulation technology and interface systems including our research group's work on electrical stimulation and interface circuits.
integrated circuits / electrical stimulation / circuits and systems / neural interface
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Brain-computer interfaces (BCIs) could potentially be used to interact with pathological brain signals to intervene and ameliorate their effects in disease states. Here, we provide proof-of-principle of this approach by using a BCI to interpret pathological brain activity in patients with advanced Parkinson disease (PD) and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered. Our goal was to demonstrate that by personalizing and optimizing stimulation in real time, we could improve on both the efficacy and efficiency of conventional continuous DBS.We tested BCI-controlled adaptive DBS (aDBS) of the subthalamic nucleus in 8 PD patients. Feedback was provided by processing of the local field potentials recorded directly from the stimulation electrodes. The results were compared to no stimulation, conventional continuous stimulation (cDBS), and random intermittent stimulation. Both unblinded and blinded clinical assessments of motor effect were performed using the Unified Parkinson's Disease Rating Scale.Motor scores improved by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (p = 0.03) and 27% (p = 0.005) better than cDBS, respectively. These improvements were achieved with a 56% reduction in stimulation time compared to cDBS, and a corresponding reduction in energy requirements (p < 0.001). aDBS was also more effective than no stimulation and random intermittent stimulation.BCI-controlled DBS is tractable and can be more efficient and efficacious than conventional continuous neuromodulation for PD.Copyright © 2013 American Neurological Association.
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This paper presents a fully intraocular self-calibrating epiretinal prosthesis with 512 independent channels in 65 nm CMOS. A novel digital calibration technique matches the biphasic currents of each channel independently while the calibration circuitry is shared among every 4 channels. Dual-band telemetry for power and data with on-chip rectifier and clock recovery reduces the number of off-chip components. The rectifier utilizes unidirectional switches to prevent reverse conduction loss in the power transistors and achieves an efficiency > 80%. The data telemetry implements a phase-shift keying (PSK) modulation scheme and supports data rates up to 20 Mb/s. The system occupies an area of 4.5 ×3.1 mm². It features a pixel size of 0.0169 mm² and arbitrary waveform generation per channel. In vitro measurements performed on a Pt/Ir concentric bipolar electrode in phosphate buffered saline (PBS) are presented. A statistical measurement over 40 channels from 5 different chips shows a current mismatch with μ = 1.12 μA and σ = 0.53 μA. The chip is integrated with flexible MEMS origami coils and parylene substrate to provide a fully intraocular implant.
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This paper presents a 4 × V neuro-stimulator in a 0.18- μm 1.8 V/3.3 V CMOS process. The self-adaption bias technique and stacked MOS configuration are used to prevent transistors from the electrical overstress and gate-oxide reliability issue. A high-voltage-tolerant level shifter with power-on protection is used to drive the neuro-stimulator The reliability measurement of up to 100 million periodic cycles with 3000- μA biphasic stimulations in 12-V power supply has verified that the proposed neuro-stimulator is robust. Precise charge balance is achieved by using a novel current memory cell with the dual calibration loops and leakage current compensation. The charge mismatch is down to 0.25% over all the stimulus current ranges (200-300 μA) The residual average dc current is less than 6.6 nA after shorting operation.
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A wireless electrical stimulation implant for peripheral nerves, achieving >10× improvement over state of the art in the depth/volume figure of merit, is presented. The fully integrated implant measures just 2 mm × 3 mm × 6.5 mm (39 mm, 78 mg), and operates at a large depth of 10.5 cm in a tissue phantom. The implant is powered using ultrasound and includes a miniaturized piezoelectric receiver (piezo), an IC designed in 180 nm HV BCD process, an off-chip energy storage capacitor, and platinum stimulation electrodes. The package also includes an optional blue light-emitting diode for potential applications in optogenetic stimulation in the future. A system-level design strategy for complete operation of the implant during the charging transient of the storage capacitor, as well as a unique downlink command/data transfer protocol, is presented. The implant enables externally programmable current-controlled stimulation of peripheral nerves, with a wide range of stimulation parameters, both for electrical (22 to 5000 μA amplitude, ∼14 to 470 μs pulse-width, 0 to 60 Hz repetition rate) and optical (up to 23 mW/mm optical intensity) stimulation. Additionally, the implant achieves 15 V compliance voltage for chronic applications. Full integration of the implant components, end-to-end in vitro system characterizations, and results for the electrical stimulation of a sciatic nerve, demonstrate the feasibility and efficacy of the proposed stimulator for peripheral nerves.
