Miniature fluorescence sensor for quantitative detection of brain tumour.

Fluorescence-guided surgery has emerged as a vital tool for tumour resection procedures. As well as intraoperative tumour visualisation, 5-ALA-induced PpIX provides an avenue for quantitative tumour identification based on ratiometric fluorescence measurement. To this end, fluorescence imaging and fibre-based probes have enabled more precise demarcation between the cancerous and healthy tissues. These sensing approaches, which rely on collecting the fluorescence light from the tumour resection site and its "remote" spectral sensing, introduce challenges associated with optical losses. In this work, we demonstrate the viability of tumour detection at the resection site using a miniature fluorescence measurement system. Unlike the current bulky systems, which necessitate remote measurement, we have adopted a millimetre-sized spectral sensor chip for quantitative fluorescence measurements. A reliable measurement at the resection site requires a stable optical window between the tissue and the optoelectronic system. This is achieved using an antifouling diamond window, which provides stable optical transparency. The system achieved a sensitivity of 92.3% and specificity of 98.3% in detecting a surrogate tumour at a resolution of 1 × 1 mm2. As well as addressing losses associated with collecting and coupling fluorescence light in the current 'remote' sensing approaches, the small size of the system introduced in this work paves the way for its direct integration with the tumour resection tools with the aim of more accurate interoperative tumour identification.

Control of Neuronal Survival and Development Using Conductive Diamond.

This study demonstrates the control of neuronal survival and development using nitrogen-doped ultrananocrystalline diamond (N-UNCD). We highlight the role of N-UNCD in regulating neuronal activity via near-infrared illumination, demonstrating the generation of stable photocurrents that enhance neuronal survival and neurite outgrowth and foster a more active, synchronized neuronal network. Whole transcriptome RNA sequencing reveals that diamond substrates improve cellular-substrate interaction by upregulating extracellular matrix and gap junction-related genes. Our findings underscore the potential of conductive diamond as a robust and biocompatible platform for noninvasive and effective neural tissue engineering.

Diamond electrodes for controlling stem cells.

Electrical stimulation is one of several methods for controlling differentiation and proliferation of stem cells. This work demonstrated the use of nitrogen-doped ultra-nanocrystalline diamond (N-UNCD) electrodes as a substrate for the growth of human mesenchymal stem cells (hMSCs). As well as exhibiting a high charge injection capacity, N-UNCD displays high cytocompatibility making it suitable electrode material for stem cell stimulation.Clinical Relevance-This work establishes that N-UNCD electrodes can support the growth of hMSCs.

Spectral and temporal detection of blood bilirubin level using a point-of-care device.

Bilirubin is a biomarker for liver inflammation used to assess liver functions. Its concentration in the blood has been measured using a range of techniques both in clinical and point-of-care settings. Existing point-of-care devices utilize a spectral approach, namely dual-wavelength absorption measurement, to assess the blood bilirubin concentration. This work examines a novel temporal approach based on the photodegradation of bilirubin in the blood sample. It demonstrates that combining photodegradation characteristics with dual-wavelength measurement produces a more accurate technique for measuring blood bilirubin concentration. Tracking the evolution of absorbed light as a function of time represents a low-cost and simple way of improving the accuracy of point-of-care devices for bilirubin measurements.Clinical Relevance - This work demonstrates a facile and cheap bilirubin monitoring approach that may allow bilirubin monitoring applications in homes after a patient is discharged from a hospital, which may decrease the burden on patients, families, and clinicians.

Semiconducting electrodes for neural interfacing: a review.

In the past 50 years, the advent of electronic technology to directly interface with neural tissue has transformed the fields of medicine and biology. Devices that restore or even replace impaired bodily functions, such as deep brain stimulators and cochlear implants, have ushered in a new treatment era for previously intractable conditions. Meanwhile, electrodes for recording and stimulating neural activity have allowed researchers to unravel the vast complexities of the human nervous system. Recent advances in semiconducting materials have allowed effective interfaces between electrodes and neuronal tissue through novel devices and structures. Often these are unattainable using conventional metallic electrodes. These have translated into advances in research and treatment. The development of semiconducting materials opens new avenues in neural interfacing. This review considers this emerging class of electrodes and how it can facilitate electrical, optical, and chemical sensing and modulation with high spatial and temporal precision. Semiconducting electrodes have advanced electrically based neural interfacing technologies owing to their unique electrochemical and photo-electrochemical attributes. Key operation modalities, namely sensing and stimulation in electrical, biochemical, and optical domains, are discussed, highlighting their contrast to metallic electrodes from the application and characterization perspective.

