High optode-density wearable diffuse optical probe for monitoring paced breathing hemodynamics in breast tissue.

SIGNIFICANCE: Diffuse optical imaging (DOI) provides in vivo quantification of tissue chromophores such as oxy- and deoxyhemoglobin (HbO2 and HHb, respectively). These parameters have been shown to be useful for predicting neoadjuvant treatment response in breast cancer patients. However, most DOI devices designed for the breast are nonportable, making frequent longitudinal monitoring during treatment a challenge. Furthermore, hemodynamics related to the respiratory cycle are currently unexplored in the breast and may have prognostic value. AIM: To design, fabricate, and validate a high optode-density wearable continuous wave diffuse optical probe for the monitoring of breathing hemodynamics in breast tissue. APPROACH: The probe has a rigid-flex design with 16 dual-wavelength sources and 16 detectors. Performance was characterized on tissue-simulating phantoms, and validation was performed through flow phantom and cuff occlusion measurements. The breasts of N = 4 healthy volunteers were measured while performing a breathing protocol. RESULTS: The probe has 512 unique source-detector (S-D) pairs that span S-D separations of 10 to 54 mm. It exhibited good performance characteristics: µa drift of 0.34%/h, µa precision of 0.063%, and mean SNR ≥ 24 dB up to 41 mm S-D separation. Absorption contrast was detected in flow phantoms at depths exceeding 28 mm. A cuff occlusion measurement confirmed the ability of the probe to track expected hemodynamics in vivo. Breast measurements on healthy volunteers during paced breathing revealed median signal-to-motion artifact ratios ranging from 8.1 to 8.7 dB. Median ΔHbO2 and ΔHHb amplitudes ranged from 0.39 to 0.67 µM and 0.08 to 0.12 µM, respectively. Median oxygen saturations at the respiratory rate ranged from 82% to 87%. CONCLUSIONS: A wearable diffuse optical probe has been designed and fabricated for the measurement of breast tissue hemodynamics. This device is capable of quantifying breathing-related hemodynamics in healthy breast tissue.

A practical approach for the optimization of channel integrity in the sealing of shallow microfluidic devices made from cyclic olefin polymer.

A reduced channel height in microfluidic Lab-on-a-Chip (LOC) devices enables a reduction in the required volume of sample and reagents. LOC devices are most often manufactured by microstructuring a planar substrate and subsequently sealing it with a cover film. However, shallow chip designs, made from polymers, are sensitive to channel deformation during the sealing of the microfluidic device. Inappropriate bonding conditions often result in the loss of the microfluidic functionality. A systematic and practical approach for the identification of suitable bonding process parameters is missing. In this article, a straightforward approach for the optimization of channel integrity in the sealing of shallow microfluidic devices made from Cyclic Olefin Polymer (COP) is presented. Two COP materials were tested: COP Zeonex 690R (Glass transition temperature Tg = 135 °C) both as a cover film and substrate material, and COP ZF14 (Tg = 135 °C) as a film material. A mechanical analysis using microstructured Zeonex 690R substrates was performed to generate a matrix of low-distortion bonding parameters, including temperature, pressure and time. The well-established method of solvent-assisted bonding was used to enhance the characteristically low bond strengths of the native COP material. In addition, plasma-assisted bonding was tested and compared. The optimization approach was validated by the manufacture of a microfluidic test device, the demonstration of its microfluidic functionality, and the quantitative evaluation of the achieved channel integrity.

Wearable near-infrared optical probe for continuous monitoring during breast cancer neoadjuvant chemotherapy infusions.

We present a new continuous-wave wearable diffuse optical probe aimed at investigating the hemodynamic response of locally advanced breast cancer patients during neoadjuvant chemotherapy infusions. The system consists of a flexible printed circuit board that supports an array of six dual wavelength surface-mount LED and photodiode pairs. The probe is encased in a soft silicone housing that conforms to natural breast shape. Probe performance was evaluated using tissue-simulating phantoms and in vivo normal volunteer measurements. High SNR (71 dB), low source-detector crosstalk ( ? 60 ?? dB ), high measurement precision (0.17%), and good thermal stability (0.22% V rms / ° C ) were achieved in phantom studies. A cuff occlusion experiment was performed on the forearm of a healthy volunteer to demonstrate the ability to track rapid hemodynamic changes. Proof-of-principle normal volunteer measurements were taken to demonstrate the ability to collect continuous in vivo breast measurements. This wearable probe is a first of its kind tool to explore prognostic hemodynamic changes during chemotherapy in breast cancer patients.

Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model.

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.

Vacuum compatible sample positioning device for matrix assisted laser desorption∕ionization Fourier transform ion cyclotron resonance mass spectrometry imaging.

The high mass accuracy and resolving power of Fourier transform ion cyclotron resonance mass spectrometers (FT-ICR MS) make them ideal mass detectors for mass spectrometry imaging (MSI), promising to provide unmatched molecular resolution capabilities. The intrinsic low tolerance of FT-ICR MS to RF interference, however, along with typically vertical positioning of the sample, and MSI acquisition speed requirements present numerous engineering challenges in creating robotics capable of achieving the spatial resolution to match. This work discusses a two-dimensional positioning stage designed to address these issues. The stage is capable of operating in ∼1 × 10(-8) mbar vacuum. The range of motion is set to 100 mm × 100 mm to accommodate large samples, while the positioning accuracy is demonstrated to be less than 0.4 micron in both directions under vertical load over the entire range. This device was integrated into three different matrix assisted laser desorption∕ionization (MALDI) FT-ICR instruments and showed no detectable RF noise. The "oversampling" MALDI-MSI experiments, under which the sample is completely ablated at each position, followed by the target movement of the distance smaller than the laser beam, conducted on the custom-built 7T FT-ICR MS demonstrate the stability and positional accuracy of the stage robotics which delivers high spatial resolution mass spectral images at a fraction of the laser spot diameter.

Low cost and manufacturable complete microTAS for detecting bacteria.

In this paper, we present a fully integrated lab-on-a-chip and associated instrument for the detection of bacteria from liquid samples. The system conducts bacterial lysis, nucleic acid isolation and concentration, polymerase chain reaction (PCR), and end-point fluorescent detection. To enable truly low-cost manufacture of the single-use disposable chip, we designed the plastic chip in a planar format without any active components to be amenable to injection molding and utilized a novel porous polymer monolith (PPM) embedded with silica that has been shown to lyse bacteria and isolate the nucleic acids from clinical samples (M. D. Kulinski, M. Mahalanabis, S. Gillers, J. Y. Zhang, S. Singh and C. M. Klapperich, Biomed. Microdevices, 2009, 11, 671-678).(1) The chip is made of Zeonex(R), a thermoplastic with a high melting temperature to allow PCR, good UV transmissibility for UV-curing of the PPM, and low auto-fluorescence for fluorescence detection of the amplicon. We have built a prototype instrument to automate control of the fluids, temperature cycling, and optical detection with the capability of accommodating various chip designs. To enable fluid control without including valves or pumps on the chip, we utilized a remote valve switching technique. To allow fluid flow rate changes on the valveless chip, we incorporated speed changing fluid reservoirs. The PCR thermal cycling was achieved with a ceramic heater and air cooling, while end-point fluorescence detection was accomplished with an optical spectrometer; all integrated in the instrument. The chip seamlessly and automatically is mated to the instrument through an interface block that presses against the chip. The interface block aligns and ensures good contact of the chip to the temperature controlled region and the optics. The integrated functionality of the chip was demonstrated using Bacillus subtilis as a model bacterial target. A Taqman assay was employed on-chip to detect the isolated bacterial DNA.