Brigham Young University

University of California

Ciena Corporation

Aaron Roe Hawkins

Holger Schmidt

John E Bowers

David W Deamer

William Dunbar

Robert K Brauer

Christopher I Pirie

Samuel E Tolley

Daniel E Austin

Ed Kinnier

Milton L Lee

Edgar D Lee

Stephen M Schultz

Hong-Wei Lee

H Dennis Tolley

Shiuh-hua Wood Chiang

Yixin Song

Travis Oliphant

Joshua Wayne Parks

Anzi Wang

Nicolaas Johannes Van Zwieten

Siebe Schootstra

Martijn Klok

Eid-Beng Goh

Marcus Michael Jaspers

Systems, methods, and techniques for optofluidic analyte detection and analysis using multi-mode interference (MMI) waveguides are disclosed herein. In some embodiments, spatially and spectrally multiplexed optical detection of particles is implemented on an optofluidic platform comprising multiple analyte channels intersecting a single MMI waveguide. In some embodiments, multi-stage photonic structures including a first stage MMI waveguide for demultiplexing optical signals by spatially separating different wavelengths of light from one another may be implemented. In some embodiments, a second stage may use single-mode waveguides and/or MMI waveguides to create multi-spot patterns using the demultiplexed, spatially separated light output from the first stage. In some embodiments, liquid-core MMI (LC-MMI) waveguides that are tunable by replacing a liquid core, heating/cooling the liquid core, and/or deforming the LC-MMI to change its width may be implemented in one or more of the analyte detection/analysis systems disclosed herein.

Optofluidic analyte detection systems using multi-mode interference waveguides

A disclosed system uses modulations of ionic current across a nanopore in a membrane to detect target molecules passing through the nanopore. This principle has been applied mainly to nucleic acid sequencing, but can also be used to detect other molecular targets such as proteins and small molecules. In addition, the system delivers target molecules to a nanopore to provide label-free single molecule analysis using a chip-based system. Target molecules are concentrated on microscale carrier beads, and the beads are delivered and optically trapped in an area within the capture radius of the nanopore. The target molecules are released from the beads and detected using nanopore current modulation. In addition, the disclosed system combines sample preparation (e.g. purification, extraction, and pre-concentration) with nanopore-based readout on a microfluidic chip. Finally, target molecules can be specifically bound to carrier beads and particles are positioned within the capture volume of a nanopore using a chip-based microfluidic platform proven to handle specific detection of molecular targets from milliliters of raw sample.

Systems and methods of delivering target molecules to a nanopore

Spatially distributed optical excitation and integrated waveguides are used for ultrasensitive particle detection based on individual electrokinetic velocities of particles. In some embodiments, chip-integrated systems are used to identify individual particles (e.g., individual molecules) based on their velocity as they move through an optically interrogated channel. Molecular species may be identified and quantified in a fully integrated setting, allowing for particle analysis including molecular analysis that can operate at low copy numbers down to the level of single-cell lysates. In some embodiments, the single-particle velocimetry-based identification and/or separation techniques are applied to various diagnostic assays, including nucleic acids, metabolites, macromolecules, organelles, cell, synthetic markers, small molecules, organic polymers, hormones, peptides, antibodies, lipids, carbohydrates, inorganic and organic microparticles and nanoparticles, whole viruses, and any combination thereof.

Velocimetry-based identification of single proteins and other particles

The present invention is a system and method for providing a charge detector that utilizes small feedback capacitors in a low-noise, high-gain, system that combines a differential topology in a solid-state amplifier implemented in a complementary metal-oxide semiconductor (CMOS) process with active reset, thereby achieving high dynamic range and robust operations. A custom optoelectronic system is used to measure gain, and while operating at a sampling frequency of 10 kHz, the active reset extends the dynamic range of the charge detector.

