Wearable Sensing System for NonInvasive Monitoring of Intracranial BioFluid Shifts in Aerospace Applications.

The alteration of the hydrostatic pressure gradient in the human body has been associated with changes in human physiology, including abnormal blood flow, syncope, and visual impairment. The focus of this study was to evaluate changes in the resonant frequency of a wearable electromagnetic resonant skin patch sensor during simulated physiological changes observed in aerospace applications. Simulated microgravity was induced in eight healthy human participants (n = 8), and the implementation of lower body negative pressure (LBNP) countermeasures was induced in four healthy human participants (n = 4). The average shift in resonant frequency was -13.76 ± 6.49 MHz for simulated microgravity with a shift in intracranial pressure (ICP) of 9.53 ± 1.32 mmHg, and a shift of 8.80 ± 5.2097 MHz for LBNP with a shift in ICP of approximately -5.83 ± 2.76 mmHg. The constructed regression model to explain the variance in shifts in ICP using the shifts in resonant frequency (R2 = 0.97) resulted in a root mean square error of 1.24. This work demonstrates a strong correlation between sensor signal response and shifts in ICP. Furthermore, this study establishes a foundation for future work integrating wearable sensors with alert systems and countermeasure recommendations for pilots and astronauts.

A Flexible Near-Field Biosensor for Multisite Arterial Blood Flow Detection.

Modern wearable devices show promising results in terms of detecting vital bodily signs from the wrist. However, there remains a considerable need for a device that can conform to the human body's variable geometry to accurately detect those vital signs and to understand health better. Flexible radio frequency (RF) resonators are well poised to address this need by providing conformable bio-interfaces suitable for different anatomical locations. In this work, we develop a compact wearable RF biosensor that detects multisite hemodynamic events due to pulsatile blood flow through noninvasive tissue-electromagnetic (EM) field interaction. The sensor consists of a skin patch spiral resonator and a wearable transceiver. During resonance, the resonator establishes a strong capacitive coupling with layered dielectric tissues due to impedance matching. Therefore, any variation in the dielectric properties within the near-field of the coupled system will result in field perturbation. This perturbation also results in RF carrier modulation, transduced via a demodulator in the transceiver unit. The main elements of the transceiver consist of a direct digital synthesizer for RF carrier generation and a demodulator unit comprised of a resistive bridge coupled with an envelope detector, a filter, and an amplifier. In this work, we build and study the sensor at the radial artery, thorax, carotid artery, and supraorbital locations of a healthy human subject, which hold clinical significance in evaluating cardiovascular health. The carrier frequency is tuned at the resonance of the spiral resonator, which is 34.5 ± 1.5 MHz. The resulting transient waveforms from the demodulator indicate the presence of hemodynamic events, i.e., systolic upstroke, systolic peak, dicrotic notch, and diastolic downstroke. The preliminary results also confirm the sensor's ability to detect multisite blood flow events noninvasively on a single wearable platform.

Non-Invasive Electromagnetic Skin Patch Sensor to Measure Intracranial Fluid-Volume Shifts.

Elevated intracranial fluid volume can drive intracranial pressure increases, which can potentially result in numerous neurological complications or death. This study's focus was to develop a passive skin patch sensor for the head that would non-invasively measure cranial fluid volume shifts. The sensor consists of a single baseline component configured into a rectangular planar spiral with a self-resonant frequency response when impinged upon by external radio frequency sweeps. Fluid volume changes (10 mL increments) were detected through cranial bone using the sensor on a dry human skull model. Preliminary human tests utilized two sensors to determine feasibility of detecting fluid volume shifts in the complex environment of the human body. The correlation between fluid volume changes and shifts in the first resonance frequency using the dry human skull was classified as a second order polynomial with R² = 0.97. During preliminary and secondary human tests, a ≈24 MHz and an average of ≈45.07 MHz shifts in the principal resonant frequency were measured respectively, corresponding to the induced cephalad bio-fluid shifts. This electromagnetic resonant sensor may provide a non-invasive method to monitor shifts in fluid volume and assist with medical scenarios including stroke, cerebral hemorrhage, concussion, or monitoring intracranial pressure.

Analysis of ischemic muscle in patients with peripheral artery disease using X-ray spectroscopy.