A purely solid-state based method for bilirubin levels determination in plasma.

In the past half-century, the advent of solid-state electronics, i.e., microcontrollers, transistors, photodiodes, light-emitting diodes and more, has led to the improvement of the tools we, as a human race, need and use in our daily lives. Solid-state electronics has specifically contributed significantly to the field of biomedical engineering and has allowed various round-the-clock point-of-care testing applications. These include handheld, wearable, and implantable sensors and devices for accelerated interventions. Furthermore, miniaturization has accelerated the implementation of low-cost and energy-efficient systems with increased performance. In this paper, we have used optical techniques along with the benefits of solid-state electronics to measure bilirubin concentration in plasma with concentrations projected from healthy individuals to hyperbilirubinemia (0 - 30 mg/dL). Traditionally, full-range spectrophotometry is the gold standard optical method and provides the most accurate results but suffers from instrument complexity. Thus, this paper proposes and investigates the measurement of bilirubin by using a dual-wavelength approach combined with photodegradation kinetics. By tracking the changes in the spectral characteristics of bilirubin for 10 minutes (~3 J/cm2), a new model was built to measure bilirubin concentrations and distinguish between low vs high and risky vs non-risky levels. Results show a high positive correlation between the optical responses and concentration (R-square > 0.93) with an average accuracy of ~1.4 mg/dL. On top of that, the technique's viability for point-of-care testing of bilirubin levels was studied using a system-on-chip optical module. Thus, this could help suggest neonatal therapeutic interventions, including enteral feeding, phototherapy, and blood transfusion.

Diamond Supercapacitors: Towards Durable, Safe, and Biocompatible Aqueous-Based Energy Storage.

Durable and safe energy storage is required for the next generation of miniature bioelectronic devices, in which aqueous electrolytes are preferred due to the advantages in safety, low cost, and high conductivity. While rechargeable aqueous batteries are among the primary choices with relatively low power requirements, their lifetime is generally limited to a few thousand charging/discharging cycles as the electrode material can degrade due to electrochemical reactions. Electrical double layer capacitors (EDLCs) possess increased cycling stability and power density, although with as-yet lower energy density, due to quick electrical adsorption and desorption of ions without involving chemical reactions. However, in aqueous solution, chemical reactions which cause electrode degradation and produce hazardous species can occur when the voltage is increased beyond its operation window to improve the energy density. Diamond is a durable and biocompatible electrode material for supercapacitors, while at the same time provides a larger voltage window in biological environments. For applications requiring higher energy density, diamond-based pseudocapacitors (PCs) have also been developed, which combine EDLCs with fast electrochemical reactions. Here we inspect the properties of diamond-related materials and discuss their advantages and disadvantages when used as EDLC and PC materials. We argue that further optimization of the diamond surface chemistry and morphology, guided by computational modelling of the interface, can lead to supercapacitors with enhanced performance. We envisage that such diamond-based supercapacitors could be used in a wide range of applications and in particular those requiring high performance in biomedical applications.

A Novel Optical Assay System for Bilirubin Concentration Measurement in Whole Blood.

As a biomarker for liver disease, bilirubin has been utilized in prognostic scoring systems for cirrhosis. While laboratory-based methods are used to determine bilirubin levels in clinical settings, they do not readily lend themselves to applications outside of hospitals. Consequently, bilirubin monitoring for cirrhotic patients is often performed only intermittently; thus, episodes requiring clinical interventions could be missed. This work investigates the feasibility of measuring bilirubin concentration in whole porcine blood samples using dual-wavelength transmission measurement. A compact and low-cost dual-wavelength transmission measurement setup is developed and optimized to measure whole blood bilirubin concentrations. Using small volumes of whole porcine blood (72 µL), we measured the bilirubin concentration within a range corresponding to healthy individuals and cirrhotic patients (1.2-30 mg/dL). We demonstrate that bilirubin levels can be estimated with a positive correlation (R-square > 0.95) and an accuracy of ±1.7 mg/dL, with higher reliability in cirrhotic bilirubin concentrations (> 4 mg/dL) - critical for high-risk patients. The optical and electronic components utilized are economical and can be readily integrated into a miniature, low-cost, and user-friendly system. This could provide a pathway for point-of-care monitoring of blood bilirubin outside of medical facilities (e.g., patient's home).

Single-Step Fabrication Method toward 3D Printing Composite Diamond-Titanium Interfaces for Neural Applications.