Solid-state charge detector

Provided is a device comprising a channel through and defined by a plurality of layers surrounding the channel, the channel connecting a first and a second chambers separated by the plurality of layers, wherein the plurality of layers comprise a first layer, a second layer; and a conductive middle layer disposed between the first and second layers, wherein the channel comprises (a) a first region defined by the first layer, denoted as an inlet, that is about 0.5 nm to about 100 nm in diameter and (b) a second region defined by the second layer, denoted as an outlet, wherein the inlet and the outlet are about 10 nm to about 1000 nm apart from each other, and wherein the first and second chambers and the middle layer are connected to a power supply. Also provided are methods of preparing and using the device, in particular for nucleic acid sequencing.

Two-chamber dual-pore device

A system and method for thermal gradient gas chromatography wherein a front or injection end of a column is heated to a higher temperature than a back or detector end to thereby create a thermal gradient having a profile that is substantially monotonically non-increasing and has a positive second derivative, and then providing a heat source to raise the thermal gradient and cause it to remain stationary or to travel through the column while maintaining a desired profile.

Gas chromatography using a thermal gradient that is substantially monotonically non-increasing and has a positive second derivative

An optofluidic platform is constructed so as to comprise a planar, liquid-core integrated optical waveguides for specific detection of nucleic acids. Most preferably, the optical waveguides comprises antiresonant reflecting optical waveguide (ARROWs). A liquid solution can be prepared and introduced into the optofluidic platform for optical excitation. The resulting optical signal can be collected at the edges of the optofluidic platform and can be analyzed to determine the existence of a single and/or a specific nucleic acid.

Method for amplification-free nucleic acid detection on optofluidic chips

An optofluidic platform is constructed to comprise a vertical integration of optical and fluidic layers. The optical layer enables interaction of light with a fluid for a variety of purposes, including particle detection, manipulation, and analysis. The vertical integration allows layers to be permanently or temporarily attached to each other. Temporary attachments provide the advantage of reusing the same optical layer with different fluidic layers. Most preferably, the optical layer comprises antiresonant reflecting optical waveguide. Further, a fluidic layer can be configured to act as an interface between the optical layer and other fluidic layers attached thereon. Moreover, the fluidic layers can be configured to perform fluidic functions. The optofluidic platform can also comprise a protective layer. As such, a liquid solution can be introduced in the optofluidic platform and single particles contained therein can be optically detected with extremely high sensitivity and without the need for advanced microscopy equipment.

Hybrid, planar optofluidic integration

A chip-scale optical approach to performing multi-target detection is based on molecular biosensing using fiber-optic based fluorescence or light scattering detection in liquid-core waveguides. Multiplexing methods are capable of registering individual nucleic acids and other optically responsive particles, and are ideal for amplification-free detection in combination with the single molecule sensitivity of optofluidic chips. This approach overcomes a critical barrier to introducing a new integrated technology for amplification-free molecular diagnostic detection. Specific examples of liquid-core optical waveguides and multi-mode interferometers are described; however, they can be implemented in a number of different ways as long as a series of excitation spots is created whose spacing varies with the excitation wavelength.

Multiplex fluorescent particle detection using spatially distributed excitation

An optical waveguide is provided comprising a non-solid core layer surrounded by a solid-state material, wherein light can be transmitted with low loss through the non-solid core layer. A vapor reservoir is in communication with the optical waveguide. One implementation of the invention employs a monolithically integrated vapor cell, e.g., an alkali vapor cell, using anti-resonant reflecting optical waveguides, or ARROW waveguides, on a substrate.

Integrated optical vapor cell apparatus for precision spectroscopy

A coaxial hybrid ion trap that uses two substantially planar opposing plates to generate electrical focusing fields that simultaneously generate at least two different types or shapes of trapping regions, wherein a first trapping region is a quadrupole trapping region disposed coaxially with respect to the opposing plates, and wherein a second trapping region is a toroidal ion trap having a toroidal trapping region that is simultaneously created around the quadrupole trapping region.

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Provo, UT, United States of America

Aaron Roe Hawkins