A Tuned Microwave Resonant System for Subcutaneous Imaging.

A compact and planar imaging system was developed using a flexible polymer substrate that can distinguish subcutaneous tissue abnormalities, such as breast tumors, based on electromagnetic-wave interactions in materials where permittivity variations affect wave reflection. The sensing element is a tuned loop resonator operating in the industrial, scientific, and medical (ISM) band at 2.423 GHz, providing a localized high-intensity electric field that penetrates into tissues with sufficient spatial and spectral resolutions. The resonant frequency shifts and magnitudes of the reflection coefficients indicate the boundaries of abnormal tissues under the skin due to their high contrasts to normal tissues. The sensor was tuned to the desired resonant frequency with a reflection coefficient of -68.8 dB for a radius of 5.7 mm, with a tuning pad. Quality factors of 173.1 and 34.4 were achieved in simulations and measurements in phantoms. An image-processing method was introduced to fuse raster-scanned 9 × 9 images of resonant frequencies and reflection coefficients for image-contrast enhancement. The results showed a clear indication of the tumor's location at a depth of 15 mm and the capability to identify two tumors both at the depth of 10 mm. The sensing element can be expanded to a four-element phased array for deeper field penetration. Field analysis showed the depths of -20 dB attenuation were improved from 19 to 42 mm, giving wider coverage in tissues at resonance. Results showed that a quality factor of 152.5 was achieved and a tumor could be identified at a depth of up to 50 mm. In this work, simulations and measurements were conducted to validate the concept, showing great potential for subcutaneous imaging in medical applications in a noninvasive, efficient, and lower-cost way.

Impedance-Based Neutralizing Antibody Detection Biosensor with Application in SARS-CoV-2 Infection.

Although safe and efficacious coronavirus disease-2019 (COVID-19) vaccines are available, real protective immunity is revealed by the serum COVID-19 neutralizing antibody (NAb) concentration. NAbs deactivate the virus by attaching to the viral receptor-binding domain (RBD), which interacts with angiotensin-converting enzyme 2 (ACE2) on the human cell. This paper introduces inexpensive, rapid, sensitive, and quantifiable impedance-based immunosensors to evaluate the NAb. The sensor limit of detection is experimentally determined in different buffer dilutions using bovine IgG-anti-bovine IgG interaction. The dominance of AC electrokinetic transport and molecular diffusion in the sensor is investigated using scaling analysis and numerical simulations. The results demonstrated that the sensor detection mechanism is mainly based on the diffusion of the biomolecules onto the electrode surface. After evaluating the sensor working principles, viral RBD buffers, including different NAb concentrations, are applied to the sensor, immobilized with the human ACE2 (hACE2). Results demonstrate that the sensor is capable of NAb detection in the analytical measuring interval between 45 ng/mL and 185 ng/mL. Since the present sensor provides fast test results with lower costs, it can be used to assess the NAb in people's blood serum before receiving further COVID vaccine doses.

Fabrication of Cu Micromembrane as a Flexible Electrode.

A Cu micromembrane is successfully fabricated and validated as a porous flexible electrode. The Cu micromembrane is prepared by functionalizing individual polypropylene (PP) fibers in a polypropylene micromembrane (PPMM) using a mixture of polydopamine (PDA) and polyethyleneimine (PEI). The mixture of PDA and PEI provides adhesive, wetting, and reducing functionalities that facilitate subsequent Ag activation and Cu electroless plating. Scanning electron microscopy reveals conformal deposition of Cu on individual PP fibers. Porometer analysis indicates that the porous nature of PPMM is properly maintained. The Cu micromembrane demonstrates impressive electrical conductivities in both the X direction (1.04 ± 0.21 S/cm) and Z direction (2.99 ± 0.54 × 10-3 S/cm). In addition, its tensile strength and strain are better than those of pristine PPMM. The Cu micromembrane is flexible and mechanically robust enough to sustain 10,000 bending cycles with moderate deterioration. Thermogravimetric analysis shows a thermal stability of 400 °C and an effective Cu loading of 5.36 mg/cm2. Cyclic voltammetric measurements reveal that the Cu micromembrane has an electrochemical surface area of 277.8 cm2 in a 1 cm2 geometric area (a roughness factor of 227.81), a value that is 45 times greater than that of planar Cu foil.