BACKGROUND: Peripheral artery disease (PAD) is a vascular disease caused by atherosclerosis, resulting in decreased blood flow to the lower extremities. The ankle-brachial index (ABI) is a standard PAD diagnostic test but only identifies reduced blood flow based on blood pressure differences. The early signs of PAD manifest themselves not only at a clinical level but also at an elemental and biochemical level. However, the biochemical and elemental alterations to PAD muscle are not well understood. The objective of this study was to compare fundamental changes in intracellular elemental compositions between control, claudicating, and critical limb ischemia muscle tissue. MATERIALS AND METHODS: Gastrocnemius biopsies from three subjects including one control (ABI ≥ 0.9), one claudicating (0.4 ≤ ABI < 0.9), and one critical limb ischemia patient (ABI < 0.4) were evaluated using a scanning electron microscope and energy dispersive X-ray spectroscopy to quantify differences in elemental compositions. Spectra were collected for five myofibers per specimen. An analysis of variance was performed to identify significant differences in muscle elemental compositions. RESULTS: This study revealed that intracellular magnesium and calcium were lower in PAD compared with control myofibers, whereas sulfur was higher. Magnesium and calcium are antagonistic, meaning, if magnesium concentrations go down calcium concentrations should go up. However, our findings do not support this antagonism in PAD. Our analysis found decreases in sodium and potassium, in PAD myofibers. CONCLUSIONS: These findings may provide insight into the pathologic mechanisms that may operate in ischemic muscle and aid in the development of specialized preventive and rehabilitative treatment plans for PAD patients.

Abnormal myofiber morphology and limb dysfunction in claudication.

BACKGROUND: Peripheral artery disease (PAD), which affects an estimated 27 million people in Europe and North America, is caused by atherosclerotic plaques that limit blood flow to the legs. Chronic, repeated ischemia in the lower leg muscles of PAD patients is associated with loss of normal myofiber morphology and myofiber degradation. In this study, we tested the hypothesis that myofiber morphometrics of PAD calf muscle are significantly different from normal calf muscle and correlate with reduced calf muscle strength and walking performance. METHODS: Gastrocnemius biopsies were collected from 154 PAD patients (Fontaine stage II) and 85 control subjects. Morphometric parameters of gastrocnemius fibers were determined and evaluated for associations with walking distances and calf muscle strength. RESULTS: Compared with control myofibers, PAD myofiber cross-sectional area, major and minor axes, equivalent diameter, perimeter, solidity, and density were significantly decreased (P < 0.005), whereas roundness was significantly increased (P < 0.005). Myofiber morphometric parameters correlated with walking distances and calf muscle strength. Multiple regression analyses demonstrated myofiber cross-sectional area, roundness, and solidity as the best predictors of calf muscle strength and 6-min walking distance, whereas cross-sectional area was the main predictor of maximum walking distance. CONCLUSIONS: Myofiber morphometrics of PAD gastrocnemius differ significantly from those of control muscle and predict calf muscle strength and walking distances of the PAD patients. Morphometric parameters of gastrocnemius myofibers may serve as objective criteria for diagnosis, staging, and treatment of PAD.

Morphometric analysis of gastrocnemius muscle biopsies from patients with peripheral arterial disease: objective grading of muscle degeneration.

Peripheral arterial disease (PAD), which affects ~10 million Americans, is characterized by atherosclerosis of the noncoronary arteries. PAD produces a progressive accumulation of ischemic injury to the legs, manifested as a gradual degradation of gastrocnemius histology. In this study, we evaluated the hypothesis that quantitative morphological parameters of gastrocnemius myofibers change in a consistent manner during the progression of PAD, provide an objective grading of muscle degeneration in the ischemic limb, and correlate to a clinical stage of PAD. Biopsies were collected with a Bergström needle from PAD patients with claudication (n = 18) and critical limb ischemia (CLI; n = 19) and control patients (n = 19). Myofiber sarcolemmas and myosin heavy chains were labeled for fluorescence detection and quantitative analysis of morphometric variables, including area, roundness, perimeter, equivalent diameter, major and minor axes, solidity, and fiber density. The muscle specimens were separated into training and validation data sets for development of a discriminant model for categorizing muscle samples on the basis of disease severity. The parameters for this model included standard deviation of roundness, standard deviation of solidity of myofibers, and fiber density. For the validation data set, the discriminant model accurately identified control (80.0% accuracy), claudicating (77.7% accuracy), and CLI (88.8% accuracy) patients, with an overall classification accuracy of 82.1%. Myofiber morphometry provided a discriminant model that establishes a correlation between PAD progression and advancing muscle degeneration. This model effectively separated PAD and control patients and provided a grading of muscle degeneration within clinical stages of PAD.

