integrated circuit and photodetection method

专利摘要:
An integrated circuit includes a photodetection region configured to receive incident photons. The photodetection region is configured to produce a plurality of charge carriers in response to incident photons. The integrated circuit also includes at least one load carrier storage region. The integrated circuit also includes a load carrier segregation structure configured to selectively target load carriers from the plurality of load carriers in at least one load carrier storage region based on the times when the load carriers were produced.
公开号:BR112017002485B1
申请号:R112017002485-3
申请日:2015-08-07
公开日:2020-12-01
发明作者:Jonathan M. Rothberg；Keith G. Fife；David Boisvert
申请人:Quantum-Si Incorporated；
IPC主号:

专利说明:

Cross Reference to Related Orders
[001] This order claims priority for US provisional application No. 62 / 035,377, filed on August 8, 2014, entitled "INTEGRATED DEVICE FOR TEMPORAL BINNING OF RECEIVED PHOTONS," and provisional application No. 62 / 164,506, filed on 20 May 2015, entitled "INTEGRATED DEVICE FOR TEMPORAL BINNING OF RECEIVED PHOTONS", each of which is incorporated herein by reference in its entirety.
[002] This order is related to the following U.S orders:
[003] U.S. Provisional Patent Application 62 / 035,258, entitled "INTEGRATED DEVICE WITH EXTERNAL LIGHT SOURCE FOR PROBING, DETECTING AND ANALYZING MOLECULES," filed on August 8, 2014;
[004] U.S. Provisional Patent Application 62 / 035,242, entitled "OPTICAL SYSTEM AND ASSAY CHIP FOR PROBING, DETECTING AND ANALYZING MOLECULES," filed on August 8, 2014;
[005] U.S. Provisional Patent Application 62 / 164,464, entitled "INTEGRATED DEVICE WITH EXTERNAL LIGHT SOURCE FOR PROBING, DETECTING, AND ANALYZING MOLECULES," filed May 20, 2015;
[006] U.S. Provisional Patent Application 62 / 164,482, entitled "METHODS FOR NUCLEIC ACID SEQUENCING," filed on May 20, 2015;
[007] a U.S. Non-Provisional Patent Application filed on the same date as this application, bearing document number R0708.70003US01, entitled "OPTICAL SYSTEM AND ASSAY CHIP FOR PROBING, DETECTING AND ANALYZING MOLECULES," and
[008] a U.S. Non-Provisional Patent Application filed on the same date as this application, bearing document number R0708.70004US02, entitled "INTEGRATED DEVICE WITH EXTERNAL LIGHT SOURCE FOR PROBING, DETECTING AND ANALYZING MOLECULES."
[009] Each of the related requests listed above is hereby incorporated by reference in its entirety. Background
[0010] Photodetectors are used to detect light in a variety of applications. Integrated photodetectors have been developed to produce an electrical signal that indicates the intensity of incident light. Integrated photodetectors for imaging applications include a set of pixels to detect the intensity of light received through a scene. Examples of integrated photodetectors include charge-coupled devices (CCDs) and Complementary Metal Oxide Semiconductor (CMOS) image sensors. summary
[0011] Some modalities refer to an integrated circuit that includes a photodetection region configured to receive incident photons, the photodetection region being configured to produce a plurality of charge carriers in response to incident photons. The integrated circuit also includes at least one load carrier storage region. The integrated circuit also includes a load carrier segregation structure configured to selectively target load carriers from the plurality of load carriers into at least one load carrier storage region based on the times at which load carriers. cargo are produced.
[0012] Some modalities refer to an integrated circuit that includes a photodetection region configured to receive incident photons, the photodetection region being configured to produce a plurality of charge carriers in response to incident photons. The integrated circuit also includes at least one load carrier storage region. The integrated circuit also includes means to selectively target load carriers from the plurality of load carriers in at least one load carrier storage region based on the times at which load carriers were produced.
[0013] Some modalities refer to a method of photodetection, comprising the receipt of incident photons and selectively targeting charge carriers from a plurality of charge carriers produced in response to incident photons in at least one charge carrier storage region based on the moments in which cargo carriers were produced.
[0014] Some modalities refer to a computer-readable storage medium having instructions stored in the same instructions, which when executed by a processor, perform a photodetection method. The method includes controlling a charge carrier segregation structure to selectively target charge carriers from a plurality of charge carriers produced in response to incident photons in at least one charge carrier storage region based on the moments in the which the cargo carriers were produced.
[0015] Some modalities refer to a method of forming an integrated circuit. The method includes forming a load carrier containment region comprising a photodetection region and a load carrier travel region. The photodetection region is configured to produce a plurality of charge carriers in response to incident photons. The method also includes the formation of a load carrier segregation structure configured to selectively target the load carriers of the plurality of load carriers into at least one load carrier storage region based on the times at which the carriers cargo are produced.
[0016] Some modalities refer to a method of sequencing nucleic acid. The method includes receiving photons of luminescent molecules attached, for at least a period of time, directly or indirectly, to the respective nucleotides of the nucleic acid. The method also includes selective targeting of charge carriers from a plurality of charge carriers produced in response to incident photons in at least one charge carrier storage region based on the times at which the charge carriers were produced.
[0017] Some modalities refer to a computer-readable storage medium having instructions stored in the same instructions, which when executed by a processor, perform a method of sequencing a nucleic acid. The method includes the sequencing of a nucleic acid using, at least in part, arrival times of incident photons detected by an integrated circuit that receives photons from luminescent molecules connected to the respective nucleotides of the nucleic acid.
[0018] Some modalities refer to a method of sequencing nucleic acid. The method includes, using an integrated circuit, the detection of incident photon arrival times from luminescent molecules connected to the respective nucleotides of the nucleic acid. The method also includes the identification of luminescent molecules using, at least in part, an integrated circuit that detects the arrival times of incident photons from the luminescent molecules.
[0019] Some modalities refer to a method of image formation of fluorescence life. The method includes the production of an image indicating the fluorescent useful lives using, at least in part, an integrated circuit that detects the arrival times of incident photons from the fluorescent molecules.
[0020] Some modalities refer to a flight time imaging method. The method includes receiving incident photons, and selective targeting of charge carriers from a plurality of charge carriers produced in response to incident photons in at least one charge carrier storage region based on the times when charge carriers are present. cargo were produced.
[0021] The above summary is provided by way of illustration and should not be limiting. Brief Description of Drawings
[0022] In the drawings, each identical or almost identical component that is illustrated in the various figures is represented by a similar reference character. For the sake of clarity, not every component can be labeled in each drawing. The drawings are not necessarily to scale, with an emphasis, instead, on illustrating various aspects of the techniques and devices described here.
[0023] Figure 1A represents the probability that a photon will be emitted as a function of time for two markers with different useful lives.
[0024] Figure 1B illustrates illustrative intensity profiles over time for an illustrative excitation pulse (dotted line) and illustrative fluorescence emission (solid line).
[0025] Figure 2A illustrates a pixel diagram of an integrated photodetector, according to some modalities.
[0026] Figure 2B illustrates the capture of a cargo carrier at a different point in time and space than in figure 2A.
[0027] Figure 3A illustrates a one pixel charge carrier confinement region, according to some modalities.
[0028] Figure 3B illustrates the pixel of figure 3A with a plurality of Vb0-Vbn, b0-bm, st1, st2 and tx0-tx3 electrodes overlapping the load carrier confinement region of figure 3A.
[0029] Figure 3C illustrates a modality in which the photon absorption / carrier generation region includes a PN junction.
[0030] Figure 3D illustrates a top view of a pixel as in figure 3C, with the addition of coating characteristics.
[0031] Figure 3E illustrates a top view of a pixel as in figure 3C, including the carrier / capture area path.
[0032] Figure 3F illustrates a set of pixels as in figure 3E Figure 3F indicates the regions of diffusion, polysilicon, contact and metal 1.
[0033] Figure 3G illustrates the set of pixels of figure 3F and also indicates the regions of diffusion, polysilicon, contact, metal 1, implant N, implant P and P-epi.
[0034] Figure 4 illustrates a pixel circuit diagram of figure 3B. The cargo carrier confinement area is illustrated with heavy dark lines.
