Multicolor fluorescence microscopy for surgical guidance using a chip-scale imager with a low-NA fiber optic plate and a multi-bandpass interference filter.

In curative-intent cancer surgery, intraoperative fluorescence imaging of both diseased and healthy tissue can help to ensure successful removal of all gross and microscopic disease with minimal damage to neighboring critical structures, such as nerves. Current fluorescence-guided surgery (FGS) systems, however, rely on bulky and rigid optics that incur performance-limiting trade-offs between sensitivity and maneuverability. Moreover, many FGS systems are incapable of multiplexed imaging. As a result, clinical FGS is currently limited to millimeter-scale detection of a single fluorescent target. Here we present a scalable, lens-less fluorescence imaging chip, VISION, capable of sensitive and multiplexed detection within a compact form factor. Central to VISION is a novel optical frontend design combining a low-numerical-aperture fiber optic plate (LNA-FOP) and a multi-bandpass interference filter, which is affixed to a custom CMOS image sensor. The LNA-FOP acts as a planar collimator to improve resolution and compensate for the angle-sensitivity of the interference filter, enabling high-resolution and multiplexed fluorescence imaging without lenses. We show VISION is capable of detecting tumor foci of less than 100 cells at near video framerates and, as proof of principle, can simultaneously visualize both tumor and nerves in ex vivo prostate tissue.

Low cost, high temporal resolution optical fiber-based γ-photon sensor for real-time pre-clinical evaluation of cancer-targeting radiopharmaceuticals.

Cancer radiopharmaceutical therapies (RPTs) have demonstrated great promise in the treatment of neuroendocrine and prostate cancer, giving hope to late-stage metastatic cancer patients with currently very few treatment options. These therapies have sparked a large amount of interest in pre-clinical research due to their ability to target metastatic disease, with many research efforts focused towards developing and evaluating targeted RPTs for different cancer types in in vivo models. Here we describe a method for monitoring real-time in vivo binding kinetics for the pre-clinical evaluation of cancer RPTs. Recognizing the significant heterogeneity in biodistribution of RPTs among even genetically identical animal models, this approach offers long-term monitoring of the same in vivo organism without euthanasia in contrast to ex vivo tissue dosimetry, while providing high temporal resolution with a low-cost, easily assembled platform, that is not present in small-animal SPECT/CTs. The method utilizes the developed optical fiber-based γ-photon biosensor, characterized to have a wide linear dynamic range with Lutetium-177 (177Lu) activity (0.5-500 µCi/mL), a common radioisotope used in cancer RPT. The probe's ability to track in vivo uptake relative to SPECT/CT and ex vivo dosimetry techniques was verified by administering 177Lu-PSMA-617 to mouse models bearing human prostate cancer tumors (PC3-PIP, PC3-flu). With this method for monitoring RPT uptake, it is possible to evaluate changes in tissue uptake at temporal resolutions <1 min to determine RPT biodistribution in pre-clinical models and better understand dose relationships with tumor ablation, toxicity, and recurrence when attempting to move therapies towards clinical trial validation.

Multicolor fluorescence microscopy for surgical guidance using a chip-scale imager with a low-NA fiber optic plate and a multi-bandpass interference filter.

In curative-intent cancer surgery, intraoperative fluorescence imaging of both diseased and healthy tissue can help to ensure the successful removal of all gross and microscopic diseases with minimal damage to neighboring critical structures, such as nerves. Current fluorescence-guided surgery (FGS) systems, however, rely on bulky and rigid optics that incur performance-limiting trade-offs between sensitivity and maneuverability. Moreover, many FGS systems are incapable of multiplexed imaging. As a result, clinical FGS is currently limited to millimeter-scale detection of a single fluorescent target. Here, we present a scalable, lens-less fluorescence imaging chip, VISION, capable of sensitive and multiplexed detection within a compact form factor. Central to VISION is a novel optical frontend design combining a low-numerical-aperture fiber optic plate (LNA-FOP) and a multi-bandpass interference filter, which is affixed to a custom CMOS image sensor. The LNA-FOP acts as a planar collimator to improve resolution and compensate for the angle-sensitivity of the interference filter, enabling high-resolution and multiplexed fluorescence imaging without lenses. We show VISION is capable of detecting tumor foci of less than 100 cells at near video framerates and, as proof of principle, can simultaneously visualize both tumors and nerves in ex vivo prostate tissue.

A Wireless, Multicolor Fluorescence Image Sensor Implant for Real-Time Monitoring in Cancer Therapy.