Sustained Releasing of Methotrexate from Injectable and Thermosensitive Chitosan-Carbon Nanotube Hybrid Hydrogels Effectively Controls Tumor Cell Growth.

Injectable thermosensitive hydrogels have been widely investigated for drug delivery systems. Chitosan (CH) is one of the most abundant natural polymers, and its biocompatibility and biodegradability make it a favorable polymer for thermosensitive hydrogel formation. The addition of nanoparticles can improve its drug release behavior, remote actuation capability, and biological interactions. Carbon nanotubes (CNTs) have been studied for the use in drug delivery systems, and they can act as drug delivery vehicles to improve the delivery of different types of therapeutic agents. In this work, carbon nanotubes were incorporated into a thermosensitive and injectable hydrogel formed by chitosan and ß-glycerophosphate (ß-GP) (CH-ß-GP-CNTs). The hybrid hydrogels loaded with methotrexate (MTX) were liquid at room temperature and became a solidified gel at body temperature. A number of tests including scanning electron microscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray diffraction were utilized to characterize the MTX-loaded CH-ß-GP-CNT hybrid hydrogels. The cell viability (alamarBlue) assay showed that hydrogels containing CNT (0.1%) were not toxic to the 3T3 cells. In vitro MTX release study revealed that CNT-containing hydrogels (with 0.1% CNT) demonstrated a decreased MTX releasing rate compared with control hydrogels without CNT. The cultured MCF-7 breast cancer cells were used to evaluate the efficacy of CH-ß-GP-CNT hybrid hydrogels delivering MTX on the control of tumor cell growth. Results demonstrated that CNT (0.1%) in the hydrogel enhanced the MTX antitumor function. Our study indicates that a thermosensitive CH-ß-GP-CNT hybrid hydrogel can be used as a potential breast cancer therapy system for controlled delivery of MTX.

Material Characterization and Bioanalysis of Hybrid Scaffolds of Carbon Nanomaterial and Polymer Nanofibers.

The interconnected porous structures that mimic the extracellular matrix support cell growth in tissue engineering. Nanofibers generated by electrospinning can act as a vehicle for therapeutic cell delivery to a neural lesion. The incorporation of carbon nanomaterials with excellent electrical conductivity in nanofibers is an attractive aspect for design of a nanodevice for neural tissue regeneration. In this study, nanoscaffolds were created by electrospinning poly(ε-caprolactone) (PCL) and three different types of carbon nanomaterials, which are carbon nanotubes, graphene, and fullerene. The component of carbon nanomaterials in nanofibers was confirmed by Fourier transform infrared spectroscopy. The fiber diameter was determined by scanning electron microscopy, and it was found that the diameter varied depending on the type of nanomaterial in the fibers. The incorporation of carbon nanotubes and graphene in the PCL fibers increased the contact angle significantly, while the incorporation of fullerene reduced the contact angle significantly. Incorporation of CNT, fullerene, and graphene in the PCL fibers increased dielectric constant. Astrocytes isolated from neonatal rats were cultured on PCL-nanomaterial nanofibers. The cell viability assay showed that the PCL-nanomaterial nanofibers were not toxic to the cultured astrocytes. The immunolabeling showed the growth and morphology of astrocytes on nanofiber scaffolds. SEM was performed to determine the cell attachment and interaction with the nanoscaffolds. This study indicates that PCL nanofibers containing nanomaterials are biocompatible and could be used for cell and drug delivery into the nervous system.

A Noninvasive, Electromagnetic, Epidermal Sensing Device for Hemodynamics Monitoring.

Non-intrusive monitoring of blood flow parameters is vital for obtaining physiological and pathophysiological information pertaining to dynamic cardiovascular events and is feasible to achieve via non-invasive, conformal, wearable technologies. Here, we present a proof-of-concept of a fully integrated, high frequency (bandwidth 40 MHz), electromagnetic sensing device for monitoring limb hemodynamics and morphology associated with blood flow. The sensing architecture integrates a novel radio frequency (RF) skin patch resonator embedded with a coplanar outer loop antenna and a scalable, standalone wireless readout hardware based on standing wave ratio (SWR) bridge. The resonator itself is a copper-based open circuit planar Archimedean spiral with a rectangular cross-sectional area, chemically etched on a flexible polyimide substrate. The readout hardware is developed exploiting off-the-shelf components, fabricated on the top of a rigid FR4 substrate. The proposed readout circuit can measure resonant frequency of an RLC network. When energized by the external oscillating RF field via loop antenna, the resonator produces an electromagnetic field response which can be perturbed by dielectric variation inside its field boundary. Through leveraging this principle, the in-vitro experimental results from the benchtop models suggest that the resonator's RF attributes such as resonant frequency shift and magnitude variation of reflection coefficient due to fluid volume displacement can be successfully detected through the proposed hardware architecture. Hence, the system could be an alternative to the conventional, multimodal, non-invasive wearable sensing with an unprecedented capability of ubiquitous fluid phenomena detection from multiple sites of the human body.