[0035] Figure 5A illustrates a potential gradient that can be established in the charge carrier confinement area in the photon absorption / carrier generation area and carrier travel / capture area along line AA 'of figure 3B .
[0036] Figure 5B illustrates that after a period of time a potential protection for electrons can be increased at a time t1 by reducing the voltage of electrode b0.
[0037] Figure 5C illustrates that after another period of time, another potential protection for electrons can be increased at time t2 by reducing the voltage of electrode b2.
[0038] Figure 5D illustrates that after another period of time, another potential protection for the electrons can be increased at time t3 by reducing the voltage of electrode b4.
[0039] Figure 5E illustrates that after another period of time, another potential protection for electrons can be increased at time t4 by reducing the voltage of electrode b6.
[0040] Figure 5F illustrates that after another period of time, another potential protection for the electrons can be increased at time t5 by reducing the voltage of the bm electrode.
[0041] Figure 6A illustrates the position of a carrier once it has been photogenerated.
[0042] Figure 6B illustrates the position of a carrier shortly thereafter, as it travels in a downward direction in response to the established potential gradient.
[0043] Figure 6C illustrates the position of the carrier as it reaches the drain.
[0044] Figure 6D illustrates the position of a carrier (for example, an electron) once it has been photogenerated.
[0045] Figure 6E illustrates the position of a carrier shortly thereafter, as it travels downward in response to the potential gradient.
[0046] Figure 6F illustrates the position of the carrier as it reaches the potential protection after moment t1.
[0047] Figure 6G illustrates that if an electron arrives between electrodes b0 and b2 between moments t1 and t2, the electron will be captured between the potential protection 501 and the potential protection 502, as illustrated in figure 6G.
[0048] Figure 6H illustrates an example in which an electron arrived between moments t1 and t2, so that it remains captured between the potential protection 501 and the potential protection 502.
[0049] Figure 6I illustrates an example in which an electron arrived between moments t1 and t2, so that it remains captured between the potential protection 501 and the potential protection 502.
[0050] Figure 6J illustrates an example in which an electron arrived between moments t1 and t2, so that it remains captured between the potential protection 501 and the potential protection 502.
[0051] Figure 6K illustrates a voltage timing diagram illustrating the voltages of electrodes b0-b8, st0 and st1 over time.
[0052] Figure 7A illustrates a representation of the potential for a cross section of the load carrier confinement area along line B-B 'of figure 3B.
[0053] Figure 7B illustrates that after moment t5, the voltage at electrodes b1, b3, b5 and b7 can optionally be reduced (not shown in figure 6K) to raise the position of an electron within the potential well, to facilitate electron transfer.
[0054] Figure 7C illustrates that at time t6 (figure 6K), the voltages at electrodes st0 and st1 can be high.
[0055] Figure 7D illustrates that at time t7, the voltage at electrode st0 can be reduced, thus confining the captured carrier (if any) in the corresponding compartment (bin2 in this example).
[0056] Figure 7E illustrates a plan view illustrating an electron captured between the potential protections 503 and 504.
[0057] Figure 7F illustrates a plan view illustrating the voltage of electrode st1 being high and the carrier being transferred.
[0058] Figure 7G illustrates a plan view showing the voltage electrode st1 being reduced and the carrier being captured in bin2.
[0059] Figure 7H illustrates the characteristics of the electrodes of a load carrier segregation structure according to some modalities.
[0060] Figure 8A illustrates a flow chart of a method that includes making a plurality of measurements, according to some modalities.
[0061] Figure 8B is a diagram illustrating an excitation pulse being generated at time t0, and bin0-bin3 time compartments.
[0062] Figure 8C illustrates a representation of the number of photons / charge carriers in each time slot for a set of fluorescence life measurements in which the probability of a fluorescent marker or matrix decreasing exponentially with time.
[0063] Figure 8D illustrates a method of operating the integrated photodetector according to some modalities in which light is received in the integrated photodetector in response to a plurality of different triggering events.
[0064] Figure 8E illustrates voltage of the electrodes of the load carrier segregation structure when performing the method of figure 8D.
[0065] Figure 9A illustrates an example of a timing diagram for sequential reading of bin0-bin3 compartments using correlated double sampling.
[0066] Figure 9B illustrates a reading sequence to perform the correlated double sampling that does not require the measurement of a reconfigured value for each signal value, according to some modalities.
[0067] Figure 10A illustrates a set of pixels having a plurality of columns C1 to Cn and a plurality of rows, with a selected row Ri being illustrated by way of illustration.
[0068] Figure 10B illustrates a modality in which a common reading circuit can be provided for a plurality of columns.
[0069] Figure 10C illustrates modalities with a plurality of reading circuits, less than the number of columns.
[0070] Figure 10D illustrates a circuit diagram illustrating the column reading circuitry that includes a sampling and retention circuitry, an amplifier circuitry and an analog to digital (A / D) converter.
[0071] Figure 10E illustrates a reading circuit set modality, where both the amplifier circuit set and the A / D converter are shared by the two columns of the pixel set.
[0072] Figure 10F illustrates a modality in which n columns of the pixel set share the set of reading circuits and / or an A / D converter.
[0073] Figure 10G illustrates an example of an amplifier circuit assembly that includes a plurality of amplifiers.
[0074] Figure 10H illustrates a diagram of the reading circuit set including the amplifier circuit set having first stage amplifiers for respective speakers and a second stage amplifier that is shared by the two speakers.
[0075] Figure 10I illustrates a diagram of the set of reading circuits including first stage amplifiers, a second stage amplifier and a third stage amplifier.
[0076] Figure 10J illustrates the set of reading circuits shared by two columns including a sampling and differential retention circuit and a differential amplifier.
[0077] Figure 10K illustrates a diagram of the differential sampling and retention circuit and a differential amplifier when the first column is in the sampling phase and the second column is in the retention phase.
[0078] Figure 10L illustrates a diagram of the differential sampling and retention circuit and a differential amplifier when the second column is in the sampling phase and the first column is in the retention phase.
[0079] Figure 10M illustrates the set of reading circuits shared by more than two columns including a sampling and differential retention circuit and a differential amplifier.
[0080] Figure 11 illustrates the timing of the time compartments that can be adaptively controlled between measurements based on the results of a set of measurements.
[0081] Figure 12 illustrates an example of a pixel that includes four subpixels.
[0082] Figure 13 illustrates a diagram of a chip architecture, according to some modalities.
[0083] Figure 14A illustrates a diagram of a modality of a chip having a set of 64 x 64 of quad pixels, according to some modalities.
[0084] Figure 14B illustrates a diagram of a modality of a chip that illustrates sets of 2 x 2, with each set having a set of 256 x 64 octal pixels of quad pixels, according to some modalities.
[0085] Figure 15A illustrates a perspective view of load confinement regions that can be formed on a semiconductor substrate.
[0086] Figure 15B shows a plan view corresponding to figure 15A.
[0087] Figure 16 illustrates the formation of electrodes through the insulating layer by the formation of a standardized polysilicon layer.
[0088] Figure 17 illustrates a coated and divided electrode having a p + region and an n + region.
[0089] Figure 18 illustrates the formation of a metallic layer (for example, metal 1) through the standardized polysilicon layer to connect to the tracks.
[0090] Figure 19 illustrates the metallic layer superimposed on the polysilicon layer and load confinement regions.
[0091] Figure 20 illustrates the formation of ways to contact the metallic layer.
[0092] Figure 21 illustrates the second metallic layer in addition to the formation of ways to contact the second metallic layer.
[0093] Figure 22 illustrates the formation of a third metallic layer.
[0094] Figure 23 illustrates an example of a drive circuit to drive an electrode of the load carrier segregation structure, according to some modalities.
[0095] Figure 24 illustrates a modality in which the chip is attached to a printed circuit board.
[0096] Figure 25 illustrates the activation of 32 rows in a central region of the chip and the deactivation of 48 rows at the edges of the chip.
