We report the development of an all-fiber-optic scanning endomicroscope capable of high-resolution second harmonic generation (SHG) imaging of biological tissues and demonstrate its utility for monitoring the remodeling of cervical collagen during gestation in mice. The endomicroscope has an overall 2.0 mm diameter and consists of a single customized double-clad fiber, a compact rapid two-dimensional beam scanner, and a miniature compound objective lens for excitation beam delivery, scanning, focusing, and efficient SHG signal collection. Endomicroscopic SHG images of murine cervical tissue sections at different stages of normal pregnancy reveal progressive, quantifiable changes in cervical collagen morphology with resolution similar to that of bench-top SHG microscopy. SHG endomicroscopic imaging of ex vivo murine and human cervical tissues through intact epithelium has also been performed. Our findings demonstrate the feasibility of SHG endomicroscopy technology for staging normal pregnancy, and suggest its potential application as a minimally invasive tool for clinical assessment of abnormal cervical remodeling associated with preterm birth.nonlinear endomicroscopy | fiber-optic scanning probe | cervical collagen remodeling | parturition T he cervix is a connective tissue-rich structure just caudal to the uterus in female mammals. Appropriate remodeling of the cervix during gestation is an essential component of the birth process (1, 2). The cervix must remain closed during pregnancy to maintain the fetus in the womb, and then open sufficiently to allow passage of the fetus at term. This shift in responsibility requires a massive rearrangement of the cervical connective tissue, in particular fibrillar collagen. Collagen is the main structural protein in the cervix. Animal studies reveal rearrangement of collagen structure is achieved in part by a decline in collagen crosslink formation, a reduction in matricellular proteins that regulate collagen fibrillogenesis, and increased synthesis of the matrix disorganizing molecule, hyaluronan (3, 4). Evidence to support a conservation of these processes in cervical remodeling in women is mounting (5). Abnormal or inappropriately timed cervical remodeling can lead to premature birth.Preterm birth (PTB), which accounts for 12.7% of all births in the United States, is the second leading cause of infant mortality and often leads to serious morbidity in surviving infants (6). Despite considerable research, the cause of PTB in 50% of cases remains elusive, and diagnostic methods to detect women at risk of PTB are limited (7). Because clinical and animal studies suggest that cervical changes precede the onset of uterine contractility in both term and PTB, premature cervical changes could be indicative of impending PTB (4, 8-10). The progressive structural changes in fibrillar collagens are directly related to cervical rigidity and thus potentially can serve as a diagnostic indicator for women at risk for PTB.Second harmonic generation (SHG) microscopy is the most effective ...

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Electrical activity in the brain spans a wide range of spatial and temporal scales, requiring simultaneous recording of multiple modalities of neurophysiological signals in order to capture various aspects of brain state dynamics. Here, we present a 16-channel neural interface integrated circuit fabricated in a 0.5 μm 3M2P CMOS process for selective digital acquisition of biopotentials across the spectrum of neural signal modalities in the brain, ranging from single spike action potentials to local field potentials (LFP), electrocorticograms (ECoG), and electroencephalograms (EEG). Each channel is composed of a tunable bandwidth, fixed gain front-end amplifier and a programmable gain/resolution continuous-time incremental ΔΣ analog-to-digital converter (ADC). A two-stage topology for the front-end voltage amplifier with capacitive feedback offers independent tuning of the amplifier bandpass frequency corners, and attains a noise efficiency factor (NEF) of 2.9 at 8.2 kHz bandwidth for spike recording, and a NEF of 3.2 at 140 Hz bandwidth for EEG recording. The amplifier has a measured midband gain of 39.6 dB, frequency response from 0.2 Hz to 8.2 kHz, and an input-referred noise of 1.94 μV rms while drawing 12.2 μA of current from a 3.3 V supply. The lower and higher cutoff frequencies of the bandpass filter are adjustable from 0.2 to 94 Hz and 140 Hz to 8.2 kHz, respectively. At 10-bit resolution, the ADC has an SNDR of 56 dB while consuming 76 μW power. Time-modulation feedback in the ADC offers programmable digital gain (1-4096) for auto-ranging, further improving the dynamic range and linearity of the ADC. Experimental recordings with the system show spike signals in rat somatosensory cortex as well as alpha EEG activity in a human subject.

Abstract-A 16-channel current-measuring VLSI sensor array system for highly sensitive electrochemical detection of electroactive neurotransmiters like dopamine and nitric-oxide is presented. Each channel embeds a current integrating potentiostat within a switched-capacitor first-order single-bit delta-sigma modulator implementing an incremental analog-to-digital converter. Dutycycle modulation of current feedback in the delta-sigma loop together with variable oversampling ratio provide programmable digital range selection of the input current spanning over six orders of magnitude from picoamperes to microamperes. The array offers 100fA input current sensitivity at 3.4 µW power consumption per channel. The operation of the 3mm x 3mm chip fabricated in 0.5 µm CMOS technology is demonstrated with real-time multi-channel acquisition of neurotransmitter concentration.