On-chip integrated label-free optical biosensing

This thesis investigates the design and implementation of a label-free optical biosensing system utilizing a robust on-chip integrated platform. The goal has been to transition optical micro-resonator based label-free biosensing from a laborious and delicate laboratory demonstration to a tool for the analytical life scientist. This has been pursued along four avenues: (1) the design and fabrication of high-$Q$ integrated planar microdisk optical resonators in silicon nitride on silica, (2) the demonstration of a high speed optoelectronic swept frequency laser source, (3) the development and integration of a microfluidic analyte delivery system, and (4) the introduction of a novel differential measurement technique for the reduction of environmental noise.

The optical part of this system combines the results of two major recent developments in the field of optical and laser physics: the high-$Q$ optical resonator and the phase-locked electronically controlled swept-frequency semiconductor laser. The laser operates at a wavelength relevant for aqueous sensing, and replaces expensive and fragile mechanically-tuned laser sources whose frequency sweeps have limited speed, accuracy and reliability. The high-$Q$ optical resonator is part of a monolithic unit with an integrated optical waveguide, and is fabricated using standard semiconductor lithography methods. Monolithic integration makes the system significantly more robust and flexible compared to current, fragile embodiments that rely on the precarious coupling of fragile optical fibers to resonators. The silicon nitride on silica material system allows for future manifestations at shorter wavelengths. The sensor also includes an integrated microfluidic flow cell for precise and low volume delivery of analytes to the resonator surface. We demonstrate the refractive index sensing action of the system as well as the specific and nonspecific adsorption of proteins onto the resonator surface with high sensitivity. Measurement challenges due to environmental noise that hamper system performance are discussed and a differential sensing measurement is proposed, implemented, and demonstrated resulting in the restoration of a high performance sensing measurement.

The instrument developed in this work represents an adaptable and cost-effective platform capable of various sensitive, label-free measurements relevant to the study of biophysics, biomolecular interactions, cell signaling, and a wide range of other life science fields. Further development is necessary for it to be capable of binding assays, or thermodynamic and kinetics measurements; however, this work has laid the foundation for the demonstration of these applications.

Nanofabrication for On-Chip Optical Levitation, Atom-Trapping, and Superconducting Quantum Circuits

Researchers have spent decades refining and improving their methods for fabricating smaller, finer-tuned, higher-quality nanoscale optical elements with the goal of making more sensitive and accurate measurements of the world around them using optics. Quantum optics has been a well-established tool of choice in making these increasingly sensitive measurements which have repeatedly pushed the limits on the accuracy of measurement set forth by quantum mechanics. A recent development in quantum optics has been a creative integration of robust, high-quality, and well-established macroscopic experimental systems with highly-engineerable on-chip nanoscale oscillators fabricated in cleanrooms. However, merging large systems with nanoscale oscillators often require them to have extremely high aspect-ratios, which make them extremely delicate and difficult to fabricate with an "experimentally reasonable" repeatability, yield and high quality. In this work we give an overview of our research, which focused on microscopic oscillators which are coupled with macroscopic optical cavities towards the goal of cooling them to their motional ground state in room temperature environments. The quality factor of a mechanical resonator is an important figure of merit for various sensing applications and observing quantum behavior. We demonstrated a technique for pushing the quality factor of a micromechanical resonator beyond conventional material and fabrication limits by using an optical field to stiffen and trap a particular motional mode of a nanoscale oscillator. Optical forces increase the oscillation frequency by storing most of the mechanical energy in a nearly loss-less optical potential, thereby strongly diluting the effects of material dissipation. By placing a 130 nm thick SiO₂ pendulum in an optical standing wave, we achieve an increase in the pendulum center-of-mass frequency from 6.2 to 145 kHz. The corresponding quality factor increases 50-fold from its intrinsic value to a final value of Q_m = 5.8(1.1) x 10⁵, representing more than an order of magnitude improvement over the conventional limits of SiO₂ for a pendulum geometry. Our technique may enable new opportunities for mechanical sensing and facilitate observations of quantum behavior in this class of mechanical systems. We then give a detailed overview of the techniques used to produce high-aspect-ratio nanostructures with applications in a wide range of quantum optics experiments. The ability to fabricate such nanodevices with high precision opens the door to a vast array of experiments which integrate macroscopic optical setups with lithographically engineered nanodevices. Coupled with atom-trapping experiments in the Kimble Lab, we use these techniques to realize a new waveguide chip designed to address ultra-cold atoms along lithographically patterned nanobeams which have large atom-photon coupling and near 4π Steradian optical access for cooling and trapping atoms. We describe a fully integrated and scalable design where cold atoms are spatially overlapped with the nanostring cavities in order to observe a resonant optical depth of d₀ ≈ 0.15. The nanodevice illuminates new possibilities for integrating atoms into photonic circuits and engineering quantum states of atoms and light on a microscopic scale. We then describe our work with superconducting microwave resonators coupled to a phononic cavity towards the goal of building an integrated device for quantum-limited microwave-to-optical wavelength conversion. We give an overview of our characterizations of several types of substrates for fabricating a low-loss high-frequency electromechanical system. We describe our electromechanical system fabricated on a Si₃N₄ membrane which consists of a 12 GHz superconducting LC resonator coupled capacitively to the high frequency localized modes of a phononic nanobeam. Using our suspended membrane geometry we isolate our system from substrates with significant loss tangents, drastically reducing the parasitic capacitance of our superconducting circuit to ≈ 2.5$ fF. This opens up a number of possibilities in making a new class of low-loss high-frequency electromechanics with relatively large electromechanical coupling. We present our substrate studies, fabrication methods, and device characterization.

