Mark J. Hsu

STI-Bounded Single-Photon Avalanche Diode in a Deep-Submicrometer CMOS Technology

This letter presents a novel and compact CMOS Geiger-mode single-photon avalanche diode (SPAD) device with an efficient guard ring structure for preventing edge breakdown. The new guard ring can withstand considerably higher electric fields than existing structures, and results in pixels which are an order of magnitude smaller and offer a nine-fold increase in fill factor compared with existing SPADs. The device has been studied numerically and experimentally on a 0.18-mum CMOS technology. Due to its small area, the detector can be operated with minimal power dissipation and has been verified to operate reliably over 5times1010 cycles. This is the first SPAD proven in a deep-submicrometer non-high-voltage technology and as such, provides unique opportunities for improved performance and for on-chip integration of the ultrafast timing circuitry required to translate the SPAD output into meaningful data

DNA‐Coated Microbubbles with Biochemically Tunable Ultrasound Contrast Activity

Changing the mechanical properties of the microbubble shell in response to a biochemical stimulus leads to vast changes in both ultrasound-induced bubble dynamics and contrast-enhanced ultrasound imaging. Here, DNA-coated microbubbles are shown to be a simple and highly versatile platform that can silence and re-activate contrast activity in response to the introduction and removal of biochemical stimuli.

Characterization of individual ultrasound microbubble dynamics with a light-scattering system

Ultrasound microbubbles are contrast agents used for diagnostic ultrasound imaging and as carriers for noninvasive payload delivery. Understanding the acoustic properties of individual microbubble formulations is important for optimizing the ultrasound imaging parameters for improved image contrast and efficient payload delivery. We report here a practical and simple optical tool for direct real-time characterization of ultrasound contrast microbubble dynamics based on light scattering. Fourier transforms of raw linear and nonlinear acoustic oscillations, and microbubble cavitations are directly recorded. Further, the power of this tool is demonstrated by comparing clinically relevant microbubble cycle-to-cycle dynamics and their corresponding Fourier transforms.

Phospholipid/Carbocyanine Dye-Shelled Microbubbles as Ultrasound-Modulated Fluorescent Contrast Agents

Fluorescent microbubbles have been fabricated with the capacity to have their emission modulated by ultrasound. These contrast agent particles could potentially be used in the future to extract fluorescence modulation from a strong light background to increase imaging depth and resolution in scattering media. Fluorescence intensity modulation was demonstrated at the ultrasound driving frequency.

Facile one-pot synthesis of polymer–phospholipid composite microbubbles with enhanced drug loading capacity for ultrasound-triggered therapy

This paper reports the one-pot synthesis of perfluorocarbon microbubbles with crosslinked shells of poly(acrylic acid) and phospholipid that boast excellent ultrasound contrast enhancement, enhanced loading capacity, and the ability to retain or release their contents through variation in the level of ultrasound exposure.

An ultrafast Geiger-mode single-photon avalanche diode in 0.18-μm CMOS technology

We demonstrate a new single-photon avalanche diode (SPAD) device, which utilizes the silicon-dioxide shallow-trench isolation (STI) structure common to all deep-submicron CMOS technologies, both for junction planarization and as an area-efficient guard-ring. This makes it possible to achieve an order-of-magnitude improvement in fill factor and a significant reduction in pixel area compared with existing CMOS SPADs, and results in improved SPAD performance. We present numerical simulations as well preliminary experimental results from a test chip, which was manufactured in an IBM 0.18 μm CMOS technology, and which incorporates the devices. With these new and efficient structures, 12 μm-pitch pixels with sub-10ns dead times are achievable without requiring active recharge, creating the opportunity to integrate large arrays of these ultra-fast SPADs for use in biological imaging systems.

Collaborative Beamfocusing Radio (COBRA)