[0097] Figure 26 is a block diagram of an illustrative computing device. Detailed Description
[0098] An integrated photodetector is described here that can accurately measure, or "pack in time", the timing of incoming photons. In some modalities, the integrated photodetector can measure the arrival of photons with resolution of nanoseconds or picoseconds. Such a photodetector can be useful in a variety of applications including detection / quantization, which can be applied to nucleic acid sequencing (for example, DNA sequencing). Such a photodetector can facilitate the time domain analysis of the arrival of incident photons of luminescent molecules used for label nucleotides, thus allowing the identification and sequencing of nucleotides based on the luminescence useful lives. Other examples of integrated photodetector applications include fluorescence life imaging and flight time imaging, as further discussed below. Discussion of Time Domain Measurements for Molecular Detection / Quantification
[0099] The detection and quantification of biological samples can be performed using biological tests ("biotests"). Biotests conventionally involve large and expensive laboratory equipment requiring trained research scientists to operate the equipment and perform the biotests. Biotests are conventionally performed in volume so that a large quantity of a particular type of sample is required for detection and quantification. Some biotests are performed by marking the samples with luminescent markers that emit light of a particular wavelength. The samples are illuminated with a light source to cause luminescence, and luminescent light is detected with a photodetector to quantify the amount of light emitted by the markers. Biotests using luminescent markers and / or reporters conventionally involve expensive laser light sources to illuminate samples and complicated optical and electronic luminescence detection parts to collect light from illuminated samples.
[00100] In some embodiments, an integrated photodetector as described here can detect the luminescence characteristics of biological and / or chemical samples in response to excitation. More specifically, such an integrated photodetector can detect the temporal characteristics of the light received from the samples. Such an integrated photodetector can allow the detection and / or discrimination of the luminescence life, for example, the fluorescence life, of the light emitted by a luminescent molecule in response to excitation. In some modalities, the identification and / or quantitative measurements of the samples can be performed based on the detection and / or discrimination of luminescence useful lives. For example, in some embodiments, the sequencing of a nucleic acid (for example, DNA, RNA) can be performed by detecting and / or discriminating the luminescence useful lives of the luminescent molecules attached to the respective nucleotides. Each luminescent molecule can be attached directly (for example, linked) to a corresponding nucleotide or indirectly attached to a corresponding nucleotide via a connecting molecule that is attached to the nucleotide and the luminescent molecule.
[00101] In some embodiments, an integrated photodetector having several photodetection structures and associated electronic parts, called "pixels", can allow the measurement and analysis of a plurality of samples in parallel (for example, hundreds, thousands, millions or more ), which can reduce the cost of performing complex measurements and rapidly advance the discovery rate. In some embodiments, each pixel of the photodetector can detect light from a sample, which can be a single molecule or more than one molecule. In some embodiments, such an integrated photodetector can be used for dynamic real-time applications such as nucleic acid sequencing (for example, DNA, RNA). Detection / Quantization of Molecules Using Useful Life Luminescence
[00102] An integrated circuit having an integrated photodetector according to the aspects of the present application can be designed with functions suitable for a variety of detection and imaging applications. As described in further detail below, such an integrated photodetector may have the ability to detect light within one or more time slots or "time slots". To collect information regarding the time of arrival of the light, charge carriers are generated in response to the incident photons and can be segregated into respective time slots based on their arrival time.
[00103] An integrated photodetector according to some aspects of the present application can be used to differentiate between sources of light emission, including luminescent molecules, such as fluorophores. Luminescent molecules vary in the wavelength of light they emit, the temporal characteristics of the light they emit (for example, their emission reduction time periods), and their response to excitation energy. Accordingly, luminescent molecules can be identified or discriminated from other luminescent molecules based on the detection of these properties. Such identification or discrimination techniques can be used alone or in any suitable combination.
[00104] In some embodiments, an integrated photodetector as described in the present application can measure or discriminate luminescence useful lives, such as fluorescence useful lives. The fluorescence life measurements are based on the excitation of one or more fluorescent molecules, and measurement of time variation in the emitted luminescence. The probability that a fluorescent molecule will emit a photon after the fluorescent molecule reaches an excited state reduces exponentially over time. The rate at which the probability decreases may be characteristic of a fluorescent molecule, and may be different for different fluorescent molecules. The detection of the temporal characteristics of light emitted by fluorescent molecules, can allow the identification of fluorescent molecules and / or discrimination of fluorescent molecules with respect to each other. Fluorescent molecules are also referred to here as luminescent markers, or simply "markers".
[00105] After reaching an excited state, a marker can emit a photon with a certain probability at a given time. The probability that a photon will be emitted from an excited marker can decrease with time after the marker is excited. The reduction in the probability of a photon being emitted over time can be represented by an exponential reduction function p (t) = et / T, where p (t) is the probability of the photon emission in a moment, t, and T it is a temporal parameter of the marker. The time parameter T indicates a moment after the excitation when the probability that the marker emits a photon is a determined value. The temporal parameter, t, is a property of a marker that can be distinguished from its spectral properties of absorption and emission. Such a time parameter, t, is referred to as the luminescence life, the fluorescence life or simply the "lifetime" of a marker.
[00106] Figure 1A represents the probability that a photon will be emitted as a function of time for two markers with different useful lives. The marker represented by the probability curve B has an emission probability that reduces more quickly than the emission probability for the marker represented by the probability curve A. The marker represented by the probability curve B has a shorter time parameter, t, or lifetime than the marker represented by the probability curve A. The markers can have fluorescence lifetimes varying from 0.1 to 20 ns, in some modalities. However, the techniques described here are not limited to the useful lives of the markers used.
[00107] The useful life of a marker can be used to distinguish between mis of a marker, and / or can be used to identify the markers. In some embodiments, fluorescence lifetime measurements can be performed in which a plurality of markers having different lifetimes are excited by an excitation source. As an example, four markers having 0.5, 1, 2 and 3 nanosecond lifetimes, respectively, can be excited by a light source that emits light having a selected wavelength (for example, 635 nm, via example). The markers can be identified or differentiated from each other based on the measurement of the lifetime of the light emitted by the markers.
[00108] Fluorescence life measurements can use relative intensity measurements by comparing how the intensity changes over time, as opposed to absolute intensity values. As a result, fluorescence life measurements can avoid some of the difficulties of absolute intensity measurements. Absolute intensity measurements may depend on the concentration of fluorophores present and calibration steps may be necessary to vary fluorophore concentrations. In contrast, fluorescence life measurements can be insensitive to the concentration of fluorophores.
[00109] Luminescent markers can be exogenous or endogenous. Exogenous markers can be external luminescent markers used as a reporter and / or marker for luminescent labeling. Examples of exogenous markers may include, fluorescent molecules, fluorophores, fluorescent ink, fluorescent stains, organic ink, fluorescent proteins, enzymes, and / or quantum dots. Such exogenous markers can be conjugated to a probe or functional group (for example, molecule, ion and / or bonds) that specifically bind to a particular target or component. The attachment of an exogenous marker or reporter to a probe allows the target to be identified by detecting the presence of an exogenous marker or reporter. Examples of probes can include proteins, nucleic acids such as DNA molecules or RNA molecules, lipids and antibody probes. The combination of the exogenous marker and a functional group can form any suitable probe, marker and / or label used for detection, including molecular probes, labeled probes, hybridization probes, antibody probes, protein probes (for example, agglutination probes) biotin), enzyme labels, fluorescent probes, fluorescent labels; and / or enzyme reporters.
[00110] While exogenous markers can be added to a sample or region, endogenous markers can already be part of the sample or region. Endogenous markers can include any luminescent markers present that can become luminescent or "automatically fluorescent" in the presence of excitation energy. Automatic fluorescence of endogenous fluorophores can provide free labeling and non-invasive labeling without requiring the introduction of endogenous fluorophores. Examples of such endogenous fluorophores may include hemoglobin, oxyhemoglobin, lipids, collagen and elastin crosslinkers, reduced nicotinamide adenine dinucleotide (NADH), oxidized flavins (FAD and FMN), lipofuscin, keratin, and / or prophyrins, by way of example and not of limitation.