Electrical and optical interconnects for high-performance computing

Technology scaling has enabled drastic growth in the computational and storage capacity of integrated circuits (ICs). This constant growth drives an increasing demand for high-bandwidth communication between and within ICs. In this dissertation we focus on low-power solutions that address this demand. We divide communication links into three subcategories depending on the communication distance. Each category has a different set of challenges and requirements and is affected by CMOS technology scaling in a different manner. We start with short-range chip-to-chip links for board-level communication. Next we will discuss board-to-board links, which demand a longer communication range. Finally on-chip links with communication ranges of a few millimeters are discussed.

Electrical signaling is a natural choice for chip-to-chip communication due to efficient integration and low cost. IO data rates have increased to the point where electrical signaling is now limited by the channel bandwidth. In order to achieve multi-Gb/s data rates, complex designs that equalize the channel are necessary. In addition, a high level of parallelism is central to sustaining bandwidth growth. Decision feedback equalization (DFE) is one of the most commonly employed techniques to overcome the limited bandwidth problem of the electrical channels. A linear and low-power summer is the central block of a DFE. Conventional approaches employ current-mode techniques to implement the summer, which require high power consumption. In order to achieve low-power operation we propose performing the summation in the charge domain. This approach enables a low-power and compact realization of the DFE as well as crosstalk cancellation. A prototype receiver was fabricated in 45nm SOI CMOS to validate the functionality of the proposed technique and was tested over channels with different levels of loss and coupling. Measurement results show that the receiver can equalize channels with maximum 21dB loss while consuming about 7.5mW from a 1.2V supply. We also introduce a compact, low-power transmitter employing passive equalization. The efficacy of the proposed technique is demonstrated through implementation of a prototype in 65nm CMOS. The design achieves up to 20Gb/s data rate while consuming less than 10mW.

An alternative to electrical signaling is to employ optical signaling for chip-to-chip interconnections, which offers low channel loss and cross-talk while providing high communication bandwidth. In this work we demonstrate the possibility of building compact and low-power optical receivers. A novel RC front-end is proposed that combines dynamic offset modulation and double-sampling techniques to eliminate the need for a short time constant at the input of the receiver. Unlike conventional designs, this receiver does not require a high-gain stage that runs at the data rate, making it suitable for low-power implementations. In addition, it allows time-division multiplexing to support very high data rates. A prototype was implemented in 65nm CMOS and achieved up to 24Gb/s with less than 0.4pJ/b power efficiency per channel. As the proposed design mainly employs digital blocks, it benefits greatly from technology scaling in terms of power and area saving.

