Emerging trends in the development of flexible optrode arrays for electrophysiology.

Optical-electrode (optrode) arrays use light to modulate excitable biological tissues and/or transduce bioelectrical signals into the optical domain. Light offers several advantages over electrical wiring, including the ability to encode multiple data channels within a single beam. This approach is at the forefront of innovation aimed at increasing spatial resolution and channel count in multichannel electrophysiology systems. This review presents an overview of devices and material systems that utilize light for electrophysiology recording and stimulation. The work focuses on the current and emerging methods and their applications, and provides a detailed discussion of the design and fabrication of flexible arrayed devices. Optrode arrays feature components non-existent in conventional multi-electrode arrays, such as waveguides, optical circuitry, light-emitting diodes, and optoelectronic and light-sensitive functional materials, packaged in planar, penetrating, or endoscopic forms. Often these are combined with dielectric and conductive structures and, less frequently, with multi-functional sensors. While creating flexible optrode arrays is feasible and necessary to minimize tissue-device mechanical mismatch, key factors must be considered for regulatory approval and clinical use. These include the biocompatibility of optical and photonic components. Additionally, material selection should match the operating wavelength of the specific electrophysiology application, minimizing light scattering and optical losses under physiologically induced stresses and strains. Flexible and soft variants of traditionally rigid photonic circuitry for passive optical multiplexing should be developed to advance the field. We evaluate fabrication techniques against these requirements. We foresee a future whereby established telecommunications techniques are engineered into flexible optrode arrays to enable unprecedented large-scale high-resolution electrophysiology systems.

Liquid crystal electro-optical transducers for electrophysiology sensing applications.

Objective.Biomedical instrumentation and clinical systems for electrophysiology rely on electrodes and wires for sensing and transmission of bioelectric signals. However, this electronic approach constrains bandwidth, signal conditioning circuit designs, and the number of channels in invasive or miniature devices. This paper demonstrates an alternative approach using light to sense and transmit the electrophysiological signals.Approach.We develop a sensing, passive, fluorophore-free optrode based on the birefringence property of liquid crystals (LCs) operating at the microscale.Main results.We show that these optrodes can have the appropriate linearity (µ± s.d.: 99.4 ± 0.5%,n = 11 devices), relative responsivity (µ± s.d.: 57 ± 12%V-1,n = 5 devices), and bandwidth (µ± s.d.: 11.1 ± 0.7 kHz,n = 7 devices) for transducing electrophysiology signals into the optical domain. We report capture of rabbit cardiac sinoatrial electrograms and stimulus-evoked compound action potentials from the rabbit sciatic nerve. We also demonstrate miniaturisation potential by fabricating multi-optrode arrays, by developing a process that automatically matches each transducer element area with that of its corresponding biological interface.Significance.Our method of employing LCs to convert bioelectric signals into the optical domain will pave the way for the deployment of high-bandwidth optical telecommunications techniques in ultra-miniature clinical diagnostic and research laboratory neural and cardiac interfaces.

Impedance Properties of Multi-Optrode Biopotential Sensing Arrays.

Recording and monitoring electrically-excitable cells is critical to understanding the complex cellular networking within organs as well as the processes underlying many electro-physiological pathologies. Biopotential recording using an optical-electrode (optrode) is a novel approach which has potential to significantly improve interface-instrumentation impedance mismatching as recording contact-sizes become smaller and smaller. Optrodes incorporate a conductive interface that can sense extracellular potential and an underlying layer of liquid crystals that passively transduces electrical signals into measurable optical signals. This study investigates the impedance properties of this optical technology by varying the diameter of recording sites and observing the corresponding changes in the impedance values. The results show that the liquid crystals in this optrode platform exhibit input impedance values (1 MΩ - 100 GΩ) that are three orders of magnitude higher than the corresponding interface impedance, which is appropriate for voltage sensing. The automatic scaling of the input impedance enabled within the optrode system maintains a relatively constant ratio between input and total system impedance of about one for sensing areas with diameters ranging from 40 µm to 1 mm, at which the calculated signal loss is predicted to be <1%. This feature preserves the interface-transducer impedance ratio, regardless of the size of the recording site, allowing development of passive optrode arrays capable of very high spatial-resolution recordings.