[00111] The differentiation between the markers by the measurements of useful life may allow less wavelengths of excitation light to be used than when the markers are differentiated by the measurements of emission spectra. In some modalities, sensors, filters and / or diffraction optics can be reduced in number or eliminated when using shorter wavelengths of excitation light and / or luminescent light. In some modalities, the labeling can be carried out with markers that have different useful lives, and the markers can be excited by light having the same excitation wavelength or spectrum. In some embodiments, an excitation light source can be used and emits light of a single wavelength or spectrum, which can reduce the cost. However, the techniques described here are not limited in this regard, since any number of wavelengths of excitation light or spectrum can be used. In some embodiments, an integrated photodetector can be used to determine both the spectral and temporal information regarding the light received. In some modalities, a quantitative analysis of the types of molecules present can be performed by determining a temporal parameter, a spectral parameter, or a combination of temporal and spectral parameters of the luminescence emitted from a marker.
[00112] An integrated photodetector that detects the arrival time of incident photons can reduce the requirements for additional optical filtering (for example, optical spectral filtering). As described below, an integrated photodetector in accordance with the present application may include a drain to remove photo-generated carriers at particular times. By removing the photo-generated carriers in this way, unwanted charge carriers produced in response to a pulse of excitation light can be discarded without the need for optical filtering to prevent light reception from the excitation pulse. Such a photodetector can reduce the complexity of integrating design as a whole, optical and / or filtering components, and / or cost.
[00113] In some embodiments, a fluorescence life can be determined by measuring the time profile of the luminescence emitted by the aggregation of charge carriers collected in one or more time compartments of the integrated photodetector to detect luminescence intensity values as a time function. In some embodiments, the life span of a marker can be determined by taking multiple measurements where the marker is excited in an excited state and then the photon emission moment is measured. For each measurement, the excitation source can generate an excitation light pulse directed towards the marker, and the time between the excitation pulse and the subsequent photon event of the marker can be determined. Additionally or alternatively, when an excitation pulse occurs repeatedly or periodically, the time between when a photon emission event occurs and the subsequent excitation pulse can be measured, and the measured time can be subtracted from the time interval between the pulses of excitation (that is, the period of the excitation pulse waveform) to determine the photon absorption event time.
[00114] By repeating such experiments with a plurality of excitation pulses, the number of cases of a photon being emitted from the marker within a given time interval after excitation can be determined, which is indicative of the probability of a photon be emitted within such a time interval after excitation. The number of photon emission events collected can be based on the number of excitation pulses emitted to the marker. The number of photon emission events over a measurement period can vary from 50-10 million or more, in some modalities, however, the techniques described here are not limited in this regard. The number of cases of a photon being emitted from the marker within a given time interval after excitation can fill in a histogram representing the number of photon emission events that occur within a series of discrete time intervals or compartments of time. The number of time slots and / or time slots in each slot can be determined and / or adjusted to identify a particular life span and / or a marker in particular. The number of time compartments and / or time intervals for each compartment may depend on the sensor used to detect the emitted photons. The number of time slots can be 1, 2, 3, 4, 5, 6, 7, 8 or more, such as 16, 32, 64 or more. A curve fitting algorithm can be used to fit a curve to the recorded histogram, resulting in a function representing the probability that a photon will be emitted after the excitation of the marker at a given time. An exponential reduction function, such as p (t) = e-t / α, can be used to approximate the histogram data. From such a curve fitting, the time parameter or useful life can be determined. The determined shelf life can be compared with known marker shelf lives to identify the type of marker present.
[00115] A useful life can be calculated from the intensity values in two time intervals. Figure 1B illustrates the illustrative intensity profiles over time for an illustrative excitation pulse (dotted line) and illustrative fluorescence emission (solid line). In the example illustrated in figure 1B, the photodetector measures the intensity across at least two time compartments. The photons that emit luminescence energy between moments t1 and t2 are measured by the photodetector as intensity I1 and luminescence energy emitted between moments t3 and t4 are measured as I2. Any suitable number of intensity values can be obtained although only two are shown in figure 1B. Such intensity measurements can then be used to calculate a useful life. When a fluorophore is present at a time, then the time-conditioned luminescence signal can be fitted into a single exponential reduction. In some embodiments, only two time slots may be needed to accurately identify the life span of a fluorophore. When two or more fluorophores are present, then the individual service lives can be identified from a combined luminescence signal by fitting the luminescence signal into multiple exponential reductions, such as double or triple exponentials. In some embodiments, two or more time slots may be required in order to accurately identify more than one fluorescence lifetime for such a luminescence signal. However, in some cases with multiple fluorophores, an average fluorescence life can be determined by fitting a singular exponential reduction to the luminescence signal.
[00116] In some cases, the probability of a photon emission event, and thus of the life span of a marker, can change based on the surroundings and / or conditions of the marker. For example, the life span of a marker confined to a volume with a diameter less than the wavelength of the excitation light may be less than when the marker is not in the volume. Lifetime measurements with known markers under conditions similar to when markers are used for labeling can be performed. The useful lives determined from such measurements with known markers can be used when identifying a marker. Sequencing Using Luminescence Lifetime Measurements
[00117] Individual pixels in an integrated photodetector may be able to measure the fluorescence life used to identify the fluorescent markers and / or reporters that label one or more targets, such as molecules or specific locations in the molecules. Any one or more of these molecules of interest can be labeled with a fluorophore, including proteins, amino acids, enzymes, lipids, nucleotides, DNA and RNA. When combined with the emitted light detection spectra or other labeling techniques, the fluorescence life can increase the total number of fluorescence markers and / or reporters that can be used. Lifetime-based identification can be used for single-molecule analytical methods to provide information on the characteristics of molecular interactions in complex mixtures where such information would be lost in the middle assembly and may include protein-protein interactions, enzymatic activity, molecular dynamics , and / or diffusion into membranes. In addition, fluorophores with different fluorescence useful lives can be used to label target components in various test methods that are based on the presence of a labeled component. In some embodiments, the components can be separated, such as by using micro-fluid systems based on the detection of particular fluorophor useful lives.
[00118] The fluorescence life measurement can be used in combination with other analytical methods. As an example, fluorescence lifetimes can be used in combination with fluorescence resonance energy transfer (FRET) techniques to discriminate between the states and / or environments of donor and recipient fluorophores located on one or more molecules. Such measurements can be used to determine the distance between the donor and the recipient. In some cases, transferring energy from the donor to the recipient can shorten the donor's life. In another example, fluorescence lifetime measurements can be used in combination with DNA sequencing techniques where four fluorophores having different lifetimes can be used to label the four different nucleotides (A, T, G, C) in one DNA molecule with an unknown nucleotide sequence. The fluorescence lifetimes, rather than emission spectra, of fluorophores can be used to identify the nucleotide sequence. By using the fluorescence lifetime instead of emission spectra for certain techniques, the accuracy and measurement resolution can be increased as artifacts from absolute intensity measurements are reduced. In addition, lifetime measurements can reduce the complexity and / or cost of the system since less excitation energy wavelengths are required and / or less emission energy wavelengths need to be detected.
[00119] The methods described here can be used for nucleic acid sequencing, such as DNA sequencing or RNA sequencing. DNA sequencing allows the determination of the order and position of the nucleotides in a target nucleic acid molecule. The technologies used for DNA sequencing vary widely in the methods used to determine the nucleic acid sequence in addition to the rate, length read and incidence of errors in the sequencing process. A number of DNA sequencing methods are based on sequencing by synthesis, where the identity of a nucleotide is determined as the nucleotide is incorporated into a newly synthesized nucleic acid sequence that is complementary to the target nucleic acid. Many sequences by synthetic methods require the presence of a population of target nucleic acid molecules (for example, copies of a target nucleic acid) or a step of target nucleic acid amplification to reach a target nucleic acid population. Improved methods of determining the sequence of single nucleic acid molecules are desired.