Owing to several key attributes, diamond is an attractive candidate material for neural interfacing electrodes. The emergence of additive-manufacturing (AM) of diamond-based materials has addressed multiple challenges associated with the fabrication of diamond electrodes using the conventional chemical vapor deposition (CVD) approach. Unlike the CVD approach, AM methods have enabled the deposition of three-dimensional diamond-based material at room temperature. This work demonstrates the feasibility of using laser metal deposition to fabricate diamond-titanium hybrid electrodes for neuronal interfacing. In addition to exhibiting a high electrochemical capacitance of 1.1 mF cm-2 and a low electrochemical impedance of 1 kΩ cm2 at 1 kHz in physiological saline, these electrodes exhibit a high degree of biocompatibility assessed in vitro using cortical neurons. Furthermore, surface characterization methods show the presence of an oxygen-rich mixed-phase diamond-titanium surface along the grain boundaries. Overall, we demonstrated that our unique approach facilitates printing biocompatible titanium-diamond site-specific coating-free conductive hybrid surfaces using AM, which paves the way to printing customized electrodes and interfacing implantable medical devices.

Laser Driven Miniature Diamond Implant for Wireless Retinal Prostheses.

The design and benchtop operation of a wireless miniature epiretinal stimulator implant is reported. The implant is optically powered and controlled using safe illumination at near-infrared wavelengths. An application-specific integrated circuit (ASIC) hosting a digital control unit is used to control the implant's electrodes. The ASIC is powered using an advanced photovoltaic (PV) cell and programmed using a single photodiode. Diamond packaging technology is utilized to achieve high-density integration of the implant optoelectronic circuitry, as well as individual connections between a stimulator chip and 256 electrodes, within a 4.6 mm × 3.7 mm × 0.9 mm implant package. An ultrahigh efficiency PV cell with a monochromatic power conversion efficiency of 55% is used to power the implant. On-board photodetection circuity with a bandwidth of 3.7 MHz is used for forward data telemetry of stimulation parameters. In comparison to implants which utilize inductively coupled coils, laser power delivery enables a high degree of miniaturization and lower surgical complexity. The device presented combines the benefits of implant miniaturization and a flexible stimulation strategy provided by a dedicated stimulator chip. This development provides a route to fully wireless miniaturized minimally invasive implants with sophisticated functionalities.

In vivo feasibility of epiretinal stimulation using ultrananocrystalline diamond electrodes.

OBJECTIVE: Due to their increased proximity to retinal ganglion cells (RGCs), epiretinal visual prostheses present the opportunity for eliciting phosphenes with low thresholds through direct RGC activation. This study characterised the in vivo performance of a novel prototype monolithic epiretinal prosthesis, containing Nitrogen incorporated ultrananocrystalline (N-UNCD) diamond electrodes. APPROACH: A prototype implant containing up to twenty-five 120 × 120 µm N-UNCD electrodes was implanted into 16 anaesthetised cats and attached to the retina either using a single tack or via magnetic coupling with a suprachoroidally placed magnet. Multiunit responses to retinal stimulation using charge-balanced biphasic current pulses were recorded acutely in the visual cortex using a multichannel planar array. Several stimulus parameters were varied including; the stimulating electrode, stimulus polarity, phase duration, return configuration and the number of electrodes stimulated simultaneously. MAIN RESULTS: The rigid nature of the device and its form factor necessitated complex surgical procedures. Surgeries were considered successful in 10/16 animals and cortical responses to single electrode stimulation obtained in eight animals. Clinical imaging and histological outcomes showed severe retinal trauma caused by the device in situ in many instances. Cortical measures were found to significantly depend on the surgical outcomes of individual experiments, phase duration, return configuration and the number of electrodes stimulated simultaneously, but not stimulus polarity. Cortical thresholds were also found to increase over time within an experiment. SIGNIFICANCE: The study successfully demonstrated that an epiretinal prosthesis containing diamond electrodes could produce cortical activity with high precision, albeit only in a small number of cases. Both surgical approaches were highly challenging in terms of reliable and consistent attachment to and stabilisation against the retina, and often resulted in severe retinal trauma. There are key challenges (device form factor and attachment technique) to be resolved for such a device to progress towards clinical application, as current surgical techniques are unable to address these issues.

Feasibility of Nitrogen Doped Ultrananocrystalline Diamond Microelectrodes for Electrophysiological Recording From Neural Tissue.