As the technology scales, the number of transistors on the chip grows. This necessitates a corresponding increase in the bandwidth of the on-chip wires. In this dissertation, we take a close look at wire scaling and investigate its effect on wire performance metrics. We explore a novel on-chip communication link based on a double-sampling architecture and dynamic offset modulation technique that enables low power consumption and high data rates while achieving high bandwidth density in 28nm CMOS technology. The functionality of the link is demonstrated using different length minimum-pitch on-chip wires. Measurement results show that the link achieves up to 20Gb/s of data rate (12.5Gb/s/$\mu$m) with better than 136fJ/b of power efficiency.

Interacting single atoms with nanophotonics for chip-integrated quantum networks

Underlying matter and light are their building blocks of tiny atoms and photons. The ability to control and utilize matter-light interactions down to the elementary single atom and photon level at the nano-scale opens up exciting studies at the frontiers of science with applications in medicine, energy, and information technology. Of these, an intriguing front is the development of quantum networks where N >> 1 single-atom nodes are coherently linked by single photons, forming a collective quantum entity potentially capable of performing quantum computations and simulations. Here, a promising approach is to use optical cavities within the setting of cavity quantum electrodynamics (QED). However, since its first realization in 1992 by Kimble et al., current proof-of-principle experiments have involved just one or two conventional cavities. To move beyond to N >> 1 nodes, in this thesis we investigate a platform born from the marriage of cavity QED and nanophotonics, where single atoms at ~100 nm near the surfaces of lithographically fabricated dielectric photonic devices can strongly interact with single photons, on a chip. Particularly, we experimentally investigate three main types of devices: microtoroidal optical cavities, optical nanofibers, and nanophotonic crystal based structures. With a microtoroidal cavity, we realized a robust and efficient photon router where single photons are extracted from an incident coherent state of light and redirected to a separate output with high efficiency. We achieved strong single atom-photon coupling with atoms located ~100 nm near the surface of a microtoroid, which revealed important aspects in the atom dynamics and QED of these systems including atom-surface interaction effects. We present a method to achieve state-insensitive atom trapping near optical nanofibers, critical in nanophotonic systems where electromagnetic fields are tightly confined. We developed a system that fabricates high quality nanofibers with high controllability, with which we experimentally demonstrate a state-insensitive atom trap. We present initial investigations on nanophotonic crystal based structures as a platform for strong atom-photon interactions. The experimental advances and theoretical investigations carried out in this thesis provide a framework for and open the door to strong single atom-photon interactions using nanophotonics for chip-integrated quantum networks.

Biotechnologies for cancer diagnostics : cell sorting, protein analysis and imaging of cellular metabolism

This thesis presents the development of chip-based technology for informative in vitro cancer diagnostics. In the first part of this thesis, I will present my contribution in the development of a technology called “Nucleic Acid Cell Sorting (NACS)”, based on microarrays composed of nucleic acid encoded peptide major histocompatibility complexes (p/MHC), and the experimental and theoretical methods to detect and analyze secreted proteins from single or few cells.

Secondly, a novel portable platform for imaging of cellular metabolism with radio probes is presented. A microfluidic chip, so called “Radiopharmaceutical Imaging Chip” (RIMChip), combined with a beta-particle imaging camera, is developed to visualize the uptake of radio probes in a small number of cells. Due to its sophisticated design, RIMChip allows robust and user-friendly execution of sensitive and quantitative radio assays. The performance of this platform is validated with adherent and suspension cancer cell lines. This platform is then applied to study the metabolic response of cancer cells under the treatment of drugs. Both cases of mouse lymphoma and human glioblastoma cell lines, the metabolic responses to the drug exposures are observed within a short time (~ 1 hour), and are correlated with the arrest of cell-cycle, or with changes in receptor tyrosine kinase signaling.

The last parts of this thesis present summaries of ongoing projects: development of a new agent as an in vivo imaging probe for c-MET, and quantitative monitoring of glycolytic metabolism of primary glioblastoma cells. To develop a new agent for c-MET imaging, the one-bead-one-compound combinatorial library method is used, coupled with iterative screening. The performance of the agent is quantitatively validated with cell-based fluorescent assays. In the case of monitoring the metabolism of primary glioblastoma cell, by RIMChip, cells were sorting according to their expression levels of oncoprotein, or were treated with different kinds of drugs to study the metabolic heterogeneity of cancer cells or metabolic response of glioblastoma cells to drug treatments, respectively.