[00120] There have been recent advances in the sequencing of single nucleic acid molecules with high precision and long reading length. The target nucleic acid used in single molecule sequencing technology, for example, SMRT technology developed by Pacific Biosciences, is a single-sequence DNA template that is added to a sample well containing at least one component of the sequencing reaction ( for example, DNA polymerase), immobilized or attached to a solid support such as the bottom of the sample well. The sample well also contains deoxyribonucleotide triphosphates, also referred to as "dNTPs", including adenine, cytosine, guanine and thymine dNTPs, which sound conjugated to detect labels, such as fluorophores. Preferably, each class of dNTPs (for example, adenine dNTPs, cytosine dNTPs, guanine dNTPs, and thymine dNTPs) are each conjugated to a distinct detection label so that the detection of the signal indicates the identity of dNTP that has been incorporated into the newly synthesized nucleic acid. The detection tag can be conjugated to dNTP in any position so that the presence of the detection tag does not inhibit the incorporation of dNTP into the newly synthesized nucleic acid sequence or polymerase activity. In some embodiments, the detection label is conjugated to the terminal phosphate (the known phosphate) of dNTP.
[00121] Any polymerase can be used for DNA sequencing of single molecule that is capable of synthesizing a nucleic acid complementary to a target nucleic acid. Examples of polymerases include E. coli DNA polymerase I, T7 DNA polymerase, bacteriophage T4 DNA polymerase, DNA 29 (psi 29) polymerase, and variations thereof. In some embodiments, the polymerase is a single subunit polymerase. After base pairing between a core base of a target nucleic acid and complementary dNTP, the polymerase incorporates dNTP into the newly synthesized nucleic acid sequence by forming a phosphodiester bond between the 3 'hydroxyl end of the newly synthesized sequence and the alpha dNTP phosphate. In the examples in which the detection label conjugated to dNTP is a fluorophore, its presence is signaled by excitation and an emission pulse is detected during the incorporation step. For detection labels that are conjugated to the terminal (gamma) phosphate of dNTP, incorporation of dNTP into the newly synthesized sequence results in the release of beta and gamma phosphates and the detection label, which is free to diffuse into the sample well, resulting in in a reduction in the detected fluorophore emission.
[00122] The techniques described here are not limited to detecting or quantizing molecules or other samples, or performing sequencing. In some modalities, an integrated photodetector can perform image formation to obtain spatial information referring to a region, object or scene and temporal information referring to the arrival of incident photons using the region, object or scene. In some modalities, the integrated photodetector can perform image formation of luminescence life of a region, object or sample, such as the formation of fluorescence life image. Additional Applications
[00123] Although the integrated photodetector described here can be applied to the analysis of a plurality of biological and / or chemical samples, as discussed above, the integrated photodetector can be applied to other applications, such as image training applications, for example . In some embodiments, the integrated photodetector may include a set of pixels that image a region, object or scene and can detect temporal characteristics of the light received in the individual pixels from different regions of the region, object or scene. For example, in some embodiments, the integrated photodetector can perform tissue imaging based on the temporal characteristics of light received from the tissue, which can allow a doctor to perform a procedure (for example, surgery) to identify an abnormal or diseased region. tissue (for example, cancerous or precancerous). In some embodiments, the integrated photodetector can be incorporated into a medical device, such as a surgical imaging tool. In some embodiments, time-domain information regarding the light emitted by the tissue in response to an excitation pulse of light can be obtained to create the image of and / or characterize the tissue. For example, image formation and / or characterization of tissue and other objects can be performed using fluorescence life imaging.
[00124] Although the integrated photodetector can be applied to a context of scientific diagnosis such as performing image formation or analysis of biological and / or chemical samples, or tissue image formation, as described above, such integrated photodetector can be used in any other suitable context. For example, in some embodiments, such an integrated photodetector can image a scene using temporal light characteristics detected in the individual pixels. An example of an application for imaging a scene is banner imaging or flight time imaging, where the amount of time it takes the light to reach the photodetector is analyzed to determine the distance traveled by the light to the photodetector. Such a technique can be used to create a three-dimensional image of a scene. For example, a scene can be illuminated with a pulse of light emitted from a known location relative to the integrated photodetector, and the reflected light detected by the photodetector. The amount of time it takes for the light to reach the photodetector integrated in the respective pixels of the set is measured to determine the distances that the light has traveled from respective parts of the scene to reach the respective pixels of the photodetector. In some embodiments, the integrated photodetector can be incorporated into a consumer electronic device such as a camera, cell phone, or tablet computer, for example, to allow such devices to capture and process images or video based on the obtained track information. .
[00125] In some embodiments, the integrated photodetector described in the present application can be used to measure low light intensities. Such a photodetector may be suitable for applications that require photodetectors with a high sensitivity, such as applications that can simultaneously use singular photon counting techniques, for example. However, the techniques described here are not limited in that regard, since the integrated photodetector described in the present applications can measure any suitable light intensity. Additional Luminescence Lifetime Applications Image Formation and Characterization Using Lifetimes
[00126] As mentioned above, the techniques described here are not limited to labeling, detection and quantization using exogenous fluorophores. In some modalities, a region, object or sample can have its image created and / or characterized using techniques of image formation of fluorescence life through the use of an integrated photodetector. In such techniques, the fluorescence characteristics of the region, object or sample itself can be used for image formation and / or characterization. Exogenous markers or endogenous markers can be detected through image formation and / or lifetime characterization. Exogenous markers attached to a probe can be provided for the region, object or sample in order to detect the presence and / or location of a target component in articular powder. The exogenous marker can serve as a marker and / or reporter as part of a labeled probe to detect parts of the region, object or sample that contain a target for the labeled probe. Automatic fluorescence of endogenous markers can provide a non-invasive, label-free contrast for spatial resolution that can be readily used for imaging without requiring the introduction of endogenous markers. For example, biological tissue automatic fluorescence signals may depend on and may be indicators of biochemical composition and tissue structure.
[00127] Fluorescence life measurements can provide a quantitative measurement of the conditions surrounding the fluorophore. Quantitative measurement of conditions can be in addition to detection or contrast. The fluorescence life for a fluorophore may depend on the surrounding environment for the fluorophore, such as pH or temperature, and a change in the fluorophore's lifetime value may indicate a change in the environment surrounding the fluorophore. As an example, imaging the lifetime of fluorescence can map changes in local environments of a sample, such as in biological tissue (for example, a tissue section or surgical resection). Auto fluorescence fluorescence life measurements of endogenous fluorophores can be used to detect physical and metabolic changes in tissue. As examples, changes in architecture, morphology, oxygenation, pH, vascularity, cell structure and / or metabolic state of tissue cells can be detected by measuring automatic fluorescence from the sample and determining a useful life from the measured autofluorescence. . Such methods can be used in clinical applications, such as monitoring image-guided biopsies or surgery, and / or endoscopy. In some embodiments, an integrated photodetector of the present application can be incorporated into a clinical tool, such as a surgical instrument, for example, to perform the fluorescence life imaging. Determination of fluorescence lifetimes based on measured autofluorescence provides clinical value as a label-free imaging method that allows a physician to quickly monitor tissue and detect minor cancers and / or precancerous lesions that are not apparent for the naked eye. Fluorescence life imaging can be used to detect and delineate malignant cells or tissue, such as tumors or cancer cells that emit luminescence having a longer fluorescence life than healthy tissue. For example, fluorescence life imaging can be used to detect cancer in optically accessible tissue, such as the gastrointestinal tract, bladder, skin, or exposed tissue surface during surgery.
[00128] In some embodiments, the fluorescence lifetimes can be used for microscopic techniques to provide contrast between different types or states of samples. Fluorescence life-imaging microscopy (FLIM) can be performed by exciting a sample with a light pulse, detecting the fluorescence signal as it falls to determine a life span, and mapping the time of reduction in the resulting image. In such microscopic images, the pixel values in the image can be based on the luminescence life determined for each pixel in the photodetector collecting the field of view. Image of a Scene or Object Using Temporal Information
[00129] As discussed above, an integrated photodetector as described in the present application can be used in scientific and clinical contexts in which the timing of the emitted light can be used to detect, quantify, and / or create the image of a region, object or sample. However, the techniques described here are not limited to scientific and clinical applications, since the integrated photodetector can be used in any image formation application that can take advantage of the temporal information regarding the arrival time of the incident photons. An example of an application is the flight time imaging. Flight Time Applications
[00130] In some modalities, an integrated photodetector can be used in image formation techniques that are based on the measurement of a time profile of scattered or reflected light, including measurements of flight time. In such measurements of flight time, a pulse of light can be emitted in a region or sample and scattered light can be detected by the integrated photodetector. The scattered or reflected light may have a distinct time profile that may indicate characteristics of the region or sample. The light scattered in the background by the sample can be detected and resolved by its flight time in the sample. Such a time profile can be a time point spreading function (TPSF). The time profile can be acquired by measuring the integrated intensity across multiple time compartments after the light pulse is emitted. The repetitions of the light pulses and the accumulation of scattered light can be performed at a set rate to ensure that all previous TPSF are completely extinguished before the generation of a subsequent light pulse. Time-resolved diffuse optical imaging methods may include spectroscopic diffuse optical tomography where the pulse of light can be infrared light in order to create the image at an additional depth in the sample. Such time-resolved diffuse optical imaging methods can be used to detect tumors in an organism or part of an organism, such as in a person's head.
