Research

My research goal is to develop a multidisciplinary research program that focuses on advancing nanotechnologies to address the grand challenges in biomedical and energy applications. I have a long-term career goal of contributing to the development of portable, inexpensive and accurate devices that will enable early stage disease diagnosis and post-treatment monitoring. I believe there is still “plenty of room at the bottom” for new nanotechnologies to stimulate novel biomedical research, and will leverage my expertise in nanoscience and engineering to study fundamental physics and biochemistry and to detect subcellular biomarkers for early-stage disease detection.


 

1. Nano-bioelectronics for Biomarker Detection

Nanopore sensing is an emerging technology, which has recently been developed towards future precision/personalized medicine applications. A nanopore sensor measures single molecules as they flow through a nanometer hole in a thin membrane separating two fluidic chambers, and collects the electronic signal as a result of modulation of the ion conductivity inside the nanopore, which correlates to the molecular signature of the tested biomolecule. Beyond the DNA primary sequence, nanopore sensors have been used to detect DNA epi-genetic information (such as DNA methylation) as well as other molecules (proteins, extracellular vesicles, etc) related to disease diagnostics. Conventionally, detection of such molecules requires complex procedures for quantification and detection, such as purification, enzymatic amplification, hybridization, etc. Therefore, the detection process is not only costly and time-consuming but also error-prone, due to inevitable bias from sample preparation and human operation errors. In comparison, nanopore sensing is advantageous for its capability of detecting at single-molecule level without complex sample preparation.

Particularly, solid-state nanopores are portable, structurally robust, and manufacturable, making them especially appealing to broad genetics-based diagnostic applications in modern clinical as well as in resource-limited settings. However, despite the efforts to improve the nanopore structure design and data analysis algorithms, it often remains difficult to accurately interpret the molecular structure from the electrical current signals. One key challenge is associated with an insufficient signal-to-noise ratio (SNR) of the existing nanopore devices. Specifically, the silicon (Si) substrate’s inherent large electrical capacitance in conventional Si nanopore devices results in a high electrical noise at high frequencies, and hence limits the data-recording speed and complicates the signal retrieval. Using DNA as an example, the complex DNA conformational changes and dynamic interaction with nanopore surface complicates the electrical signal deconvolution partly due to complex DNA translocation dynamics in small solid-state nanopores. Currently, high-speed and accurate DNA detection at the single-molecule level still lags behind.

To address these challenges, we are developing a novel sapphire based solid-state platform that can minimize the device capacitance by more than 2 orders of magnitude and accordingly significantly improve the signal bandwidth and reduce the noise. Importantly, the fabrication method of our platform is compatible with high-throughput batch processing, thus very desirable for large-scale and low-cost production of future electronic sequencers. Specifically, we propose to use anisotropic wet etching to create novel triangular shaped membranes and nanopores on insulating sapphire crystal over a wafer scale. We are investigating a variety of strategies to precisely define the membrane size and thickness. We expect to fabricate ultrathin (1-10 nm thick) and ultrasmall (<10 µm wide) membranes in a variety of materials (SiN, TiO2, and 2D materials) that will yield a device capacitance <1 pF, which will essentially eliminate the nanopore device impact on the electronic noise. Finally, we will study the high-frequency (up to 1 MHz) current noise response and DNA signal integrity using the sapphire chips. Our approach eliminates high-temperature or wet processes that are ineffective and detrimental to ultrasmall structures, which is critical to high-yield manufacturing.

Reference: Pengkun Xia, Jiawei Zuo, Pravin Paudel, and Chao Wang, “Scalable fabrication of triangular nanopore membranes on sapphire substrate for low-noise DNA detection,” presented at the The International Conference on Electron, Ion, and Photon Beam Technology and Nanofabrication Minneapolis, MN, 2019.