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This paper presents a power-efficient neural stimulator integrated circuit, designed to take advantage of our understanding of iridium-oxide electrode impedance. It efficiently creates a programmable set of voltage supplies directly from a secondary power telemetry coil, then switches the target electrode sequentially through the voltage steps. This sequence of voltages mimics the voltage of the electrode under the constant current drive, resulting in approximately constant current without the voltage drop of the more commonly used linear current source. This method sacrifices some precision, but drastically reduces the series losses seen in traditional current sources and attains power savings of 53%-66% compared to these designs. The proof-of-concept circuit consumes 125 μW per electrode and was fabricated in a 1.5-μm CMOS process, in a die area of 4.76 mm(2).
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Ensuring safe operation of stimulators is the most important issue in neural stimulation. Safety, in terms of stimulators' electrical performances, can be related mainly to two factors; the zero-net charge transfer to tissue and the heat generated by power dissipation at tissue. This paper presents a safety ensuring neuro-stimulator for retinal vision prostheses, featuring precise charge balancing capability and low power consumption, using a 0.35 μm HV (high voltage) CMOS process. Also, the required matching accuracy of the biphasic current pulse for safe stimulation is mathematically derived. Accurate charge balance is achieved by employing a dynamic current mirror at the output of a stimulator. In experiments, using a simple electrode model (a resistor (R) and a capacitor (C) in parallel), the proposed stimulator ensures less than 30 nA DC current flowing into tissue over all stimulation current ranges (32 μA-1 mA), without shorting. With shorting enabled, further reduction is achieved down to 1.5 nA. Low power consumption was achieved by utilising small bias current, sharing of key biasing blocks, and utilising a short duty cycle for stimulation. Less than 30 μW was consumed during stand-by mode, mostly by bias circuitry.
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This paper presents a fully integrated RF energy harvester (EH) with 30% end-to-end power harvesting efficiency (PHE) and supports high output voltage operation, up to 9.3V, with a 1.07 GHz input and under the electrode model for neural applications. The EH is composed of a novel 10-stage self-biased gate (SBG) rectifier with an on-chip matching network. The SBG topology elevates the gate-bias of transistors in a non-linear manner to enable higher conductivity. The design also achieves >20% PHE range of 12-dB. The design was fabricated in 65 nm CMOS technology and occupies an area of 0.0732-mm with on-chip matching network. In addition to standalone EH characterization measurement results, animal tissue stimulation test was performed to evaluate its performance in a realistic neural implant application.
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An implantable prosthesis that stimulates vestibular nerve branches to restore sensation of head rotation and vision-stabilizing reflexes could benefit individuals disabled by bilateral loss of vestibular sensation. The normal vestibular system encodes head movement by increasing or decreasing firing rate of the vestibular afferents about a baseline firing rate in proportion to head rotation velocity. Our multichannel vestibular prosthesis emulates this encoding scheme by modulating pulse rate and pulse current amplitude above and below a baseline stimulation rate (BSR) and a baseline stimulation current. Unilateral baseline prosthetic stimulation that mimics normal vestibular afferent baseline firing results in vestibulo-ocular reflex (VOR) eye responses with a wider range of eye velocity in response to stimuli modulated above baseline (excitatory) than below baseline (inhibitory). Stimulus modulation about higher than normal baselines resulted in increased range of inhibitory eye velocity, but decreased range of excitatory eye velocity. Simultaneous modulation of rate and current (co-modulation) above all tested baselines elicited a significantly wider range of excitatory eye velocity than rate or current modulation alone. Time constants associated with the recovery of VOR excitability following adaptation to elevated BSRs implicate synaptic vesicle depletion as a possible mechanism for the small range of excitatory eye velocity elicited by rate modulation alone. These findings can be used toward selecting optimal baseline levels for vestibular stimulation that would result in large inhibitory eye responses while maintaining a wide range of excitatory eye velocity via co-modulation.
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In neuroprostheses applications requiring simultaneous stimulations on a multielectrode array, electric crosstalk, the spatial interaction between electric fields from various electrodes is a major limitation to the performance of multichannel stimulation. This paper presents a multichannel stimulator design that combines high-frequency current stimulation (using biphasic charge-balanced chopped pulse profile) with a switched-capacitor power isolation method. The approach minimizes crosstalk and is particularly suitable for fully integrated realization. A stimulator fabricated in a 0.6 μm CMOS high-voltage technology is presented. It is used to implement a multichannel, high-frequency, power-isolated stimulator. Crosstalk reduction is demonstrated with electrodes in physiological media while the efficacy of the high-frequency stimulator chip is proven in vivo. The stimulator provides fully independent operation on multiple channels and full flexibility in the design of neural modulation protocols.
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