[00131] Additionally or alternatively, flight time measurements can be used to measure distance or a range of distances based on the speed of light and time between an emitted light pulse and detection of reflected light from an object. Such flight time techniques can be used in a variety of applications, including cameras, proximity sensors in automobiles, human-machine interfaces, robotics and other applications that can use three-dimensional information collected by such techniques. Integrated Photodetector for Photogenerated Load Carriers with Time Conditioning
[00132] Some modalities refer to an integrated circuit having a photodetector that produces charge carriers in response to incident photons and that is able to discriminate the timing in which charge carriers are generated by the arrival of incident photons with respect to a time reference point (for example, a trigger event). In some embodiments, a cargo carrier segregation structure segregates cargo carriers generated at different times and directs cargo carriers to one or more cargo carrier storage regions (called "compartments") that aggregate cargo carriers produced within different time periods. Each compartment stores the load carriers produced within a selected time interval. Reading the charge stored in each compartment can provide information on the number of photons arriving within each time interval. Such an integrated circuit can be used in any of a variety of applications, such as those described here.
[00133] An example of an integrated circuit having a photodetection region and a load carrier segregation structure will be described. In some embodiments, the integrated circuit may include a set of pixels, and each pixel may include one or more photodetection regions and one or more charge carrier segregation structures, as discussed below. Pixel Structure and Operation Overview
[00134] Figure 2A illustrates a 100 pixel diagram, according to some modalities. Pixel 100 includes a photon absorption / carrier generation region 102 (also referred to as a photodetection region), a carrier path / capture region 106, a carrier storage region 108 having one or more carrier storage regions load carrier, also referred to herein as "load carrier storage compartments" or simply "compartments" and a reading circuit assembly 110 for reading signals from the load carrier storage compartments.
[00135] The region of photon absorption / carrier generation 102 can be a region of semiconductor material (for example, silicon) that can convert the incident photons into photogenerated charge carriers. The region of photon absorption / carrier generation 102 can be exposed to light, and can receive incident photons. When a photon is absorbed by the photon absorption / carrier generation region 102, it can generate photogenerated charge carriers, such as an electron / hole pair. Photogenerated charge carriers are also referred to here simply as "charge carriers".
[00136] An electric field can be established in the region of photon absorption / carrier generation 102. In some embodiments, the electric field can be "static" as distinguished from the changing electric field in the carrier path / capture region 106. The electric field in the photon absorption / carrier generation region 102 may include a side component, a vertical component, or both a lateral or vertical component. The lateral component of the electric field can be in the downward direction of Figure 2A, as indicated by the arrows, which induces a force in the photogenerated charge carriers that drives them in the direction of the carrier / capture path region 106. The electric field can be formed in various ways.
[00137] In some embodiments, one or more electrodes can be formed through the photon absorption / carrier generation region 102. The electrodes may have voltages applied to them to establish an electric field in the photon absorption / carrier generation region 102. Such electrodes can be called "photoportas". In some embodiments, the photon absorption / carrier 102 generation region may be a silicon region that is completely depleted of charge carriers.
[00138] In some embodiments, the electric field in the region of photon absorption / carrier generation 102 can be established by a junction, such as a PN junction. The semiconductor material of the photon absorption / carrier generation region 102 can be coated to form the PN junction with an orientation and / or shape that produces an electric field that induces a force in the photogenerated charge carriers that drives them in the direction of carrier path / capture region 106. The production of the electric field using a junction can improve quantum efficiency with respect to the use of electrodes by overlapping the photon absorption / carrier generation 102 region that can prevent a portion of the incident photons from reaching the region of photon absorption / carrier generation 102. Using a junction it is possible to reduce the dark current with respect to the use of photoportes. It was appreciated that the dark current can be generated by imperfections on the surface of the semiconductor substrate that can produce the carriers. In some embodiments, the P terminal of the PN junction diode can be connected to a terminal that sets its voltage. Such a diode can be referred to as a "pinned" photodiode. A pinned photodiode can promote carrier recombination on the surface, due to the terminal that configures its voltage and attracts carriers, which can reduce dark current. Photogenerated charge carriers that are desirable to be captured can pass under the recombination area on the surface. In some embodiments, the lateral electric field can be established using a coating concentration classified in the semiconductor material.
[00139] In some embodiments, an absorption / carrier generation region 102 that has a junction to produce an electric field may have one or more of the following characteristics: an exhausted n-type region that is tapered away from the variable time field; a p-type implant surrounding the n-type region with a space for transiting the electric field laterally to the n-type region; and / or a p-type surface implant that buries the n-type region and serves as a recombination region for parasitic electrons.
[00140] In some modalities, the electric field can be established in the region of photon absorption / generation of carrier 102 by a combination of a junction and at least one electrode. For example, a junction and a single electrode, or two or more electrodes, can be used. In some embodiments, one or more electrodes can be positioned close to the carrier path / capture region 106 to establish the potential gradient close to carrier path / capture region 106, which can be positioned relatively distant from the junction.
[00141] As illustrated in figure 2A, a photon can be captured and a charge carrier 101A (for example, an electron) can be produced at time t1. In some embodiments, an electric potential gradient can be established across the photon absorption / carrier generation region 102 and the carrier path / capture region 106 that causes charge carrier 101A to travel in the downward direction of the figure 2A (as illustrated by the arrows shown in figure 2A). In response to the potential gradient, load carrier 101A can move from its position at time t1 to a second position at time t2, a third position at time t3, a fourth position at time t4, and a fifth position at time t5. Load carrier 101A thus moves into carrier travel / capture region 106 in response to the potential gradient.
[00142] Carrier path / capture region 106 may be a semiconductor region. In some embodiments, the carrier path / capture region 106 may be a semiconductor region of the same material as the carrier photon absorption / generation region 102 (for example, silicon) with the exception that the path / capture region of the carrier 106 can be protected against incident light (for example, by an opaque superimposed material, such as a metallic layer).
[00143] In some modalities, and as further discussed below, a potential gradient can be established in the photon absorption / carrier generation 102 region and the carrier path / capture 106 region by the electrodes positioned above these regions. An example of electrode placement will be discussed with reference to figure 3B. However, the techniques described here are not limited to the particular positions of the electrodes used to produce a gradient of electrical potential. Nor are the techniques described here limited to establishing an electric potential gradient using electrodes. In some embodiments, an electric potential gradient can be established using a spatially classified coating profile and / or a PN junction. Any suitable technique can be used to establish a gradient of electrical potential that causes charge carriers to travel along the region of photon absorption / carrier generation 102 and the carrier path / capture region 106.
[00144] A load carrier segregation structure can be formed on the pixel to allow the segregation of load carriers produced at different times. In some embodiments, at least part of the charge carrier segregation structure may be formed through the carrier travel / capture region 106. As will be described below, the charge carrier segregation structure may include one or more electrodes formed across carrier path / capture 106, the voltage of which can be controlled by the set of control circuits to change the electrical potential in carrier path / capture 106.