 

2. Nanophotonics and Quantum Optics 

Quantum optics studies the interaction between light and matter at the most fundamental level where single quanta of light (photons) and single entities of matter (quantum emitters) are controllably coupled. The ability of nanostructured metamaterials to tailor and control measurable changes in the quantum properties of light has enabled encoding quantum information using photon spin and orbital momentum energy transfer, and accordingly has resulted in a breakthrough that could play a prominent role in the future of computing. However, serious challenges still exist in the stringent design and manufacturing of an efficient quantum interface that enables strong coupling between an optical nanocavity and a single quantum emitter at room temperature (RT).

First, a large coupling strength  is key to overcoming the optical loss from the emitter and the cavity in order to achieve a large Rabi energy splitting (e.g. >200 meV), which is very desirable for RT coherent Rabi oscillation. A large  requires a large emitter dipole moment  and a small cavity mode volume . However, the dipole moment for a single emitter is typically limited by its own material properties, and the cavity mode volume  is generally too large using conventional high quality factor dielectric microcavities (107 to 108 nm3). Second, there is a lack of needed accuracy to place a single emitter into the cavity at the highest field intensity in incumbent strategies to study the single emitter-cavity interactions at quantum scale. Current emitter placement approaches employ random dispersion or growth of quantum dot (QD) emitters in a cavity without precise control in number and location, but relies on one-by-one searching to identity the single emitter by coincidence. Some others assemble a large number of QDs or organic dyes without a feasible route to achieve precisely single-emitter control. Third, existing emitter-cavity system designs rely on complicated nanomanufacturing processes to tune the cavity resonance and integrate the quantum emitters, and are not scalable for future quantum optical applications requiring a network of such systems.

In this direction, our group, in collaboration with Dr. Hao Yan, is using programmed DNA origami (DO) and single stranded DNA linkers to deterministically assemble anisotropic metallic nanoparticles (MNPs) and emitters with precisely determined geometries and locations, forming plasmonic metamaterial with critical dimensions down to single-digit nanometer scale and achieving strong electromagnetic field interaction with a single emitter at the cavities. We aim to study the fundamental emitter-cavity interactions at nanometer scale assisted by biomolecular assembly. Specifically, we will innovative three-dimensional DO designs to assemble anisotropic nanoparticle dimer cavities. Further, we will attach single QD and organic dye emitters to each DO template and the MNP cavity in a deterministic strategy, and use the DO assembled system as a metamaterial platform to experimentally quantify the emission decay rates, Purcell factor, coupling strength, Rabi vacuum energy splitting, and quantum auto-correlation measurements.

Reference: Zhi Zhao, Xiahui Chen, Ali Basiri, Yu Yao, Yan Liu, Hao Yan, and Chao Wang, “DNA Origami-Templated Assembly of Heterogeneous Nanocavity for Quantum Emitter,” presented at the The International Conference on Electron, Ion, and Photon Beam Technology and Nanofabrication Minneapolis, MN, 2019.            


 

3. Integrated Molecular Sensing 

3.1 Plasmonic Nanosensors 

Plasmonic nanosensors, in combination with microfluidics, have emerged as a promising technology for label-free, nondestructive, fast, and sensitive detection. Plasmonic sensors can detect molecular binding to its surface from the induced change in optical refractive index without requiring laborious sample labelling, hence significantly reducing sample processing time and cost. Currently, the two main challenges in plasmonic nanosensing are: (a) to improve the sensitivity of a small analyte that has only a small impact on the local refractive index; and (b) to improve the specificity in detecting the analyte to avoid false signals.

Recently, we reported a plasmonic nanosensor for label-free, sensitive, specific, and quantitative identification of nanometer-sized molecules in the infrared range. The device design is based on vertically coupled complementary antennas with densely patterned hot-spots. The elevated metallic nanobars and complimentary nanoslits in the substrate strongly couple at vertical nano-gaps between them, resulting in dual-mode sensing dependent on the light polarization parallel or perpendicular to the nanobars. We demonstrate experimentally that a monolayer of octadecanethiol (ODT) molecules (thickness 2.5 nm) leads to significant antenna resonance wavelength shift over 136 nm, corresponding to 7.5 nm for each carbon atom in the molecular chain or 54 nm for each nanometer in analyte thickness. Additionally, all the four characteristic vibrational fingerprint signals, including the weak CH3– modes, are clearly delineated experimentally in both sensing modes. Such a dual-mode sensing with a broad wavelength design range (2.5 µm to 4.5 µm) is potentially useful for multi-analyte detection.

