Design and Analysis of a Sample-and-Hold CMOS Electrochemical Sensor for Aptamer-based Therapeutic Drug Monitoring.

In this paper, we present the design and the analysis of an electrochemical circuit for measuring the concentrations of therapeutic drugs using structure-switching aptamers. Aptamers are single-stranded nucleic acids, whose sequence is selected to exhibit high affinity and specificity toward a molecular target, and change its conformation upon binding. This property, when coupled with a redox reporter and electrochemical detection, enables reagent-free biosensing with a sub-minute temporal resolution for in vivo therapeutic drug monitoring. Specifically, we design a chronoamperometry-based electrochemical circuit that measures the direct changes in the electron transfer (ET) kinetics of a methylene blue reporter conjugated at the distal-end of the aptamer. To overcome the high-frequency noise amplification issue when interfacing with a large-size (> 0.25 mm2) implantable electrode, we present a sample-and-hold (S/H) circuit technique in which the desired electrode potentials are held onto noiseless capacitors during the recording of the redox currents. This allows disconnecting the feedback amplifiers to avoid its noise injection while reducing the total power consumption. A prototype circuit implemented in 65-nm CMOS demonstrates a cell-capacitance-insensitive input-referred noise (IRN) current of 15.2 pArms at a 2.5-kHz filtering bandwidth. We tested our system in human whole blood samples and measured the changes in the ET kinetics from the redox-labeled aptamers at different kanamycin concentrations. By employing principal component analysis (PCA) to compensate for the sampling errors, we report a molecular noise floor (at SNR = 1) of 3.1 µM with sub 1-sec acquisition time at 0.22-mW power consumption.

Extremely bendable, high-performance integrated circuits using semiconducting carbon nanotube networks for digital, analog, and radio-frequency applications.

Solution-processed thin-films of semiconducting carbon nanotubes as the channel material for flexible electronics simultaneously offers high performance, low cost, and ambient stability, which significantly outruns the organic semiconductor materials. In this work, we report the use of semiconductor-enriched carbon nanotubes for high-performance integrated circuits on mechanically flexible substrates for digital, analog and radio frequency applications. The as-obtained thin-film transistors (TFTs) exhibit highly uniform device performance with on-current and transconductance up to 15 µA/µm and 4 µS/µm. By performing capacitance-voltage measurements, the gate capacitance of the nanotube TFT is precisely extracted and the corresponding peak effective device mobility is evaluated to be around 50 cm(2)V(-1)s(-1). Using such devices, digital logic gates including inverters, NAND, and NOR gates with superior bending stability have been demonstrated. Moreover, radio frequency measurements show that cutoff frequency of 170 MHz can be achieved in devices with a relatively long channel length of 4 µm, which is sufficient for certain wireless communication applications. This proof-of-concept demonstration indicates that our platform can serve as a foundation for scalable, low-cost, high-performance flexible electronics.

Self-aligned, extremely high frequency III-V metal-oxide-semiconductor field-effect transistors on rigid and flexible substrates.

This paper reports the radio frequency (RF) performance of InAs nanomembrane transistors on both mechanically rigid and flexible substrates. We have employed a self-aligned device architecture by using a T-shaped gate structure to fabricate high performance InAs metal-oxide-semiconductor field-effect transistors (MOSFETs) with channel lengths down to 75 nm. RF measurements reveal that the InAs devices made on a silicon substrate exhibit a cutoff frequency (f(t)) of ∼165 GHz, which is one of the best results achieved in III-V MOSFETs on silicon. Similarly, the devices fabricated on a bendable polyimide substrate provide a f(t) of ∼105 GHz, representing the best performance achieved for transistors fabricated directly on mechanically flexible substrates. The results demonstrate the potential of III-V-on-insulator platform for extremely high-frequency (EHF) electronics on both conventional silicon and flexible substrates.

Dual-Aptamer Drift Canceling Techniques to Improve Long-Term Stability of Real-Time Structure-Switching Aptasensors.