[00145] The electrical potential in the carrier 106 path / capture region can be changed to allow the capture of a charge carrier. The potential gradient can be altered by changing the voltage at one or more electrodes overlapping the carrier travel / capture region 106 to produce potential protection that can confine a carrier within a predetermined spatial region. For example, the voltage at an electrode superimposed on the dashed line in the carrier path / capture region 106 of figure 2A can be changed at time t5 to raise a potential protection along the dashed line in the carrier path / capture region 106 2A, thus capturing the load carrier 101A. As shown in figure 2A, the carrier captured at time t5 can be transferred to a "bin0" compartment in the carrier storage region 108. The transfer of the carrier to the cargo carrier storage compartment can be accomplished by changing the potential in the carrier / travel region 106 and / or carrier storage region 108 (for example, by changing the voltage of the electrodes superimposed on these regions) to cause the carrier to travel into the charge carrier storage compartment.
[00146] Changing the potential at a given time within a predetermined spatial region of the carrier path / capture region 106 may allow the trapping of a carrier that was generated by the photon absorption that occurred within a specific time interval. By trapping photogenerated charge carriers at different times and / or different locations, the times at which charge carriers were generated by photon absorption can be broken down. In this sense, a load carrier can be "packaged in time" by trapping the load carrier at a given time and / or space after the occurrence of a triggering event. The time storage of a charge carrier within a particular compartment provides information about the time in which the photogenerated charge carrier was generated by the absorption of an incident photon, and thus, in the same way, "time compartments" with in relation to the triggering event, the arrival of incident photons that produced the photogenerated charge carrier.
[00147] Figure 2B illustrates the capture of a cargo carrier at a different point in time and space. As illustrated in figure 2B, the voltage at an electrode superimposed on the dashed line in the carrier / capture region 106 can be changed at time t9 to raise a potential protection along the dashed line in the carrier / capture region 106 of figure 2B, thus capturing the carrier 101B. As shown in figure 2B, the carrier captured at time t9 can be transferred to a "bin1" compartment of carrier storage region 108. Since load carrier 101B is trapped at time t9, it represents an absorption event photon that occurred at a different time (ie, time t6) from the photon absorption event (ie, at t1) for carrier 101A, which is captured at time t5.
[00148] Carrying out multiple measurements and aggregating load carriers in the load carrier storage compartments of the carrier storage region 108 based on the times at which the load carriers are captured can provide information on the times at which photons are captured in the photon absorption / carrier generation 102 area. Such information can be useful in a variety of applications, as discussed above. Illustrative Description of the Structure and Operation of Pixel
[00149] Figure 3A illustrates a load carrier containment region 103 of a pixel 100A, according to some embodiments. As illustrated in Figure 3A, pixel 100A may include a photon absorption / carrier generation area 102A (also referred to as a photodetection region), a carrier path / capture area 106A, a drain 104, a plurality of compartments load carrier storage bin0, bin1, bin2, bin3 of a carrier storage region 108A, and a reading region 110A.
[00150] The load carrier containment region 103 is a region in which the photogenerated load carriers move in response to the gradient of electrical potential produced by a load carrier segregation structure. Charge carriers can be generated in the photon absorption / carrier generation 102A area within charge carrier confinement region 103.
[00151] The load carrier containment region 103 can be formed from any suitable material, such as a semiconductor material (e.g., silicon). However, the techniques described here are not limited in this regard, since any suitable material can form the load carrier containment region 103. In some embodiments, the load carrier containment region 103 may be surrounded by an insulator ( for example, silicon oxide) to confine charge carriers within the charge carrier containment region 103.
[00152] The portion of the charge carrier confinement region 103 in the photon absorption / carrier generation area 102A may be of any suitable shape. As illustrated in figure 3A, in some embodiments the part of the load carrier confinement region 103 in the photon absorption / carrier generation area 102A may be tapered in shape, so that its width is gradually reduced near the path area / carrier capture 106A. Such a format can improve the efficiency of charge handling, which can be particularly useful in cases where few photons must reach. In some embodiments, the portion of the charge carrier confinement region 103 in the photon absorption / carrier generation area 102A may be less tapered, or may not be tapered, which may increase the dynamic range. However, the techniques described here are not limited to the shape of the charge carrier confinement region 103 in the photon absorption / carrier generation 102A area.
[00153] As illustrated in Figure 3A, a first part of the load carrier confinement region 103 in the carrier path / capture area 106A can extend from the photon absorption / carrier generation area 102A to a drain 104 The load carrier confinement region 103 extensions extend into the respective load storage compartments, allowing load carriers to be directed into the load carrier storage compartments by a load carrier segregation structure as described with reference to figure 3B. In some embodiments, the number of extensions of the load carrier confinement region 103 that is present can be equal to the number of load carrier storage compartments, with each extension extending to a respective load carrier storage compartment.
[00154] The reading region 110A may include a floating diffusion node fd for reading the cargo storage compartments. The floating diffusion node fd can be formed by diffusing the n-type coatings into a p-type material (for example, p-type substrate), for example. However, the techniques described here are not limited to the particular coating types or coating techniques.
[00155] Figure 3B illustrates pixel 100A of figure 3A establishes an electrical potential within the load carrier confinement region 103. In some embodiments, the electrodes Vb0-Vbn, b0-bm may have a voltage applied to them to establish a potential gradient within regions 102A and 106A so that charge carriers, for example, electrons, travel in the downward direction of figure 3B towards drain 104. Vb0-Vbn electrodes can establish a potential gradient in the region of load confinement 103 of the photon absorption area / carrier generation 102A. In some embodiments, the respective Vb0-Vbn electrodes may be at constant voltages. The b0-bm electrodes can establish a potential gradient in the load confinement region 103 of the carrier travel / capture area 106A. In some embodiments, the b0-bm electrodes may have their voltages determined at different levels to allow the trapping of charge carriers and / or the transfer of charge carriers to one or more load storage compartments.
[00156] The electrodes st0 and st1 may have voltages that change to transfer the carriers to the load storage compartments of the 108A load carrier storage region. Transfer ports tx0, tx1, tx2 and tx3 allow the transfer of cargo from the cargo storage compartments to the floating diffusion node fd. The reading circuit assembly 110 including the reconfiguration transistor rt, the amplification transistor sf and the selection transistor rs is also illustrated.
[00157] In some embodiments, the potentials of the floating diffusion node fd and each of the transfer ports tx0-tx3 may allow excessive flow of charge carriers into the floating diffusion instead of into the path / capture area 106A carrier. When load carriers are transferred into a compartment within carrier storage region 108, the potentials of the floating diffusion node fd and the transfer ports tx0-tx3 may be high enough to allow any load carriers to flow surplus in the compartment flow to the floating diffusion. Such a "carrier overflow protection" technique can reduce overflow of carriers and diffusion into carrier path / capture area 106A and / or other pixel areas. In some embodiments, an overflow protection technique can be used to remove any overflow charge carriers generated by an excitation pulse. By allowing the overflow charge carriers to flow into the floating diffusion, these charge carriers are not captured in one or more time slots, thereby reducing the impact of the excitation pulse on the time slot sials during reading.
[00158] In some modalities in which the Vb0-Vbn and b0-bm electrodes are arranged through the photon absorption / carrier generation 102 region and / or carrier path / capture region 106, the Vb0-Vbn and b0 electrodes -bm can be configured for voltages that increase to positions progressing from top to bottom of figure 3B, thus establishing the potential gradient that causes load carriers to travel downward in figure 3B towards drain 104. In In some embodiments, the potential gradient can vary monotonically in the photon absorption / carrier generation region 102 and / or carrier path / capture region 106, which can allow charge carriers to travel along the potential gradient inward. the carrier 106 route / capture region. In some modalities, the potential gradient may change linearly with respect to the position along line A-A '. A linear potential gradient can be established by configuring electrodes for voltages that vary linearly through the vertical dimension of figure 3B. However, the techniques described here are not limited to a linear potential gradient, as any suitable potential gradient can be used. In some embodiments, the electric field in the carrier travel / capture region 106 may be high enough so that charge carriers move fast enough in the carrier travel / capture region 106 so that transit time is short compared to how long the photons can reach. For example, in the context of fluorescence life measurement, the transit time of charge carriers can be reduced compared to the life of a luminescent marker being measured. Transit time can be reduced by producing an electric field sufficiently classified in the carrier travel / capture region 106.