Currently, our research focuses on a few directions. First, we are designing different molecular sensor structures that operate in the near-infrared and visible range. This will make the detection system less bulky and less expensive, with an ultimate potential to integrate with portable personal devices. Second, we are interrogating the molecule-structure interactions to optimize the device sensitivity while minimizing nonspecific interactions that contribute to the noise in the signal.

The molecules we are interested in detecting include microRNAs, proteins, extracellular vesicles, and metabolites. Our close collaborators include Dr. Liangcai Gu from University of Washington at Seattle and Debabrata Mukhopadhyay at Mayo Clinic.

Reference: (1)   Xiahui Chen †, Chu Wang, Yu Yao *, and Chao Wang *, “Plasmonic Vertically Coupled Complementary Antennas for Dual-Mode Infrared Molecule Sensing,” ACS Nano, vol. 11, pp. 8034-8046, 2017.


3.2 Integrated Exosome Molecular Analyzers 

Recent studies have revealed the significant clinical potential of extracellular vescicles (e.g. exosome), both as a point of intervention in the treatment of carcinoma and a potential biomarker for disease diagnosis and prognosis. Despite the great promise of exosome-based molecular diagnostics, a number of technological challenges seriously hinders its accuracy and reliability in disease detection. First, the exosome purification process is either too time-consuming (ultracentrifugation) or bias-prone (conventional immunoprecipitation suffers from poor antibody specificity), thus resulting in serious pre-analytical errors and poor statistical stability. Second, concomitant molecular profiling of exosome protein markers and cargo microRNAs promises to significantly improve the diagnostic accuracy, but requires lengthy detection steps, complex sample processing, and frequently introduces biases. The long-term goal of our group to build a fully integrated and multifunctional optofluidic diagnostic technology that seamlessly incorporates exosome purification and exosomal protein and microRNA (miRNA) profiling on a single device to achieve rapid and accurate screening and disease detection at early stage.

Our design will integrate multiple functional modules on the same chip to sequentially achieve label-free exosome purification, surface protein profiling on plasmonic sensors, and multiplexed microRNA detection. Specifically, exosomes will be continuously sorted by size in nanofluidic pillar array, which is based on my previous development at IBM (nnano.2016.134). The purified exosomes will then be captured onto plasmonic sensors labeled with nanometer-sized antibody pairs highly specific to the exosome protein markers for sensitive optical detection. 

Reference:
(1)   Benjamin H. Wunsch †, Joshua T. Smith, Stacey M. Gifford, Chao Wang, Markus Brink, Robert Bruce, Robert H. Austin, Gustavo Stolovitzky, and Yann Astier, “Nanoscale Lateral Displacement Arrays for Separation of Exosomes and Colloids Down to 20nm,” Nat. Nanotechnol., vol. 11, pp. 936–940, 2016.

(2)   Benjamin H. Wunsch, Sung-Cheol Kim, Stacey M. Gifford, Yann Astier, Chao Wang, Robert L. Bruce, Jyotica V. Patel, Elizabeth A. Duch, Simon Dawes, Gustavo Stolovitzky, and Joshua T. Smith, “Gel-on-a-chip: continuous, velocity-dependent DNA separation using nanoscale lateral displacement”, Lab on a Chip, vol. 19, pp. 1567-1578, 2019.

(3)   Lotien Richard Huang, Edward C Cox, Robert H Austin, and James C Sturm, “Continuous particle separation through deterministic lateral displacement,” Science, vol. 304, pp. 987-990, 2004.