Neural prostheses that can monitor the physiological state of a subject are becoming clinically viable through improvements in the capacity to record from neural tissue. However, a significant limitation of current devices is that it is difficult to fabricate electrode arrays that have both high channel counts and the appropriate electrical properties required for neural recordings. In earlier work, we demonstrated nitrogen doped ultrananocrystalline diamond (N-UNCD) can provide efficacious electrical stimulation of neural tissue, with high charge injection capacity, surface stability and biocompatibility. In this work, we expand on this functionality to show that N-UNCD electrodes can also record from neural tissue owing to its low electrochemical impedance. We show that N-UNCD electrodes are highly flexible in their application, with successful recordings of action potentials from single neurons in an in vitro retina preparation, as well as local field potential responses from in vivo visual cortex tissue. Key properties of N-UNCD films, combined with scalability of electrode array fabrication with custom sizes for recording or stimulation along with integration through vertical interconnects to silicon based integrated circuits, may in future form the basis for the fabrication of versatile closed-loop neural prostheses that can both record and stimulate.

Diamond Devices for High Acuity Prosthetic Vision.

Retinal implants restore a sense of vision, for a growing number of users worldwide. Nevertheless, visual acuities provided by the current generation of devices are low. The quantity of information transferable to the retina using existing implant technologies is limited, far below receptor cells' capabilities. Many agree that increasing the information density deliverable by a retinal prosthesis requires devices with stimulation electrodes that are both dense and numerous. This work describes a new generation of retinal prostheses capable of upscaling the information density conveyable to the retina. Centered on engineered diamond materials, the implant is very well tolerated and long-term stable in the eye's unique physiological environment and capable of delivering highly versatile stimulation waveforms - both key attributes in providing useful vision. Delivery of high-density information, close to the retina with the flexibility to alter stimulation parameters in situ provides the best chance for success in providing high acuity prosthetic vision.

Optimizing growth and post treatment of diamond for high capacitance neural interfaces.

Electrochemical and biological properties are two crucial criteria in the selection of the materials to be used as electrodes for neural interfaces. For neural stimulation, materials are required to exhibit high capacitance and to form intimate contact with neurons for eliciting effective neural responses at acceptably low voltages. Here we report on a new high capacitance material fabricated using nitrogen included ultrananocrystalline diamond (N-UNCD). After exposure to oxygen plasma for 3 h, the activated N-UNCD exhibited extremely high electrochemical capacitance greater than 1 mF/cm(2), which originates from the special hybrid sp(2)/sp(3) structure of N-UNCD. The in vitro biocompatibility of the activated N-UNCD was then assessed using rat cortical neurons and surface roughness was found to be critical for healthy neuron growth, with best results observed on surfaces with a roughness of approximately 20 nm. Therefore, by using oxygen plasma activated N-UNCD with appropriate surface roughness, and considering the chemical and mechanical stability of diamond, the fabricated neural interfaces are expected to exhibit high efficacy, long-term stability and a healthy neuron/electrode interface.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity.

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

Development of a Magnetic Attachment Method for Bionic Eye Applications.

Successful visual prostheses require stable, long-term attachment. Epiretinal prostheses, in particular, require attachment methods to fix the prosthesis onto the retina. The most common method is fixation with a retinal tack; however, tacks cause retinal trauma, and surgical proficiency is important to ensure optimal placement of the prosthesis near the macula. Accordingly, alternate attachment methods are required. In this study, we detail a novel method of magnetic attachment for an epiretinal prosthesis using two prostheses components positioned on opposing sides of the retina. The magnetic attachment technique was piloted in a feline animal model (chronic, nonrecovery implantation). We also detail a new method to reliably control the magnet coupling force using heat. It was found that the force exerted upon the tissue that separates the two components could be minimized as the measured force is proportionately smaller at the working distance. We thus detail, for the first time, a surgical method using customized magnets to position and affix an epiretinal prosthesis on the retina. The position of the epiretinal prosthesis is reliable, and its location on the retina is accurately controlled by the placement of a secondary magnet in the suprachoroidal location. The electrode position above the retina is less than 50 microns at the center of the device, although there were pressure points seen at the two edges due to curvature misalignment. The degree of retinal compression found in this study was unacceptably high; nevertheless, the normal structure of the retina remained intact under the electrodes.

Orthogonal Thin Film Photovoltaics on Vertical Nanostructures.