Passive Self Resonant Skin Patch Sensor to Monitor Cardiac Intraventricular Stroke Volume Using Electromagnetic Properties of Blood.

This paper focuses on the development of a passive, lightweight skin patch sensor that can measure fluid volume changes in the heart in a non-invasive, point-of-care setting. The wearable sensor is an electromagnetic, self-resonant sensor configured into a specific pattern to formulate its three passive elements (resistance, capacitance, and inductance). In an animal model, a bladder was inserted into the left ventricle (LV) of a bovine heart, and fluid was injected using a syringe to simulate stoke volume (SV). In a human study, to assess the dynamic fluid volume changes of the heart in real time, the sensor frequency response was obtained from a participant in a 30° head-up tilt (HUT), 10° HUT, supine, and 10° head-down tilt positions over time. In the animal model, an 80-mL fluid volume change in the LV resulted in a downward frequency shift of 80.16 kHz. In the human study, there was a patterned frequency shift over time which correlated with ventricular volume changes in the heart during the cardiac cycle. Statistical analysis showed a linear correlation [Formula: see text] and 0.87 between the frequency shifts and fluid volume changes in the LV of the bovine heart and human participant, respectively. In addition, the patch sensor detected heart rate in a continuous manner with a 0.179% relative error compared to electrocardiography. These results provide promising data regarding the ability of the patch sensor to be a potential technology for SV monitoring in a non-invasive, continuous, and non-clinical setting.

Passive Wearable Skin Patch Sensor Measures Limb Hemodynamics Based on Electromagnetic Resonance.

OBJECTIVE: The objectives of this study were to design and develop an open-circuit electromagnetic resonant skin patch sensor, characterize the fluid volume and resonant frequency relationship, and investigate the sensor's ability to measure limb hemodynamics and pulse volume waveform features. METHODS: The skin patch was designed from an open-circuit electromagnetic resonant sensor comprised of a single baseline trace of copper configured into a square planar spiral which had a self-resonating response when excited by an external radio frequency sweep. Using a human arm phantom with a realistic vascular network, the sensor's performance to measure limb hemodynamics was evaluated. RESULTS: The sensor was able to measure pulsatile blood flow which registered as shifts in the sensor's resonant frequencies. The time-varying waveform pattern of the resonant frequency displayed a systolic upstroke, a systolic peak, a dicrotic notch, and a diastolic down stroke. The resonant frequency waveform features and peak systolic time were validated against ultrasound pulse wave Doppler. A statistical correlation analysis revealed a strong correlation () between the resonant sensor peak systolic time and the pulse wave Doppler peak systolic time. CONCLUSION: The sensor was able to detect pulsatile flow, identify hemodynamic waveform features, and measure heart rate with 98% accuracy. SIGNIFICANCE: The open-circuit resonant sensor design leverages the architecture of a thin planar spiral which is passive (does not require batteries), robust and lightweight (does not have electrical components or electrical connections), and may be able to wirelessly monitor cardiovascular health and limb hemodynamics.

Structural and biological properties of thermosensitive chitosan-graphene hybrid hydrogels for sustained drug delivery applications.

Chitosan has the ability to make injectable thermosensitive hydrogels which has been highly investigated for drug delivery applications. The addition of nanoparticles is one way to increase the mechanical strength of thermosensitive chitosan hydrogel and subsequently and control the burst release of drug. Graphene nanoparticles have shown unique mechanical, optical and electrical properties which can be exploited for biomedical applications, especially in drug delivery. This study, have focused on the mechanical properties of a thermosensitive and injectable hybrid chitosan hydrogel incorporated with graphene nanoparticles. Scanning electron microscope (SEM), Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and X-ray diffraction (XRD) have been used for morphological and chemical characterization of graphene infused chitosan hydrogels. The cell viability and cytotoxicity of graphene-contained hydrogels were analyzed using the alamarBlue® technique. In-vitro methotrexate (MTX) release was investigated from MTX-loaded hybrid hydrogels as well. As a last step, to evaluate their efficiency as a cancer treatment delivery system, an in vitro anti-tumor test was also carried out using MCF-7 breast cancer cell lines. Results confirmed that a thermosensitive chitosan-graphene hybrid hydrogel can be used as a potential breast cancer therapy system for controlled delivery of methotrexate. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2381-2390, 2017.