Bright-field and fluorescence chip-scale microscopy for biological imaging

Optical microscopy is an essential tool in biological science and one of the gold standards for medical examinations. Miniaturization of microscopes can be a crucial stepping stone towards realizing compact, cost-effective and portable platforms for biomedical research and healthcare. This thesis reports on implementations of bright-field and fluorescence chip-scale microscopes for a variety of biological imaging applications. The term “chip-scale microscopy” refers to lensless imaging techniques realized in the form of mass-producible semiconductor devices, which transforms the fundamental design of optical microscopes.

Our strategy for chip-scale microscopy involves utilization of low-cost Complementary metal Oxide Semiconductor (CMOS) image sensors, computational image processing and micro-fabricated structural components. First, the sub-pixel resolving optofluidic microscope (SROFM), will be presented, which combines microfluidics and pixel super-resolution image reconstruction to perform high-throughput imaging of fluidic samples, such as blood cells. We discuss design parameters and construction of the device, as well as the resulting images and the resolution of the device, which was 0.66 µm at the highest acuity. The potential applications of SROFM for clinical diagnosis of malaria in the resource-limited settings is discussed.

Next, the implementations of ePetri, a self-imaging Petri dish platform with microscopy resolution, are presented. Here, we simply place the sample of interest on the surface of the image sensor and capture the direct shadow images under the illumination. By taking advantage of the inherent motion of the microorganisms, we achieve high resolution (~1 µm) imaging and long term culture of motile microorganisms over ultra large field-of-view (5.7 mm × 4.4 mm) in a specialized ePetri platform. We apply the pixel super-resolution reconstruction to a set of low-resolution shadow images of the microorganisms as they move across the sensing area of an image sensor chip and render an improved resolution image. We perform longitudinal study of Euglena gracilis cultured in an ePetri platform and image based analysis on the motion and morphology of the cells. The ePetri device for imaging non-motile cells are also demonstrated, by using the sweeping illumination of a light emitting diode (LED) matrix for pixel super-resolution reconstruction of sub-pixel shifted shadow images. Using this prototype device, we demonstrate the detection of waterborne parasites for the effective diagnosis of enteric parasite infection in resource-limited settings.

Then, we demonstrate the adaptation of a smartphone’s camera to function as a compact lensless microscope, which uses ambient illumination as its light source and does not require the incorporation of a dedicated light source. The method is also based on the image reconstruction with sweeping illumination technique, where the sequence of images are captured while the user is manually tilting the device around any ambient light source, such as the sun or a lamp. Image acquisition and reconstruction is performed on the device using a custom-built android application, constructing a stand-alone imaging device for field applications. We discuss the construction of the device using a commercial smartphone and demonstrate the imaging capabilities of our system.

Finally, we report on the implementation of fluorescence chip-scale microscope, based on a silo-filter structure fabricated on the pixel array of a CMOS image sensor. The extruded pixel design with metal walls between neighboring pixels successfully guides fluorescence emission through the thick absorptive filter to the photodiode layer of a pixel. Our silo-filter CMOS image sensor prototype achieves 13-µm resolution for fluorescence imaging over a wide field-of-view (4.8 mm × 4.4 mm). Here, we demonstrate bright-field and fluorescence longitudinal imaging of living cells in a compact, low-cost configuration.

Label-free detection of single biological molecules using microtoroid optical resonators