A Ziva team has recently demonstrated a novel technique called Collaborative Beamfocusing Radios (COBRA) which enables an ad-hoc collection of distributed commercial off-the-shelf software defined radios to coherently align and beamform to a remote radio. COBRA promises to operate even in high multipath and non-line-of-sight environments as well as mobile applications without resorting to computationally expensive closed loop techniques that are currently unable to operate with significant movement. COBRA exploits two key technologies to achieve coherent beamforming. The first is Time Reversal (TR) which compensates for multipath and automatically discovers the optimal spatio-temporal matched filter to enable peak signal gains (up to 20 dB) and diffraction-limited focusing at the intended receiver in NLOS and severe multipath environments. The second is time-aligned buffering which enables TR to synchronize distributed transmitters into a collaborative array. This time alignment algorithm avoids causality violations through the use of reciprocal buffering. Preserving spatio-temporal reciprocity through the TR capture and retransmission process achieves coherent alignment across multiple radios at ~GHz carriers using only standard quartz-oscillators. COBRA has been demonstrated in the lab, aligning two off-the-shelf software defined radios over-the-air to an accuracy of better than 2 degrees of carrier alignment at 450 MHz. The COBRA algorithms are lightweight, with computation in 5 ms on a smartphone class microprocessor. COBRA also has low start-up latency, achieving high accuracy from a cold-start in 30 ms. The COBRA technique opens up a large number of new capabilities in communications, and electronic warfare including selective spatial jamming, geolocation and anti-geolocation.

Ultrasound-modulated fluorescent contrast agent for optical imaging through turbid media

Optical imaging in a highly scattering medium is effective only at very shallow depths which limits its use as a diagnostic tool in biomedical imaging. By combining optical and acoustic modalities, high-contrast, physiologicallyrelevant optical information at higher spatial resolutions can be achieved. Hybrid imaging modalities such as acoustooptic and photoacoustic imaging improve resolution over conventional optical imaging, but tissue scattering results in poor signal-to-background ratios especially in deeper tissues. To overcome these challenges, we have developed a novel microbubble (MB) contrast agent surface-loaded with a self-quenching fluorophore. In response to ultrasound, the MB expands and contracts, generating changes in fluorophore surface density. The changes in physical separation between fluorophores modulate the quenching efficiency and produce a fluorescence intensity modulation. To our knowledge, this is the first experimental demonstration of ultrasound modulation of fluorescence using a self-quenching MB scheme. The modulation is spatially localized to the ultrasound focal zone where the pressure is greatest and the largest MB oscillations are induced. The modulated signal can be extracted from a large constant light background, increasing detection sensitivity. This technique can enable sensitive optical imaging with ultrasound-scale sub-millimeter spatial resolution, overcoming significant challenges of optical imaging in deep tissue. The contrast agent MBs were prepared with a shell of phospholipid and lipophilic self-quenching fluorophore. MB ultrasound response was studied in a custom setup which monitored fluorescence emitted from an insonified sample. Fluorescence signals displayed clearly modulated intensity and the fast Fourier transform (FFT) showed a strong component at the ultrasound driving frequency.

Manipulating nanoscale features on the surface of dye-loaded microbubbles to increase their ultrasound-modulated fluorescence output.

The nanoscale surface features of lipid-coated microbubbles can dramatically affect how the lipids interact with one another as the microbubble diameter expands and contracts under the influence of ultrasound. During microbubble manufacturing, the different lipid shell species naturally partition forming concentrated lipid islands. In this study the dynamics of how these nanoscale islands accommodate the expansion of the microbubbles are monitored by measuring the fluorescence intensity changes that occur as self-quenching lipophilic dye molecules embedded in the lipid layer change their distance from one another. It was found that when the dye molecules were concentrated in islands, less than 5% of the microbubbles displayed measurable fluorescence intensity modulation indicating the islands were not able to expand sufficiently for the dye molecules to separate from one another. When the microbubbles were heated and cooled rapidly through the lipid transition temperature the islands were melted creating an even distribution of dye about the surface. This resulted in over 50% of the microbubbles displaying the fluorescence-modulated signal indicating that the dye molecules could now separate sufficiently to change their self-quenching efficiency. The separation of the surface lipids in these different formations has significant implications for microbubble development as ultrasound and optical contrast agents.

Detection of ultrasound-modulated photons and enhancement with ultrasound microbubbles

In vivo acousto-optic imaging promises to provide optical contrast at superior ultrasound spatial resolution. The main challenge is to detect ultrasound-modulated photons in the overwhelming presence of un-modulated photons. We have demonstrated in vitro detection of ultrasound-modulated photons with a variety of detection methods. Furthermore, we have detected ultrasound-modulated fluorescence offering potential for acousto-optic molecular imaging. Moreover, we have demonstrated the use of ultrasound microbubbles to significantly enhance the acousto-optic signal at the ultrasound frequency with the additional generation of higher order harmonic frequencies. Here the results from our various detection methods, ultrasound-modulated fluorescence, and enhancement with microbubbles are presented.