A flexible IrO2 membrane for pH sensing.

An optimized mixture of polydopamine (PDA) and polyvinyl alcohol (PVA) is employed as the surface functionalizing agent and reducing agent to encapsulate individual polypropylene (PP) fibers of polypropylene micromembrane (PPMM). The functionalized PPMM becomes hydrophilic to allow the formation of Au nuclei for subsequent electroless Au deposition. The metalized PPMM is further deposited with IrO2 nanoparticles, and evaluated as a flexible and porous pH sensor. Images from scanning electron microscope confirms the uniform formation of IrO2 nanoparticles on Au-coated PP fibers. For pH-sensing performance, the IrO2-decorated metalized PPMM reveals a super-Nernstian response for a sensing slope of -74.45 mV/pH in aqueous solutions with pH value ranging between 2 and 12. In addition, the pH-sensing performance is properly maintained after 5000 bending cycles and hysteresis is modest in an acidic environment. The cell viability test indicates a negligible bio-toxicity. Our strategy of using a conductive polymeric membrane decorated with IrO2 nanoparticles enables possible sensing applications in wearable and implantable electronics.

Correcting anisotropic intensity in light sheet images using dehazing and image morphology.

Light-sheet fluorescence microscopy (LSFM) provides access to multi-dimensional and multi-scale in vivo imaging of animal models with highly coherent volumetric reconstruction of the tissue morphology, via a focused laser light sheet. The orthogonal illumination and detection LSFM pathways account for minimal photobleaching and deep tissue optical sectioning through different perspective views. Although rotation of the sample and deep tissue scanning constitutes major advantages of LSFM, images may suffer from intrinsic problems within the modality, such as light mismatch of refractive indices between the sample and mounting media and varying quantum efficiency across different depths. To overcome these challenges, we hereby introduce an illumination correction technique integrated with depth detail amelioration to achieve symmetric contrast in large field-of-view images acquired using a low power objective lens. Due to an increase in angular dispersion of emitted light flux with the depth, we combined the dehazing algorithm with morphological operations to enhance poorly separated overlapping structures with subdued intensity. The proposed method was tested on different LSFM modalities to illustrate its applicability on correcting anisotropic illumination affecting the volumetric reconstruction of the fluorescently tagged region of interest.

Lactate Sensors on Flexible Substrates.

Lactate detection by an in situ sensor is of great need in clinical medicine, food processing, and athletic performance monitoring. In this paper, a flexible, easy to fabricate, and low-cost biosensor base on lactate oxidase is presented. The fabrication processes, including metal deposition, sol-gel IrOx deposition, and drop-dry enzyme loading method, are described in detail. The loaded enzyme was examined by scanning electron microscopy. Cyclic voltammetry was used to characterize the sensors. Durability, sensibility, and selectivity of the biosensors were examined. The comparison for different electrode sizes and different sensing film materials was conducted. The sensor could last for four weeks with an average surface area normalized sensitivity of 950 nA/(cm² mM) and 9250 nA/(cm² mM) for Au-based electrodes, and IrOx-modified electrodes respectively, both with an electrode size of 100 × 50 µm. The self-referencing method to record noises simultaneously with the working electrode greatly improved sensor sensitivity and selectivity. The sensor showed little response to interference chemicals, such as glutamate and dopamine.

Reduced local field potential power in the medial prefrontal cortex by noxious stimuli.

Nociceptive signals produced by noxious stimuli at the periphery reach the brain through ascending pathways. These signals are processed by various brain areas and lead to activity changes in those areas. The medial prefrontal cortex (mPFC) is involved in higher cognitive functions and emotional processing. It receives projections from brain areas involved in nociception. In this study, we investigated how nociceptive input from the periphery changes the local field potential (LFP) activity in the mPFC. Three different types of noxious stimuli were applied to the hind paw contralateral to the LFP recording site. They were transcutaneous electrical stimulations, mechanical stimuli and a chemical stimulus (formalin injection). High intensity transcutaneous stimulations (10V to 50V) and noxious mechanical stimulus (pinch) significantly reduced the LFP power during the stimulating period (p<0.05), but not the low intensity subcutaneous stimulations (0.1V to 5V) and other innocuous mechanical stimuli (brush and pressure). More frequency bands were inhibited with increased intensity of transcutaneous electrical stimulation, and almost all frequency bands were inhibited by stimulations at or higher than 30v. Pinch significantly reduced the power for beta band and formalin injection significantly reduced the power of alpha and beta band. Our data demonstrated the noxious stimuli-induced reduction of LFP power in the mPFC, which indicates the active processing of nociceptive information by the mPFC.