Real-time monitoring of dynamic biological processes in the body is critical to understanding disease progression and treatment response. This data, for instance, can help address the lower than 50% response rates to cancer immunotherapy. However, current clinical imaging modalities lack the molecular contrast, resolution, and chronic usability for rapid and accurate response assessments. Here, we present a fully wireless image sensor featuring a 2.5×5 mm2 CMOS integrated circuit for multicolor fluorescence imaging deep in tissue. The sensor operates wirelessly via ultrasound (US) at 5 cm depth in oil, harvesting energy with 221 mW/cm2 incident US power density (31% of FDA limits) and backscattering data at 13 kbps with a bit error rate <10-6. In-situ fluorescence excitation is provided by micro-laser diodes controlled with a programmable on-chip driver. An optical frontend combining a multi-bandpass interference filter and a fiber optic plate provides >6 OD excitation blocking and enables three-color imaging for detecting multiple cell types. A 36×40-pixel array captures images with <125 µm resolution. We demonstrate wireless, dual-color fluorescence imaging of both effector and suppressor immune cells in ex vivo mouse tumor samples with and without immunotherapy. These results show promise for providing rapid insight into therapeutic response and resistance, guiding personalized medicine.

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.

Enhancement of Physical Characteristics of Styrene-Acrylonitrile Nanofiber Membranes Using Various Post-Treatments for Membrane Distillation.

Insufficient mechanical strength and wide pore size distribution of nanofibrous membranes are the key hindrances for their concrete applications in membrane distillation. In this work, various post-treatment methods such as dilute solvent welding, vapor welding, and cold-/hot-pressing processes were used to enhance the physical properties of styrene-acrylonitrile (SAN) nanofiber membranes fabricated by the modified electrospinning process. The effects of injection rate of welding solution and a working distance during the welding process with air-assisted spraying on characteristics of SAN nanofiber membranes were investigated. The welding process was made less time-consuming by optimizing system parameters of the electroblowing process to simultaneously exploit residual solvents of fibers and hot solvent vapor to reduce exposure time. As a result, the welded SAN membranes showed considerable enhancement in mechanical robustness and membrane integrity with a negligible reduction in surface hydrophobicity. The hot-pressed SAN membranes obtained the highest mechanical strength and smallest mean pore size. The modified SAN membranes were used for the desalination of synthetic seawater in a direct contact membrane distillation (DCMD). As a result, it was found that the modified SAN membranes performed well (>99.9% removal of salts) for desalination of synthetic seawater (35 g/L NaCl) during 30 h operation without membrane wetting. The cold-/hot-pressing processes were able to improve mechanical strength and boost liquid entry pressure (LEP) of water. In contrast, the welding processes were preferred to increase membrane flexibility and permeation.

Microfluidic Packaging Integration with Electronic-Photonic Biosensors Using 3D Printed Transfer Molding.

Multiplexed sensing in integrated silicon electronic-photonic platforms requires microfluidics with both high density micro-scale channels and meso-scale features to accommodate for optical, electrical, and fluidic coupling in small, millimeter-scale areas. Three-dimensional (3D) printed transfer molding offers a facile and rapid method to create both micro and meso-scale features in complex multilayer microfluidics in order to integrate with monolithic electronic-photonic system-on-chips with multiplexed rows of 5 µm radius micro-ring resonators (MRRs), allowing for simultaneous optical, electrical, and microfluidic coupling on chip. Here, we demonstrate this microfluidic packaging strategy on an integrated silicon photonic biosensor, setting the basis for highly multiplexed molecular sensing on-chip.

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.

Time-domain ultra-wideband synthetic imager (TUSI) in silicon.

This paper introduces a silicon-based imaging array for remote measurements of complex permittivity of tissue. Using a coherent pulsed measurement approach, this time-frequency resolved technique recovers the three dimensional mapping of electrical properties of the subject in the microwave/millimeter-wave frequency spectrum. Some of the major challenges in the design of the system are described. Initial measurement results from the prototype high-resolution transmitter fabricated in a 0.13 µm SiGe process are described. The transmitter achieves pulse widths suitable for millimeter-level accuracy imaging.

Parallel array InAs nanowire transistors for mechanically bendable, ultrahigh frequency electronics.

The radio frequency response of InAs nanowire array transistors on mechanically flexible substrates is characterized. For the first time, GHz device operation of nanowire arrays is demonstrated, despite the relatively long channel lengths of ∼1.5 µm used in this work. Specifically, the transistors exhibit an impressive maximum frequency of oscillation, f(max) ∼ 1.8 GHz, and a cutoff frequency, f(t) ∼ 1 GHz. The high-frequency response of the devices is due to the high saturation velocity of electrons in high-mobility InAs nanowires. The work presents a new platform for flexible, ultrahigh frequency devices with potential applications in high-performance digital and analog circuitry.