This paper presents a dual-aptamer scheme to mitigate signal drifts caused by structure-switching aptamers during long-term monitoring. Electrochemical aptamer-based (E-AB) biosensors have recently shown great potential for continuous in vivo monitoring. However, the accuracy of detection is often limited by signaling drifts. Traditional approaches rely on kinetic differential measurements (KDM) coupled with square-wave voltammetry to eliminate these drifts. Yet, we have discovered that KDM does not apply universally to all aptamers, as their responses at different SWV frequencies heavily rely on their structure-switching characteristics and the electron transfer (ET) kinetics of the redox reporters. In light of this, we propose a "dual-aptamer" scheme that utilizes two aptamers, each responding differently to the same target molecule to cancel out drift. These paired aptamers are identified through (1) screening from an existing pool of aptamers and (2) engineering the signaling behavior of the redox reporters. We demonstrate the differential signaling of the aptamer pair in the presence of ampicillin and ATP molecules and show that the pair exhibits similar drifts in undiluted goat serum. By implementing drift cancelation, sensor drift is reduced by a factor of 370. Additionally, the differential signaling enables an increased recording throughput by leveraging differential readout electronics. The authors believe that the proposed technique holds significant benefits for long-term in vivo monitoring.

Combinatorial Polyacrylamide Hydrogels for Preventing Biofouling on Implantable Biosensors.

Biofouling on the surface of implanted medical devices and biosensors severely hinders device functionality and drastically shortens device lifetime. Poly(ethylene glycol) and zwitterionic polymers are currently considered "gold-standard" device coatings to reduce biofouling. To discover novel anti-biofouling materials, a combinatorial library of polyacrylamide-based copolymer hydrogels is created, and their ability is screened to prevent fouling from serum and platelet-rich plasma in a high-throughput parallel assay. It is found that certain nonintuitive copolymer compositions exhibit superior anti-biofouling properties over current gold-standard materials, and machine learning is used to identify key molecular features underpinning their performance. For validation, the surfaces of electrochemical biosensors are coated with hydrogels and their anti-biofouling performance in vitro and in vivo in rodent models is evaluated. The copolymer hydrogels preserve device function and enable continuous measurements of a small-molecule drug in vivo better than gold-standard coatings. The novel methodology described enables the discovery of anti-biofouling materials that can extend the lifetime of real-time in vivo sensing devices.

A high-throughput flow cytometry-on-a-CMOS platform for single-cell dielectric spectroscopy at microwave frequencies.

This work presents a microfluidics-integrated label-free flow cytometry-on-a-CMOS platform for the characterization of the cytoplasm dielectric properties at microwave frequencies. Compared with MHz impedance cytometers, operating at GHz frequencies offers direct intracellular permittivity probing due to electric fields penetrating through the cellular membrane. To overcome the detection challenges at high frequencies, the spectrometer employs on-chip oscillator-based sensors, which embeds simultaneous frequency generation, electrode excitation, and signal detection capabilities. By employing an injection-locking phase-detection technique, the spectrometer offers state-of-the-art sensitivity, achieving a less than 1 aFrms capacitance detection limit (or 5 ppm in frequency-shift) at a 100 kHz noise filtering bandwidth, enabling high throughput (>1k cells per s), with a measured cellular SNR of more than 28 dB. With CMOS/microfluidics co-design, we distribute four sensing channels at 6.5, 11, 17.5, and 30 GHz in an arrayed format whereas the frequencies are selected to center around the water relaxation frequency at 18 GHz. An issue in the integration of CMOS and microfluidics due to size mismatch is also addressed through introducing a cost-efficient epoxy-molding technique. With 3-D hydrodynamic focusing microfluidics, we perform characterization on four different cell lines including two breast cell lines (MCF-10A and MDA-MB-231) and two leukocyte cell lines (K-562 and THP-1). After normalizing the higher frequency signals to the 6.5 GHz ones, the size-independent dielectric opacity shows a differentiable distribution at 17.5 GHz between normal (0.905 ± 0.160, mean ± std.) and highly metastatic (1.033 ± 0.107) breast cells with p ≪ 0.001.