A current-mode system to self-measure temperature on implantable optoelectronics.

BACKGROUND: One of the major concerns in implantable optoelectronics is the heat generated by emitters such as light emitting diodes (LEDs). Such devices typically produce more heat than light, whereas medical regulations state that the surface temperature change of medical implants must stay below + 2 °C. The LED's reverse current can be employed as a temperature-sensitive parameter to measure the temperature change at the implant's surface, and thus, monitor temperature rises. The main challenge in this approach is to bias the LED with a robust voltage since the reverse current is strongly and nonlinearly sensitive to the bias voltage. METHODS: To overcome this challenge, we have developed an area-efficient LED-based temperature sensor using the LED as its own sensor and a CMOS electronic circuit interface to ensure stable bias and current measurement. The circuit utilizes a second-generation current conveyor (CCII) configuration to achieve this and has been implemented in 0.35 µm CMOS technology. RESULTS: The developed circuits have been experimentally characterized, and the temperature-sensing functionality has been tested by interfacing different mini-LEDs in saline models of tissue prior to in vivo operation. The experimental results show the functionality of the CMOS electronics and the efficiency of the CCII-based technique with an operational frequency up to 130 kHz in achieving a resolution of 0.2 °C for the surface temperature up to + 45 °C. CONCLUSIONS: We developed a robust CMOS current-mode sensor interface which has a reliable CCII to accurately convey the LED's reverse current. It is low power and robust against power supply ripple and transistor mismatch which makes it reliable for sensor interface. The achieved results from the circuit characterization and in vivo experiments show the feasibility of the whole sensor interface in monitoring the tissue surface temperature in optogenetics.

Reliable fabrication of sub-10 nm silicon nanowires by optical lithography.

The reliable and controllable fabrication of silicon nanowires is achieved, using mature CMOS technology processes. This will enable a low-cost route to integrating novel nanostructures with CMOS logic. The challenge of process repeatability has been overcome by careful study of material properties for processes such as etching and oxidation. By controlling anisotropic wet etching conditions, selection of nitride mask layer properties and sidewall oxidation, a robust process was achieved to realize silicon nanowires with sub 10 nm features. Surface roughness of nanowires was improved by a suitable oxidation step. The influence of process conditions on the shape of the nanowire was studied using TCAD simulation.

Experimental observation of negative capacitance in ferroelectrics at room temperature.

Effective negative capacitance has been postulated in ferroelectrics because there is a hysteresis in plots of polarization-electric field. Compelling experimental evidence of effective negative capacitance is presented here at room temperature in engineered devices, where it is stabilized by the presence of a paraelectric material. In future integrated circuits, the incorporation of such negative capacitance into MOSFET gate stacks would reduce the subthreshold slope, enabling low power operation and reduced self-heating.

What Is the Correlation between Coronal Plane Alignment Measured on Pre- and Postoperative Weight-bearing Radiographs and Intraoperative Navigation When Stress Is Applied to the Knee?

This study examines the correlation between the weight-bearing (WB) long leg radiograph (LLR)-derived hip-knee-ankle angle (HKAA) and intraoperative supine computer-assisted surgery (CAS)-derived HKAA measurements at the beginning and end of total knee arthroplasty (TKA). The primary aim of the study was to determine if WB alignment could be mimicked or inferred based on intraoperative alignment findings. We conducted a prospective analysis from a cohort of 129 TKAs undergoing a CAS TKA at a single center by a single surgeon. The HKAA was recorded using the CAS navigation system immediately postregistration of navigation data and after implantation of the prosthesis. The intraoperative HKAA was recorded in both the supine "resting" position of the knee and also while the knee was manipulated in an effort to replicate the patient's WB alignment. These measurements were compared with the HKAA recorded on pre- and postoperative WB LLRs. There was a strong correlation between the preoperative WB LLR HKAA and the intraoperative preimplant CAS-derived stressed HKAA (R = 0.946). However, there was no correlation between the postoperative WB LLR HKAA and the postimplant insertion HKAA as measured intraoperatively via CAS for either a "resting" or "stressed" position of the operated knee (R = 0.165 and R = 0.041, respectively). Thus, the interpretation of intraoperative alignment data is potentially problematic. Despite technological advances in the development and utilization of computer navigation and robotics in arthroplasty to help obtain the optimal alignment, it would seem apparent from our study that this alignment does not correlate to upright stance postoperatively. Surgeons should apply caution to the strength of assumptions they place on intraoperative coronal plane alignment findings.