Photodiode working in zero-mode: detecting light power change with DC rejection and AC amplification.

We propose a new mode of operation when using a photodiode to extract a variable optical signal from a constant (ambient) background. The basic idea of this 'zero-mode' of operation is to force the photodiode to operate at either zero current or zero voltage. We present possible implementations of this novel approach and provide the corresponding equivalent circuits while also demonstrating experimentally its performance. The gain and bandwidth of the zero-mode photodetector are measured and simulated, and they show highly agreement. The gain compression effect because of the nonlinearity of the forward bias region is also explored. Comparing to the conventional photoconductive photodetector, the zero-mode photodetector is able to obtain higher AC gain and lower noise. With the same component used in the circuit, the measured input referred root mean square noise of zero-mode photodetector is 4.4mV whereas that of the photoconductive mode photodetector is 96.9mV respectively, showing the feasibility of the zero-mode of operation for measuring the small variable light signal under a high power constant background light.

Instantaneous VO2 from a wearable device.

We present a method for calculating instantaneous oxygen uptake (VO2) through the use of a non-invasive and non-obtrusive (i.e. without a face mask) wearable device, together with its clinical evaluation against a standard technique based upon expired gas calorimetry. This method can be integrated with existing wearable devices, we implemented it in the "Device for Reliable Energy Expenditure Monitoring" (DREEM). The DREEM comprises a single lead electrocardiogram (ECG) device combined with a tri-axial accelerometer and is worn around the waist. Our clinical evaluation tests the developed method against a gold standard for VO2, expired gas calorimetry, using an ethically approved protocol comprising active exercise and sedentary periods. The study was performed on 42 participants from a wide sample population including healthy people, athletes and an at-risk health group including persons affected by obesity. We developed an algorithm combining heart rate (HR) and the integral of absolute acceleration (IAA), with results showing a correlation of r = 0.93 for instantaneous VO2, and r = 0.97 for 3 min mean VO2, this is a considerably improved estimation of VO2 in comparison to methods utilising HR and IAA independently.

A 0.04 mm (2) Buck-Boost DC-DC Converter for Biomedical Implants Using Adaptive Gain and Discrete Frequency Scaling Control.

This paper presents the design of a reconfigurable buck-boost switched-capacitor DC-DC converter suitable for use in a wide range of biomedical implants. The proposed converter has an extremely small footprint and uses a novel control method that allows coarse and fine control of the output voltage. The converter uses adaptive gain control, discrete frequency scaling and pulse-skipping schemes to regulate the power delivered to a range of output voltages and loads. Adaptive gain control is used to implement variable switching gain ratios from a reconfigurable power stage and thereby make coarse steps in output voltage. A discrete frequency scaling controller makes discrete changes in switching frequency to vary the power delivered to the load and perform fine tuning when the output voltage is within 10% of the target output voltage. The control architecture is predominately digital and it has been implemented as part of a fully-integrated switched-capacitor converter design using a standard bulk CMOS 0.18 µm process. Measured results show that the converter has an output voltage range of 1.0 to 2.2 V, can deliver up to 7.5 mW of load power and efficiency up to 75% using an active area of only 0.04 mm (2), which is significantly smaller than that of other designs. This low-area, low-complexity reconfigurable power converter can support low-power circuits in biomedical implant applications.

Concept Design for a 1-Lead Wearable/Implantable ECG Front-End: Power Management.