Optical probing of gastrocnemius in patients with peripheral artery disease characterizes myopathic biochemical alterations and correlates with stage of disease.

Peripheral artery disease (PAD) is a condition caused by atherosclerotic blockages in the arteries supplying the lower limbs and is characterized by ischemia of the leg, progressive myopathy, and increased risk of limb loss. The affected leg muscles undergo significant changes of their biochemistry and metabolism including variations in the levels of many key proteins, lipids, and nucleotides. The mechanisms behind these changes are poorly understood. The objective of this study was to correlate the severity of the PAD disease stage and associated hemodynamic limitation (determined by the ankle brachial index, ABI) in the legs of the patients with alterations in the biochemistry of chronically ischemic leg muscle as determined by ATR-Fourier transform infrared micro-spectroscopy. Muscle (gastrocnemius) biopsies were collected from 13 subjects including four control patients (ABI≥0.9), five claudicating patients (0.4 ≤ ABI<0.9), and four critical limb ischemia (CLI) patients (ABI<0.4). Slide mounted specimens were analyzed by ATR-Fourier transform infrared micro-spectroscopy. An analysis of variance and a partial least squares regression model were used to identify significant differences in spectral peaks and correlate them with the ABI The spectra revealed significant differences (P < 0.05) across control, claudicating, and CLI patients in the fingerprint and functional group regions. Infrared microspectroscopic probing of ischemic muscle biopsies demonstrates that PAD produces significant and unique changes to muscle biochemistry in comparison to control specimens. These distinctive biochemical profiles correlate with disease progression and may provide insight and direction for new targets in the diagnosis and therapy of muscle degeneration in PAD.

Surface-enhanced Raman spectral biomarkers correlate with Ankle Brachial Index and characterize leg muscle biochemical composition of patients with peripheral arterial disease.

Peripheral arterial disease (PAD) is characterized by atherosclerotic blockages of the arteries supplying the lower extremities, which cause a progressive accumulation of ischemic injury to the skeletal muscles of the lower limbs. This injury includes altered metabolic processes, damaged organelles, and compromised bioenergetics in the affected muscles. The objective of this study was to explore the association of Raman spectral signatures of muscle biochemistry with the severity of atherosclerosis in the legs as determined by the Ankle Brachial Index (ABI) and clinical presentation. We collected muscle biopsies from the gastrocnemius (calf muscle) of five patients with clinically diagnosed claudication, five patients with clinically diagnosed critical limb ischemia (CLI), and five control patients who did not have PAD. A partial least squares regression (PLSR) model was able to predict patient ABI with a correlation coefficient of 0.99 during training and a correlation coefficient of 0.85 using a full cross-validation. When using the first three PLS factor scores in combination with linear discriminant analysis, the discriminant model was able to correctly classify the control, claudicating, and CLI patients with 100% accuracy, using a full cross-validation procedure. Raman spectroscopy is capable of detecting and measuring unique biochemical signatures of skeletal muscle. These signatures can discriminate control muscles from PAD muscles and correlate with the ABI and clinical presentation of the PAD patient. Raman spectroscopy provides novel spectral biomarkers that may complement existing methods for diagnosis and monitoring treatment of PAD patients.

Optical scattering with hyperspectral imaging to classify longissimus dorsi muscle based on beef tenderness using multivariate modeling.

The objective of this study was to develop a non-destructive method for classifying cooked-beef tenderness using hyperspectral imaging of optical scattering on fresh beef muscle tissue. A hyperspectral imaging system (λ=922-1739 nm) was used to collect hyperspectral scattering images of the longissimus dorsi muscle (n=472). A modified Lorentzian function was used to fit optical scattering profiles at each wavelength. After removing highly correlated parameters extracted from the Lorentzian function, principal component analysis was performed. Four principal component scores were used in a linear discriminant model to classify beef tenderness. In a validation data set (n=118 samples), the model was able to successfully classify tough and tender samples with 83.3% and 75.0% accuracies, respectively. Presence of fat flecks did not have a significant effect on beef tenderness classification accuracy. The results demonstrate that hyperspectral imaging of optical scattering is a viable technology for beef tenderness classification.