Electrical cross-sectional imaging of human motor units in vivo.

OBJECTIVES: In many neuromuscular diseases, weakness results from a disruption in muscle fibres' arrangement within a motor unit. Limitations in current techniques mean that the spatial distribution of fibres in human motor units remains unknown. METHODS: A flexible multi-channel electrode was developed and bonded to a clinical electromyography (EMG) needle. Muscle fibre action potentials were localised using a novel deconvolution method. This was tested using simulated data, and in recordings collected from the tibialis anterior muscle of healthy subjects. RESULTS: Simulated data indicated good localisation reliability across all sections of the electrode except the end sections. A corrected fibre density was estimated up to 1.4 fibres/mm2. Across five recordings from three individuals, between 4 and 14 motor units were detected. Between 1 and 20 muscle fibres were localised per motor unit within the electrode detection area, with up to 220 muscle fibres localised per recording, with overlapping motor unit territories. CONCLUSIONS: We provide the first direct evidence that human motor units spatially overlap, as well as data related to the spatial arrangement of muscle fibres within a motor unit. SIGNIFICANCE: As well as providing insights into normal human motor physiology, this technology could lead to faster and more accurate diagnosis in patients with neuromuscular diseases.

A Closed-Loop Optogenetic Platform.

Neuromodulation is an established treatment for numerous neurological conditions, but to expand the therapeutic scope there is a need to improve the spatial, temporal and cell-type specificity of stimulation. Optogenetics is a promising area of current research, enabling optical stimulation of genetically-defined cell types without interfering with concurrent electrical recording for closed-loop control of neural activity. We are developing an open-source system to provide a platform for closed-loop optogenetic neuromodulation, incorporating custom integrated circuitry for recording and stimulation, real-time closed-loop algorithms running on a microcontroller and experimental control via a PC interface. We include commercial components to validate performance, with the ultimate aim of translating this approach to humans. In the meantime our system is flexible and expandable for use in a variety of preclinical neuroscientific applications. The platform consists of a Controlling Abnormal Network Dynamics using Optogenetics (CANDO) Control System (CS) that interfaces with up to four CANDO headstages responsible for electrical recording and optical stimulation through custom CANDO LED optrodes. Control of the hardware, inbuilt algorithms and data acquisition is enabled via the CANDO GUI (Graphical User Interface). Here we describe the design and implementation of this system, and demonstrate how it can be used to modulate neuronal oscillations in vitro and in vivo.

A novel hybrid technique to fabricate silicon-based micro-implants with near defect-free quality for neuroprosthetics application.

This paper introduces a new hybrid microfabrication technique which combines ultra-precision micro-milling and a ductile sacrificial material deposition process to fabricate a silicon-based implant for neuroprosthetics applications with near defect-free quality at several hundreds of micrometres in thickness. The sacrificial materials can influence the quality of silicon during machining. The cutting mechanism and feasibility of the hybrid technique are studied by molecular dynamics (MD) simulations and experiments. Due to the complexity of modelling PMMA and SU-8 structures in MD environment, only copper was modelled as the simulation is intended to understand the performance of using a ductile sacrificial layer structure in silicon machining. MD analysis shows that the reduced stress intensity and subsurface damage were mainly attributed to workpiece plasticity enhancement, where its mechanism was contributed by better deformability of the ductile sacrificial layer and enhanced thermal softening from the heat generated by the high interfacial stress between the sacrificial layer and silicon substrate. Despite the MD simulation and experiment having different machining scale in terms of cutting parameters, phenomenal behaviours of the cutting performance when observed under the experimental conditions are in good agreement with simulation. Experimental verification shows that near defect-free quality was achieved at large cutting depth of 150 µm when silicon is coated either with PMMA or SU-8. An exemplary implant structure was also fabricated to better demonstrate the hybrid technique's capability. In addition, the hybrid technique will be beneficial for low volume high customisation applications as it is a serial process.