Power supply quality and stability are critical for wearable and implantable biomedical applications. For this reason we have designed a reconfigurable switched-capacitor DC-DC converter that, aside from having an extremely small footprint (with an active on-chip area of only 0.04 mm²), uses a novel output voltage control method based upon a combination of adaptive gain and discrete frequency scaling control schemes. This novel DC-DC converter achieves a measured output voltage range of 1.0 to 2.2 V with power delivery up to 7.5 mW with 75% efficiency. In this paper, we present the use of this converter as a power supply for a concept design of a wearable (15 mm × 15 mm) 1-lead ECG front-end sensor device that simultaneously harvests power and communicates with external receivers when exposed to a suitable RF field. Due to voltage range limitations of the fabrication process of the current prototype chip, we focus our analysis solely on the power supply of the ECG front-end whose design is also detailed in this paper. Measurement results show not just that the power supplied is regulated, clean and does not infringe upon the ECG bandwidth, but that there is negligible difference between signals acquired using standard linear power-supplies and when the power is regulated by our power management chip.

A novel method for non-invasive respiration monitoring.

In this paper we present an atypical method for measuring respiration volume. We infer heart rate variability (HRV) from an electrocardiogram (ECG) and present results from a pilot study of 6 participants to validate measuring respiration volume from HRV in comparison to the Cosmed K4b(2). We show a qualitative correlation and trend between the known respiration volume as measured by the Cosmed K4b(2) and the new method for measuring lung volume. From these results, we propose guidelines for an in-depth study of measuring respiration volumes from heart rate variability.

Safety ensuring retinal prosthesis with precise charge balance and low power consumption.

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.

The ripple pond: enabling spiking networks to see.

We present the biologically inspired Ripple Pond Network (RPN), a simply connected spiking neural network which performs a transformation converting two dimensional images to one dimensional temporal patterns (TP) suitable for recognition by temporal coding learning and memory networks. The RPN has been developed as a hardware solution linking previously implemented neuromorphic vision and memory structures such as frameless vision sensors and neuromorphic temporal coding spiking neural networks. Working together such systems are potentially capable of delivering end-to-end high-speed, low-power and low-resolution recognition for mobile and autonomous applications where slow, highly sophisticated and power hungry signal processing solutions are ineffective. Key aspects in the proposed approach include utilizing the spatial properties of physically embedded neural networks and propagating waves of activity therein for information processing, using dimensional collapse of imagery information into amenable TP and the use of asynchronous frames for information binding.

New methods for clinical pathways-Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM).

PURPOSE: Clinical pathways (CP) are nowadays used in numerous institutions, but their real impact is still a matter of debate. The optimal design of a clinical pathway remains unclear and is mainly determined by the expectations of the individual institution. The purpose of the here described pilot project was the development of two CP (colon and rectum carcinoma) according to Business Process Modeling Notation (BPMN) and Tangible Business Process Modeling (t.BPM). METHODS: BPMN is an established standard for business process modelling in industry and economy. It is, in the broadest sense, a computer programme which enables the description and a relatively easy graphical imaging of complex processes. t.BPM is a modular construction system of the BPMN symbols which enables the creation of an outline or raw model, e.g. by placing the symbols on a spread-out paper sheet. The thus created outline can then be transferred to the computer and further modified as required. CP for the treatment of colon and rectal cancer have been developed with support of an external IT coach. RESULTS: The pathway was developed in an interdisciplinary and interprofessional manner (55 man-days over 15 working days). During this time, necessary interviews with medical, nursing and administrative staffs were conducted as well. Both pathways were developed parallel. Subsequent analysis was focussed on feasibility, expenditure, clarity and suitability for daily clinical practice. The familiarization with BPMN was relatively quick and intuitive. The use of t.BPM enabled the pragmatic, effective and results-directed creation of outlines for the CP. The development of both CP was finished from the diagnostic evaluation to the adjuvant/neoadjuvant therapy and rehabilitation phase. The integration of checklists, guidelines and important medical or other documents is easily accomplished. A direct integration into the hospital computer system is currently not possible for technical reasons. CONCLUSION: BPMN and t.BPM are sufficiently suitable for the planned modelling and imaging of CP. The application in medicine is new, and transfer from the industrial process management is in principle possible. BPMN-CP may be used for teaching and training, patient information and quality management. The graphical image is clearly structured and appealing. Even though the efficiency in the creation of BPMN-CP increases markedly after the training phase, high amounts of manpower and time are required. The most sensible and consequent application of a BPMN-CP would be the direct integration into the hospital computer system. The integration of a modelling language, such as BPMN, into the hospital computer systems could be a very sensible approach for the development of new hospital information systems in the future.