Being able to detect a single molecule without the use of labels has been a long standing goal of bioengineers and physicists. This would simplify applications ranging from single molecular binding studies to those involving public health and security, improved drug screening, medical diagnostics, and genome sequencing. One promising technique that has the potential to detect single molecules is the microtoroid optical resonator. The main obstacle to detecting single molecules, however, is decreasing the noise level of the measurements such that a single molecule can be distinguished from background. We have used laser frequency locking in combination with balanced detection and data processing techniques to reduce the noise level of these devices and report the detection of a wide range of nanoscale objects ranging from nanoparticles with radii from 100 to 2.5 nm, to exosomes, ribosomes, and single protein molecules (mouse immunoglobulin G and human interleukin-2). We further extend the exosome results towards creating a non-invasive tumor biopsy assay. Our results, covering several orders of magnitude of particle radius (100 nm to 2 nm), agree with the `reactive' model prediction for the frequency shift of the resonator upon particle binding. In addition, we demonstrate that molecular weight may be estimated from the frequency shift through a simple formula, thus providing a basis for an ``optical mass spectrometer'' in solution. We anticipate that our results will enable many applications, including more sensitive medical diagnostics and fundamental studies of single receptor-ligand and protein-protein interactions in real time. The thesis summarizes what we have achieved thus far and shows that the goal of detecting a single molecule without the use of labels can now be realized.

Injection Locked Clocking and Transmitter Equalization Techniques for Chip to Chip Interconnects

Semiconductor technology scaling has enabled drastic growth in the computational capacity of integrated circuits (ICs). This constant growth drives an increasing demand for high bandwidth communication between ICs. Electrical channel bandwidth has not been able to keep up with this demand, making I/O link design more challenging. Interconnects which employ optical channels have negligible frequency dependent loss and provide a potential solution to this I/O bandwidth problem. Apart from the type of channel, efficient high-speed communication also relies on generation and distribution of multi-phase, high-speed, and high-quality clock signals. In the multi-gigahertz frequency range, conventional clocking techniques have encountered several design challenges in terms of power consumption, skew and jitter. Injection-locking is a promising technique to address these design challenges for gigahertz clocking. However, its small locking range has been a major contributor in preventing its ubiquitous acceptance.

In the first part of this dissertation we describe a wideband injection locking scheme in an LC oscillator. Phase locked loop (PLL) and injection locking elements are combined symbiotically to achieve wide locking range while retaining the simplicity of the latter. This method does not require a phase frequency detector or a loop filter to achieve phase lock. A mathematical analysis of the system is presented and the expression for new locking range is derived. A locking range of 13.4 GHz–17.2 GHz (25%) and an average jitter tracking bandwidth of up to 400 MHz are measured in a high-Q LC oscillator. This architecture is used to generate quadrature phases from a single clock without any frequency division. It also provides high frequency jitter filtering while retaining the low frequency correlated jitter essential for forwarded clock receivers.

To improve the locking range of an injection locked ring oscillator; QLL (Quadrature locked loop) is introduced. The inherent dynamics of injection locked quadrature ring oscillator are used to improve its locking range from 5% (7-7.4GHz) to 90% (4-11GHz). The QLL is used to generate accurate clock phases for a four channel optical receiver using a forwarded clock at quarter-rate. The QLL drives an injection locked oscillator (ILO) at each channel without any repeaters for local quadrature clock generation. Each local ILO has deskew capability for phase alignment. The optical-receiver uses the inherent frequency to voltage conversion provided by the QLL to dynamically body bias its devices. A wide locking range of the QLL helps to achieve a reliable data-rate of 16-32Gb/s and adaptive body biasing aids in maintaining an ultra-low power consumption of 153pJ/bit.

From the optical receiver we move on to discussing a non-linear equalization technique for a vertical-cavity surface-emitting laser (VCSEL) based optical transmitter, to enable low-power, high-speed optical transmission. A non-linear time domain optical model of the VCSEL is built and evaluated for accuracy. The modelling shows that, while conventional FIR-based pre-emphasis works well for LTI electrical channels, it is not optimum for the non-linear optical frequency response of the VCSEL. Based on the simulations of the model an optimum equalization methodology is derived. The equalization technique is used to achieve a data-rate of 20Gb/s with power efficiency of 0.77pJ/bit.