Decoupling paths of carrier collection and illumination within photovoltaic devices is one promising approach for improving their efficiency by simultaneously increasing light absorption and carrier collection efficiency. Orthogonal photovoltaic devices are core-shell type structures consisting of thin film photovoltaic stack on vertical nanopillar scaffolds. These types of devices allow charge collection to take place in the radial direction, perpendicular to the path of light in the vertical direction. This approach addresses the inherently high recombination rate of disordered thin films, by allowing semiconductor films with minimal thicknesses to be used in photovoltaic devices, without performance degradation associated with incomplete light absorption. This work considers effects which influence the performance of orthogonal photovoltaic devices. Illumination non-uniformity as light travels across the depth of the pillars, electric field enhancement due to the nanoscale size and shape of the pillars, and series resistance due to the additional surface structure created through the use of pillars are considered. All of these effects influence the operation of orthogonal solar cells and should be considered in the design of vertically nanostructured orthogonal photovoltaics.

Hermetic diamond capsules for biomedical implants enabled by gold active braze alloys.

As the field of biomedical implants matures the functionality of implants is rapidly increasing. In the field of neural prostheses this is particularly apparent as researchers strive to build devices that interact with highly complex neural systems such as vision, hearing, touch and movement. A retinal implant, for example, is a highly complex device and the surgery, training and rehabilitation requirements involved in deploying such devices are extensive. Ideally, such devices will be implanted only once and will continue to function effectively for the lifetime of the patient. The first and most pivotal factor that determines device longevity is the encapsulation that separates the sensitive electronics of the device from the biological environment. This paper describes the realisation of a free standing device encapsulation made from diamond, the most impervious, long lasting and biochemically inert material known. A process of laser micro-machining and brazing is described detailing the fabrication of hermetic electrical feedthroughs and laser weldable seams using a 96.4% gold active braze alloy, another material renowned for biochemical longevity. Accelerated ageing of the braze alloy, feedthroughs and hermetic capsules yielded no evidence of corrosion and no loss of hermeticity. Samples of the gold braze implanted for 15 weeks, in vivo, caused minimal histopathological reaction and results were comparable to those obtained from medical grade silicone controls. The work described represents a first account of a free standing, fully functional hermetic diamond encapsulation for biomedical implants, enabled by gold active alloy brazing and laser micro-machining.

Fabrication of planarised conductively patterned diamond for bio-applications.

The development of smooth, featureless surfaces for biomedical microelectronics is a challenging feat. Other than the traditional electronic materials like silicon, few microelectronic circuits can be produced with conductive features without compromising the surface topography and/or biocompatibility. Diamond is fast becoming a highly sought after biomaterial for electrical stimulation, however, its inherent surface roughness introduced by the growth process limits its applications in electronic circuitry. In this study, we introduce a fabrication method for developing conductive features in an insulating diamond substrate whilst maintaining a planar topography. Using a combination of microwave plasma enhanced chemical vapour deposition, inductively coupled plasma reactive ion etching, secondary diamond growth and silicon wet-etching, we have produced a patterned substrate in which the surface roughness at the interface between the conducting and insulating diamond is approximately 3 nm. We also show that the patterned smooth topography is capable of neuronal cell adhesion and growth whilst restricting bacterial adhesion.

An all-diamond, hermetic electrical feedthrough array for a retinal prosthesis.

The interface between medical implants and the human nervous system is rapidly becoming more and more complex. This rise in complexity is driving the need for increasing numbers of densely packed electrical feedthrough to carry signals to and from implanted devices. This is particularly crucial in the field of neural prosthesis where high resolution stimulating or recording arrays near peripheral nerves or in the brain could dramatically improve the performance of these devices. Here we describe a flexible strategy for implementing high density, high count arrays of hermetic electrical feedthroughs by forming conducting nitrogen doped nanocrystalline diamond channels within an insulating polycrystalline diamond substrate. A unique feature of these arrays is that the feedthroughs can themselves be used as stimulating electrodes for neural tissue. Our particular application is such a feedthrough, designed as a component of a retinal implant to restore vision to the blind. The hermeticity of the feedthroughs means that the array can also form part of an implantable capsule which can interface directly with internal electronic chips. The hermeticity of the array is demonstrated by helium leak tests and electrical and electrochemical characterisation of the feedthroughs is described. The nitrogen doped nanocrystalline diamond forming the electrical feedthroughs is shown to be non-cyctotoxic. New fabrication strategies, such as the one described here, combined with the exceptional biostability of diamond can be exploited to generate a range of biomedical implants that last for the lifetime of the user without fear of degradation.