Required matching accuracy of biphasic current pulse in multi-channel current mode bipolar stimulation for safety.

In neural stimulation, a current mode stimulation is preferred to a voltage mode stimulation, as it has more control over injecting charge into tissue. A matched biphasic current pulse is often employed in current mode stimulation. For safe neural stimulation, in other words, to ensure zero-net charge transfer (charge balance) into tissue, it is required to utilise a precisely matched biphasic current pulse. Mismatch in the biphasic current pulse causes residual charge on stimulating electrodes during stimulation, which will induce DC current flowing into tissue, possibly leading to tissue damage. In this paper, we derive mathematical expressions of the required matching accuracy on the biphasic current pulse under 4 different situations to ensure a safe neural stimulation; 1) single channel stimulation without shorting, 2) single channel stimulation with shorting, 3) multi-channel stimulation without shorting and 4) multi-channel stimulation with shorting.

Towards a chip scale neurostimulator: system architecture of a current-driven 98 channel neurostimulator via a two-wire interface.

With more clinical trials proving viability of visual prosthesis follows the demand for higher resolution devices. As the number of electrodes increases, due to surgical difficulties, it is preferred to keep their length short by placing the implant close to the stimulation site, where there are considerable constraints on device size. On the contrary, the physical volume of the implant generally increases with increasing number of electrodes. Splitting the implant into two modules and placing only the essential circuits near the site of stimulation solves the aforementioned problem. However now the problem is redirected to the robustness and the safety of the interface joining these modules. A novel two-wire interface driving a 98 channel neurostimulator incorporating the split-architecture is presented. The stimulator is provided with both power and data by sending square current waveforms via the two-wire interface. The stimulator itself is fabricated using 0.35 µm HVCMOS technology and occupies 4.9 × 4.9 mm(2) and requires no external decoupling capacitor.

Laser-micromachined, chip-scaled ceramic carriers for implantable neurostimulators.

Hermetic encapsulation of long-term implantable devices using ceramics has been investigated over several decades. Our studies focus on the miniaturization of ceramic encapsulations for large numbers of stimulation channels. Laser-patterning of screen printed platinum (Pt) paste on cofired ceramics has been shown to enable the construction of features comparable in size to classical screen printing. A novel technique for embedding Pt structures into the surface of Al(2)O(3) substrates is shown to produce features with a line width minimum of 20 µm and a pitch of 40 µm. Polishing the ceramic substrates enables flip-chip bonding of application specific integrated circuits (ASIC) using gold stud bumps. A new technique for fine tuning of an ASIC stimulator with stud bump bridges is described. The technique eliminates the need for wire bond loops and increases reliability and integration density of the system, which are major requirements used to construct a visual prosthesis or other implantable devices requiring miniaturization. The methods for laser-patterned Pt tracks in alumina for fine pitch structures are described. Feasibility studies for flip-chip bonding and stud bump bridges were undertaken and the results were found to be promising.

Retinal neurostimulator for a multifocal vision prosthesis.

A neurostimulator application-specific integrated circuit (ASIC) with scalable circuitry that can stimulate 14 channels, has been developed for an epi-retinal vision prosthesis. This ASIC was designed to allow seven identical units to be connected to control up to 98 channels, with the ability to stimulate 14 electrodes simultaneously. The neurostimulator forms part of a vision prosthesis, designed to restore vision to patients who have lost their sight due to retinal diseases such as retinitis pigmentosa and macular degeneration. For charge balance, the neurostimulator was designed to stimulate with current sources and sinks operating together, and with the ability to drive a hexagonal mosaic of electrodes to reduce the electrical crosstalk that occurs when multiple bipolar stimulation sites are active simultaneously. A hexagonal mosaic of electrodes surrounds each stimulation site and has been shown to effectively isolate each site, increasing the ability to inject localized independent charge into multiple regions simultaneously.