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Sol-gel deposition of iridium oxide for biomedical micro-devices.

Flexible iridium oxide (IrOx)-based micro-electrodes were fabricated on flexible polyimide substrates using a sol-gel deposition process for utilization as integrated pseudo-reference electrodes for bio-electrochemical sensing applications. The fabrication method yields reliable miniature on-probe IrOx electrodes with long lifetime, high stability and repeatability. Such sensors can be used for long-term measurements. Various dimensions of sol-gel iridium oxide electrodes including 1 mm × 1 mm, 500 µm × 500 µm, and 100 µm × 100 µm were fabricated. Sensor longevity and pH dependence were investigated by immersing the electrodes in hydrochloric acid, fetal bovine serum (FBS), and sodium hydroxide solutions for 30 days. Less pH dependent responses, compared to IrOx electrodes fabricated by electrochemical deposition processes, were measured at 58.8 ± 0.4 mV/pH, 53.8 ± 1.3 mV/pH and 48 ± 0.6 mV/pH, respectively. The on-probe IrOx pseudo-reference electrodes were utilized for dopamine sensing. The baseline responses of the sensors were higher than the one using an external Ag/AgCl reference electrode. Using IrOx reference electrodes integrated on the same probe with working electrodes eliminated the use of cytotoxic Ag/AgCl reference electrode without loss in sensitivity. This enables employing such sensors in long-term recording of concentrations of neurotransmitters in central nervous systems of animals and humans.

Fabrication and characterization of biomimetic multichanneled crosslinked-urethane-doped polyester tissue engineered nerve guides.

Biomimetic scaffolds that replicate the native architecture and mechanical properties of target tissues have been recently shown to be a very promising strategy to guide cellular growth and facilitate tissue regeneration. In this study, porous, soft, and elastic crosslinked urethane-doped polyester (CUPE) tissue engineered nerve guides were fabricated with multiple longitudinally oriented channels and an external non-porous sheath to mimic the native endoneurial microtubular and epineurium structure, respectively. The fabrication technique described herein is highly adaptable and allows for fine control over the resulting nerve guide architecture in terms of channel number, channel diameter, porosity, and mechanical properties. Biomimetic multichanneled CUPE guides were fabricated with various channel numbers and displayed an ultimate peak stress of 1.38 ± 0.22 MPa with a corresponding elongation at break of 122.76 ± 42.17%, which were comparable to that of native nerve tissue. The CUPE nerve guides were also evaluated in vivo for the repair of a 1 cm rat sciatic nerve defect. Although histological evaluations revealed collapse of the inner structure from CUPE TENGs, the CUPE nerve guides displayed fiber populations and densities comparable with nerve autograft controls after 8 weeks of implantation. These studies are the first report of a CUPE-based biomimetic multichanneled nerve guide and warrant future studies towards optimization of the channel geometry for use in neural tissue engineering.

An endoscopic wireless gastrostimulator (with video).

BACKGROUND: Gastric electric stimulation (GES) at a high-frequency, low-energy setting is an option for treating refractory gastroparesis. The currently available commercial stimulator, the Enterra neurostimulator (Medtronic Inc, Minneapolis, MN), however, requires surgical implantation and is powered by a nonrechargeable battery. OBJECTIVE: To develop and test a miniature wireless GES device for endoscopic implantation in an experimental model. DESIGN: In-vivo gastric signals were recorded and measured in a nonsurvival swine model (n = 2; 110-lb animals). INTERVENTION: An endoscopically placed, wireless GES device was inserted into the stomach through an overtube; the two GES electrodes were endoscopically attached to the gastric mucosa and secured with endoclips to permit stimulation. MAIN OUTCOME MEASUREMENTS: Stable electrogastrogram measures were observed during GES stimulation. RESULTS: Electrogastrogram recordings demonstrated that gastric slow waves became more regular and of constant amplitudes when stomach tissues were stimulated, in comparison with no stimulation. The frequency-to-amplitude ratio also changed significantly with stimulation. LIMITATION: Nonsurvival pig studies. CONCLUSION: Gastric electric stimulation is feasible by our endoscopically implanted, wireless GES device.