Development of Microfluidic Devices with the Use of Nanotechnology to Aid in the Analysis of Biological Systems Including Membrane Protein Separation, Single Cell Analysis, and Genetic Markers

Computation technology has dramatically changed the world around us; you can hardly find an area where cell phones have not saturated the market, yet there is a significant lack of breakthroughs in the development to integrate the computer with biological environments. This is largely the result of the incompatibility of the materials used in both environments; biological environments and experiments tend to need aqueous environments. To help aid in these development chemists, engineers, physicists and biologists have begun to develop microfluidics to help bridge this divide. Unfortunately, the microfluidic devices required large external support equipment to run the device. This thesis presents a series of several microfluidic methods that can help integrate engineering and biology by exploiting nanotechnology to help push the field of microfluidics back to its intended purpose, small integrated biological and electrical devices. I demonstrate this goal by developing different methods and devices to (1) separate membrane bound proteins with the use of microfluidics, (2) use optical technology to make fiber optic cables into protein sensors, (3) generate new fluidic devices using semiconductor material to manipulate single cells, and (4) develop a new genetic microfluidic based diagnostic assay that works with current PCR methodology to provide faster and cheaper results. All of these methods and systems can be used as components to build a self-contained biomedical device.

Holistic Design In High-Speed Optical Interconnects

Integrated circuit scaling has enabled a huge growth in processing capability, which necessitates a corresponding increase in inter-chip communication bandwidth. As bandwidth requirements for chip-to-chip interconnection scale, deficiencies of electrical channels become more apparent. Optical links present a viable alternative due to their low frequency-dependent loss and higher bandwidth density in the form of wavelength division multiplexing. As integrated photonics and bonding technologies are maturing, commercialization of hybrid-integrated optical links are becoming a reality. Increasing silicon integration leads to better performance in optical links but necessitates a corresponding co-design strategy in both electronics and photonics. In this light, holistic design of high-speed optical links with an in-depth understanding of photonics and state-of-the-art electronics brings their performance to unprecedented levels. This thesis presents developments in high-speed optical links by co-designing and co-integrating the primary elements of an optical link: receiver, transmitter, and clocking.

In the first part of this thesis a 3D-integrated CMOS/Silicon-photonic receiver will be presented. The electronic chip features a novel design that employs a low-bandwidth TIA front-end, double-sampling and equalization through dynamic offset modulation. Measured results show -14.9dBm of sensitivity and energy efficiency of 170fJ/b at 25Gb/s. The same receiver front-end is also used to implement source-synchronous 4-channel WDM-based parallel optical receiver. Quadrature ILO-based clocking is employed for synchronization and a novel frequency-tracking method that exploits the dynamics of IL in a quadrature ring oscillator to increase the effective locking range. An adaptive body-biasing circuit is designed to maintain the per-bit-energy consumption constant across wide data-rates. The prototype measurements indicate a record-low power consumption of 153fJ/b at 32Gb/s. The receiver sensitivity is measured to be -8.8dBm at 32Gb/s.

Next, on the optical transmitter side, three new techniques will be presented. First one is a differential ring modulator that breaks the optical bandwidth/quality factor trade-off known to limit the speed of high-Q ring modulators. This structure maintains a constant energy in the ring to avoid pattern-dependent power droop. As a first proof of concept, a prototype has been fabricated and measured up to 10Gb/s. The second technique is thermal stabilization of micro-ring resonator modulators through direct measurement of temperature using a monolithic PTAT temperature sensor. The measured temperature is used in a feedback loop to adjust the thermal tuner of the ring. A prototype is fabricated and a closed-loop feedback system is demonstrated to operate at 20Gb/s in the presence of temperature fluctuations. The third technique is a switched-capacitor based pre-emphasis technique designed to extend the inherently low bandwidth of carrier injection micro-ring modulators. A measured prototype of the optical transmitter achieves energy efficiency of 342fJ/bit at 10Gb/s and the wavelength stabilization circuit based on the monolithic PTAT sensor consumes 0.29mW.

Lastly, a first-order frequency synthesizer that is suitable for high-speed on-chip clock generation will be discussed. The proposed design features an architecture combining an LC quadrature VCO, two sample-and-holds, a PI, digital coarse-tuning, and rotational frequency detection for fine-tuning. In addition to an electrical reference clock, as an extra feature, the prototype chip is capable of receiving a low jitter optical reference clock generated by a high-repetition-rate mode-locked laser. The output clock at 8GHz has an integrated RMS jitter of 490fs, peak-to-peak periodic jitter of 2.06ps, and total RMS jitter of 680fs. The reference spurs are measured to be –64.3dB below the carrier frequency. At 8GHz the system consumes 2.49mW from a 1V supply.