W:Ti Flexible Transversal Electrode Array for Peripheral Nerve Stimulation: A Feasibility Study.

The development of hardware for neural interfacing remains a technical challenge. We introduce a flexible, transversal intraneural tungsten:titanium electrode array for acute studies. We characterize the electrochemical properties of this new combination of tungsten and titanium using cyclic voltammetry and electrochemical impedance spectroscopy. With an in-vivo rodent study, we show that the stimulation of peripheral nerves with this electrode array is possible and that more than half of the electrode contacts can yield a stimulation selectivity index of 0.75 or higher at low stimulation currents. This feasibility study paves the way for the development of future cost-effective and easy-to-fabricate neural interfacing electrodes for acute settings, which ultimately can inform the development of technologies that enable bi-directional communication with the human nervous system.

Design Considerations for Artefact-Free Optoelectronic Systems.

This paper proposes design considerations that need to be followed in order to eliminate potential sources of artefact that could distort a recorded neural signal. The artefact that appears in a recorded signal has a combination of potential sources each of which contributes towards its formation. As such, these sources of artefact have been addressed in three main categories: a) electronics artefact, b) encapsulation artefact and c) interface artefact. Each source (component) is analyzed further and appropriate design techniques and considerations are suggested towards its mitigation.

Self-sensing of temperature rises on light emitting diode based optrodes.

OBJECTIVE: This work presents a method to determine the surface temperature of microphotonic medical implants like LEDs. Our inventive step is to use the photonic emitter (LED) employed in an implantable device as its own sensor and develop readout circuitry to accurately determine the surface temperature of the device. APPROACH: There are two primary classes of applications where microphotonics could be used in implantable devices; opto-electrophysiology and fluorescence sensing. In such scenarios, intense light needs to be delivered to the target. As blue wavelengths are scattered strongly in tissue, such delivery needs to be either via optic fibres, two-photon approaches or through local emitters. In the latter case, as light emitters generate heat, there is a potential for probe surfaces to exceed the 2 °C regulatory. However, currently, there are no convenient mechanisms to monitor this in situ. MAIN RESULTS: We present the electronic control circuit and calibration method to monitor the surface temperature change of implantable optrode. The efficacy is demonstrated in air, saline, and brain. SIGNIFICANCE: This paper, therefore, presents a method to utilize the light emitting diode as its own temperature sensor.

Voltage Controlled Hot Carrier Injection Enables Ohmic Contacts Using Au Island Metal Films on Ge.

We introduce a new approach to creating low-resistance metal-semiconductor ohmic contacts, illustrated using high conductivity Au island metal films (IMFs) on Ge, with hot carrier injection initiated at low applied voltage. The same metallization process simultaneously allows ohmic contact to n-Ge and p-Ge, because hot carriers circumvent the Schottky barrier formed at metal/n-Ge interfaces. A 2.5× improvement in contact resistivity is reported over previous techniques to achieve ohmic contact to both n- and p- semiconductor. Ohmic contacts at 4.2 K confirm nonequilibrium current transport. Self-assembled Au IMFs are strongly orientated to Ge by annealing near the Au/Ge eutectic temperature. Au IMF nanostructures form, provided the Au layer is below a critical thickness. We anticipate that optimized IMF contacts may have applicability to many material systems. Optimizing this new paradigm for metal-semiconductor contacts offers the prospect of improved nanoelectronic systems and the study of voltage controlled hot holes and electrons.

Mechanical Flexibility Reduces the Foreign Body Response to Long-Term Implanted Microelectrodes in Rabbit Cortex.