Septal stimulation inhibits spinal cord dorsal horn neuronal activity.

Deep brain stimulation (DBS) has been used for relieving chronic pain in patients that have been through other existing options. The septum has been one of the targets for such treatment. The purpose of this study was to determine the inhibitory effect of electrical stimulation in the medial septum diagonal band of broca (MSDB) on neuronal activity in the spinal cord of rats anesthetized with sodium pentobarbital. While unilaterally stimulating the MSDB, wide dynamic range neurons in the lumbar region of the spinal cord were recorded in response to graded mechanical stimulation of the hind paws (brush, pressure, and pinch). Stimulation was at 1, 5, 10, and 20V, at 100Hz, and 0.1ms duration. Significant bilateral reduction was observed in response to pressure (ipsilaterally: 0.90±0.05, 0.48±0.06*, 0.55±0.05*, 0.40±0.05*; and contralaterally: 0.70±0.06*, 0.59±0.08*, 0.75±0.05*, 0.49±0.07*) and pinch (ipsilaterally: 0.89±0.08, 0.46±0.05*, 0.54±0.04*, 0.50±0.05*; and contralaterally: 0.78±0.05, 0.61±0.07*, 0.64±0.04*, 0.53±0.06*). Data were expressed as a fraction of control. Significant changes were also found in responses to brush in certain groups (ipsilaterally: 1.08±0.08, 0.72±0.06*, 1.00±0.12, 0.65±0.06*; and contralaterally: 0.93±0.05, 0.77±0.07*, 0.98±0.05, 0.84±0.07). Further analysis suggested that 5V was adequate for achieving optimal inhibition. It is concluded that the MSDB can be used as alternative target for DBS in the treatment of pain.

Synthesis and characterization of a biodegradable elastomer featuring a dual crosslinking mechanism.

The need for advanced materials in emerging technologies such as tissue engineering has prompted increased research to produce novel biodegradable polymers elastic in nature and mechanically compliant with the host tissue. We have developed a soft biodegradable elastomeric platform biomaterial created from citric acid, maleic anhydride, and 1,8-octanediol, poly(octamethylene maleate (anhydride) citrate) (POMaC), which is able to closely mimic the mechanical properties of a wide range of soft biological tissues. POMaC features a dual crosslinking mechanism, which allows for the option of the crosslinking POMaC using UV irradiation and/or polycondensation to fit the needs of the intended application. The material properties, degradation profiles, and functionalities of POMaC thermoset networks can all be tuned through the monomer ratios and the dual crosslinking mechanism. POMaC polymers displayed an initial modulus between 0.03 and 1.54 MPa, and elongation at break between 48% and 534% strain. In vitro and in vivo evaluation using cell culture and subcutaneous implantation, respectively, confirmed cell and tissue biocompatibility. POMaC biodegradable polymers can also be combined with MEMS technology to fabricate soft and elastic 3D microchanneled scaffolds for tissue engineering applications. The introduction of POMaC will expand the choices of available biodegradable polymeric elastomers. The dual crosslinking mechanism for biodegradable elastomer design should contribute to biomaterials science.

Regenerated spider silk as a new biomaterial for MEMS.

Spider drag-line silk is introduced for the first time as a new biomaterial for Micro-Electro-Mechanical Systems (MEMS). The tasks accomplished in this paper were focused on mechanical characterization of regenerated spider silk under two conditions: (1) spin-coated thin film formed onto a silicon substrate; and (2) formation of a free-standing microbridge (800 x 800 x 40 microm3) obtained by a surface micromachining process. Micromechanical tests using a nano indentation machine showed the spider silk film having an elastic modulus of 7.3 GPa, a loss tangent of 0.044 and an UTS (Ultimate Tensile Strength) of 85.1 MPa.