An apparatus may include a semiconductor chip and a fluidics assembly. The semiconductor chip has an array of wells and an array of sensors and each sensor of the array of sensors is in fluid communication with a well of the array of wells. The fluidics assembly is located on top of the semiconductor chip and is configured to deliver fluids to the semiconductor chip. The fluidics assembly includes a flow expansion chamber configured to introduce the fluids, an outlet portion configured to pipe out the fluids, and a flow chamber portion. The flow chamber portion is configured to allow the fluids to flow from the flow expansion chamber to the outlet portion and to allow the fluids to interact along the way with material in the array of wells. The flow expansion chamber has a curved wall at the top or bottom so that the height of the flow expansion chamber at the center is less than at the walls that restrict the fluids to the left and right.

Methods and apparatus for measuring analytes using large scale fet arrays

Methods and apparatus relating to FET arrays including large FET arrays for monitoring chemical and/or biological reactions such as nucleic acid sequencing-by-synthesis reactions. Some methods provided herein relate to improving signal (and also signal to noise ratio) from released hydrogen ions during nucleic acid sequencing reactions.

Methods and apparatus for measuring analytes

Methods and apparatuses relating to large scale FET arrays for analyte detection and measurement are provided. ChemFET (e.g., ISFET) arrays may be fabricated using conventional CMOS processing techniques based on improved FET pixel and array designs that increase measurement sensitivity and accuracy, and at the same time facilitate significantly small pixel sizes and dense arrays. Improved array control techniques provide for rapid data acquisition from large and dense arrays. Such arrays may be employed to detect a presence and/or concentration changes of various analyte types in a wide variety of chemical and/or biological processes.

Methods and apparatus for detecting molecular interactions using FET arrays

The invention is directed to apparatus and methods for delivering multiple reagents to, and monitoring, a plurality of analytical reactions carried out on a large-scale array of electronic sensors underminimal noise conditions. In one aspect, the invention provides method of improving signal-to-noise ratios of output signals from the electronic sensors sensing analytes or reaction byproducts by subtracting an average of output signals measured from neighboring sensors where analyte or reaction byproducts are absent. In other aspects, the invention provides an array of electronic sensors integrated with a microwell array for confining analytes and/or particles for analytical reactions and a method for identifying microwells containing analytes and/or particles by passing a sensor-active reagent over the array and correlating sensor response times to the presence or absence of analytes or particles. Such detection of analyte- or particle-containing microwells may be used as a step in additional noise reduction methods.

Apparatus and methods for performing electrochemical reactions

The invention is directed to apparatus and chips comprising a large scale chemical field effect transistor arrays that include an array of sample-retaining regions capable of retaining a chemical or biological sample from a sample fluid for analysis. In one aspect such transistor arrays have a pitch of 10 μm or less and each sample-retaining region is positioned on at least one chemical field effect transistor which is configured to generate at least one output signal related to a characteristic of a chemical or biological sample in such sample-retaining region. In one embodiment, the characteristic of said chemical or biological sample is a concentration of a charged species and wherein each of said chemical field effect transistors is an ion-sensitive field effect transistor having a floating gate with a dielectric layer on a surface thereof, the dielectric layer contacting said sample fluid and being capable of accumulating charge in proportion to a concentration of the charged species in said sample fluid. In one embodiment such charged species is a hydrogen ion such that the sensors measure changes in pH of the sample fluid in or adjacent to the sample-retaining region thereof. Apparatus and chips of the invention may be adapted for large scale pH-based DNA sequencing and other bioscience and biomedical applications.

Integrated sensor arrays for biological and chemical analysis

A sampling circuit according to correlated double sampling to generate a difference of two voltages at a sampling node, with the second voltage representing the sum of an input signal and an offset, and the first voltage representing the offset alone. In an embodiment, a first capacitor is charged to the first voltage in a first phase. A second capacitor is then charged to the second voltage in a second phase. In a third phase, the first capacitor is coupled to the input terminal of the amplifier and the second capacitor is coupled between the input and output terminals of the amplifier to cause the amplifier to generate the difference of the first and second voltages. The first capacitor has a capacitance much less than the second capacitor, thereby minimizing the noise power at the output of the amplifier.

Correlated double sampling technique

Output voltage of a charge-to-voltage converter used in an image sensing system is compared with one or more thresholds to determine if the output voltage exceeds predetermined threshold levels. If the output voltage exceeds one or more of the threshold levels, the input terminal of the charge-to-voltage converter is connected to a reference voltage to prevent the charge-to-voltage converter from saturating. Problems that could be caused due to overload of the voltage-to-charge converter are obviated. In an embodiment, the charge-to-voltage converter is implemented by an operational amplifier (OPAMP). A pair of comparators compares the output of the OPAMP with corresponding threshold voltages. The result of the comparison is used to generate a signal for connecting the input of the OPAMP to the reference voltage, thereby preventing saturation of the OPAMP.

Mitigating the effects of signal overload in analog front-end circuits used in image sensing systems

A photon counting system includes a photon sensor, a charge-sensitive amplifier (CSA) and an analog-to-digital converter (ADC). The CSA is configured to convert photon energy detected by the photon sensor to voltage pulses. The ADC is configured to digitize the voltage pulses generated by the CSA. The ADC includes successive approximation circuitry. The successive approximation circuitry includes an N-bit digital-to-analog converter (DAC), an N-bit successive approximation register (SAR), a plurality of N-bit registers, and a multiplexer configured to selectively route outputs of the SAR and outputs of the N-bit registers to the DAC for conversion to an analog signal.

Configurable analog-to-digital converter and processing for photon counting

The disclosure provides a circuit that includes a charge sensitive amplifier (CSA) that generates an integrated signal in response to a current signal An active comparator is coupled to the CSA The active comparator receives the integrated signal and a primary reference voltage signal, and generates an event detect signal A first delay element is coupled to the active comparator and provides a fixed delay to the event detect signal to generate a convert signal A discriminator system is coupled to the CSA The discriminator system samples the integrated signal when activated by the convert signal

Low power photon counting system

A photon counting system includes a photon sensor and pixel circuitry. The pixel circuitry includes a charge sensitive amplifier (CSA), an analog to digital converter (ADC), an event detector, and a coincidence detector. The CSA is configured to convert photon energy detected by the photon sensor to a voltage pulse. The ADC is coupled to an output of the CSA. The ADC is configured to digitize the voltage pulses generated by the CSA. The event detector is configured to determine whether output voltage of the CSA exceeds an event threshold voltage, and to trigger the ADC to digitize the output voltage based on the output voltage exceeding the event threshold voltage. The coincidence detector is configured to determine whether the output voltage of the CSA exceeds a coincidence threshold voltage, and to trigger the ADC to digitize the output voltage based on the output voltage exceeding the coincidence threshold voltage.

Nagesh Surendranath

Papers

Correlated double sampling technique

Mitigating the effects of signal overload in analog front-end circuits used in image sensing systems

Configurable analog-to-digital converter and processing for photon counting

Low power photon counting system

Photon counting with coincidence detection