Micromotion between the brain and implanted electrodes is a major contributor to the failure of invasive microelectrodes. Movements of the electrode tip cause recording instabilities while spike amplitudes decline over the weeks/months post-implantation due to glial cell activation caused by sustained mechanical trauma. We compared the glial response over a 26-96 week period following implantation in the rabbit cortex of microwires and a novel flexible electrode. Horizontal sections were used to obtain a depth profile of the radial distribution of microglia, astrocytes and neurofilament. We found that the flexible electrode was associated with decreased gliosis compared to the microwires over these long indwelling periods. This was in part due to a decrease in overall microgliosis and enhanced neuronal density around the flexible probe, especially at longer periods of implantation.

The sinusoidal probe: a new approach to improve electrode longevity.

Micromotion between the brain and implanted electrodes is a major contributor to the failure of invasive brain-machine interfaces. Movements of the electrode tip cause recording instabilities while spike amplitudes decline over the weeks/months post-implantation due to glial cell activation caused by sustained mechanical trauma. We have designed a sinusoidal probe in order to reduce movement of the recording tip relative to the surrounding neural tissue. The probe was microfabricated from flexible materials and incorporated a sinusoidal shaft to minimize tethering forces and a 3D spheroid tip to anchor the recording site within the brain. Compared to standard microwire electrodes, the signal-to-noise ratio and local field potential power of sinusoidal probe recordings from rabbits was more stable across recording periods up to 678 days. Histological quantification of microglia and astrocytes showed reduced neuronal tissue damage especially for the tip region between 6 and 24 months post-implantation. We suggest that the micromotion-reducing measures incorporated into our design, at least partially, decreased the magnitude of gliosis, resulting in enhanced longevity of recording.

Genome-wide association study of multiplex schizophrenia pedigrees.

OBJECTIVE: The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD: The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS: No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10(-17), explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS: Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia.

We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r(2)>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10 × 10(-3) and rs2274736, P=1.21 × 10(-3)). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86-0.97, P=5.45 × 10(-3) and rs2401751, OR=0.92, 95% CI: 0.86-0.97, P=5.29 × 10(-3)). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR=1.08, 95% CI: 1.02-1.14, P=6.43 × 10(-3)). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.

Pediatric trampoline injuries.

INTRODUCTION: The recreational use of trampolines has increased dramatically during the last 10 years. There has been a striking increase in the number of children presenting to fracture clinics with injuries associated with trampoline use. This increase in trampoline injuries has been reported in North America, but there has been a paucity of research in this area in Europe. METHODS: We prospectively recorded details of patients presenting to our institution, Our Lady's Children's Hospital, Crumlin (Dublin, Ireland), during the busy summer months of June, July, and August 2005. Details recorded included type and mechanism of injury, the mode of referral, treatment, inpatient days, outpatient visits, specific details relating to trampoline safety, and an analysis of the cost of medical care. RESULTS: There were 101 patients treated for trampoline-related injuries in 3 months from June to August 2005. This represented 1.5% of the total attendances to the emergency department. The average age was 8.5 years (range, 1.4-17.4 years). There were 55 fractures, 38 soft tissue injuries, 5 head injuries, and 5 neck injuries, with an average Pediatric Trauma Score of 11.4. Fifty seven percent (58/101) of patients were on the trampoline with at least 1 other person. Twenty patients (19.8%) were admitted to hospital requiring 71 inpatient days. Twelve patients were treated in theatre. There were 163 fracture clinic visits, 212 x-rays, and 2 magnetic resonance imaging scans. CONCLUSIONS: Trampolines are a high-risk activity with the potential for significant orthopaedic injury. In Ireland, we have recently seen a dramatic increase in pediatric trampoline-related injuries mirroring the trend in the United States during the last 10 to 15 years. We found that more than 1 individual on a trampoline is a major risk factor for injury, where the lightest person is 14 times more likely to be injured than the heavier. The lighter person also has a greater chance of being injured with smaller numbers on the trampoline. We reiterate the American Academy of Pediatrics policy statement advice that trampolines be used only in supervised training programs--never at home, in outdoor playgrounds, or in schools. The public should be made aware of the potential dangers of trampolines through public health campaigns, radio, and television.