[00159] Figure 3C illustrates a modality in which a photon absorption / carrier generation 102 region includes a PN junction. Figure 3C illustrates an external electrode 302, which can be at a relatively low potential, "pinning", thus, the surface potential at a relatively low potential. A 304 electrode can be included to assist in producing the potential gradient for a static electric field that drives carriers towards carrier path / capture area 106 (bottom of carrier path / capture area 106 is not illustrated ). Figure 3C indicates the regions of diffusion, polysilicon, contact and metal 1.
[00160] The 3D figure shows a top view of a pixel as in figure 3C, with the addition of coating characteristics. Figure 3D also illustrates carriers sweeping the electric field to region 106 along the potential gradient established by the PN junction and electrode 304. Figure 3D indicates the regions of diffusion, polysilicon, contact, metal 1, implant N, implant P, and P-epi.
[00161] Figure 3E illustrates a top view of a pixel as in figure 3C, including the carrier travel / capture area 106.
[00162] Figure 3F illustrates a set of pixels as in figure 3E. Figure 3F indicates the regions of diffusion, polysilicon, contact and metal 1.
[00163] Figure 3G illustrates the set of pixels of figure 3F and also indicates the regions of diffusion, polysilicon, contact, metal 1, implant N, implant P and P-epi.
[00164] Figure 4 shows a circuit diagram of pixel 100A of figure 3B. The cargo carrier confinement area 103 is illustrated by heavy dark lines. In addition, the electrodes, charge carrier storage area 108 and reading circuit set 110 are illustrated. In this embodiment, the charge storage compartments bin0, bin1, bin2, and bin3 of the carrier storage region 108 are within the containment area of carrier 103 under electrode st1. As discussed above, in some embodiments, a junction can be used to produce a static field in region 102 instead of or in addition to the electrodes.
[00165] Light is received from a light source 120 in the photon absorption / carrier generation 102 area. Light source 120 can be any type of light source, including a luminescent sample (for example, connected to a nucleic acid) or a region or scene to be created, by way of example and not limitation. A light shield 121 prevents light from reaching the travel / capture area of carrier 106. Light shield 121 can be formed from any suitable material, such as metallic layer of the integrated circuit, by way of example and not by limitation.
[00166] Figure 5A illustrates a potential gradient that can be established in the charge carrier confinement area 103 in the photon absorption / carrier generation area 102 and carrier path / capture area 106 along line AA ' of figure 3B. As illustrated in figure 5A, a charge carrier (for example, an electron) can be generated by absorbing a photon within the area of photon absorption / carrier generation 102. The Vb0-Vbn and b0-bm electrodes are configured to voltages that increase to the right of figure 5A to establish the potential gradient that causes electrons to flow to the right in figure 5A (the downward direction of figure 3B). Additionally or alternatively, a PN junction may be present to establish or assist in establishing the field. In such an embodiment, carriers can flow beyond the surface, and figure 5A (and related figures) illustrates the potential in the region where carriers flow. Initially, carriers can flow through carrier travel / capture area 106 into drain 104, as illustrated in figures 6A, 6B and 6C. Figure 6A illustrates the position of a carrier 101 once it is photogenerated. Figure 6B illustrates the position of a carrier 101 shortly thereafter, as it travels downward in response to the established potential gradient. Figure 6C illustrates the position of carrier 101 as it reaches drain 104.
[00167] Figure 5B illustrates that after a period of time a potential protection 501 for electrons can be increased at a time t1 by reducing the voltage of electrode b0. Potential protection 501 can prevent an electron from traveling to the right in figure 5B, as shown in figure 6D, 6E and 6F. Figure 6D illustrates the position of a carrier 101 (for example, an electron) since it is photogenerated. Figure 6E illustrates the position of a carrier 101 shortly thereafter, as it travels downward in response to the potential gradient. Figure 6F illustrates the position of the carrier 101 as it reaches the potential protection 501 after the moment t1.
[00168] Figure 5C illustrates that after another period of time, another potential protection 502 for electrons can be increased at time t2 by reducing the voltage of electrode b2. If an electron arrives between electrodes b0 and b2 between moments t1 and t2, the electron will be captured between the potential protection 501 and the potential protection 502, as shown in figure 5C and figure 6G.
[00169] Figure 5D illustrates that after another period of time, another potential protection 503 for electrons can be increased at time t3 by reducing the voltage of electrode b4. If an electron arrives between electrodes b2 and b4 between moments t2 and t3, the electron will be trapped in a location between the potential protection 502 and the potential protection 503. In the example in figure 5D and 6H, an electron arrived between the moments t1 and t2, so that it remains captured between the potential protection 501 and the potential protection 502.
[00170] Figure 5E illustrates that after another period of time, another potential protection 504 for electrons can be increased at time t4 by reducing the voltage of electrode b6. If an electron arrives between electrodes b4 and b6 between moments t3 and t4, the electron will be trapped in a location between potential protection 503 and potential protection 504. In the example in figures 5E and 6I, an electron arrived between moments t1 and t2, so that it remained between the potential protection 501 and the potential protection 502.
[00171] Figure 5F illustrates that after another period of time, another potential protection 505 for electrons can be increased at time t5 by reducing the voltage of the electrode bm. If an electron arrives between electrodes b6 and bm between moments t4 and t5, the electron will be trapped in a location between potential protection 504 and potential protection 505. In the example in figure 5F and 6J, an electron arrived between moments t1 and t2, so that it remained between the potential protection 501 and the potential protection 502.
[00172] Figure 6K illustrates a voltage timing diagram illustrating the voltages of electrodes b0-b8, st0 and st1 over time. A cargo carrier moving through the carrier path / capture area 106 during the elevation sequence of the potential protections 501-505 will be captured at a location within the carrier path / capture area 106 which depends on the moment it arrived at the travel / capture area of carrier 106, which, in turn, depends on the moment at which the charge carrier was generated by photon absorption in the photon absorption / carrier generation 102 area. The timing with which potential 501-505 are high configures the timing of the bin0-bin3 load storage compartments. As illustrated in figure 6K, a carrier arriving between times t1 and t2 will be trapped within a time slot for bin0, a carrier arriving between times t2 and t3 will be trapped within a time slot for bin1, a carrier arriving between times t3 and t4 will be trapped within a time slot for bin2, and a carrier arriving between moments t4 and t5 will be trapped within a time slot for bin3.
[00173] After the sequence illustrated in figures 5A to 5F, a captured cargo carrier can then be transferred to the appropriate cargo carrier storage compartment based on the location in which the cargo carrier is captured within the travel area / carrier capture 106. In this mode, if an electron is captured under electrode b1, it is transferred to bin0. If an electron is captured under electrode b3, it is transferred to bin1. If an electron is captured under electrode b5, it is transferred to bin2. If an electron is captured under electrode b7, it is transferred to bin3. In some embodiments, the transfer of any carrier captured within the carrier route / capture area 106 to their corresponding compartments can be performed in parallel (for example, simultaneously). However, the techniques described here are not limited to transferring captured carriers to parallel cargo storage compartments.
[00174] As illustrated in figure 6K, after the sequence illustrated in figures 5A to 5F, the voltages at electrodes st0 and st1 can be changed to transfer any captured charge carriers to the corresponding charge carrier storage compartments. An illustrative sequence for transferring captured cargo carriers will be discussed with respect to figures 6K and 7A to 7G.
[00175] Figure 7A illustrates a representation of a potential for a cross section of the load carrier confinement area 103 along line B-B 'of figure 3B. Figure 7A illustrates the potential at time t5 (figure 6K) in an example in which an electron is captured between the potential shields 503 and 504. A plan view illustrating an electron captured between the potential shields 503 and 504 is illustrated in the figure 7E.
[00176] Figure 7B illustrates that after moment t5 the voltage at electrodes b1, b3, b5 and b7 can optionally be reduced (not shown in figure 6K0 to raise the position of an electron within the potential well, to facilitate electron transfer.
[00177] Figure 7C illustrates that at time t6 (figure 6K), the voltages at electrodes st0 and st1 can be high. Changing the electrode voltages in this way can provide a potential gradient that causes a transfer from the charge carrier captured in the carrier path / capture area 106 to a corresponding charge storage compartment under electrode st1. A plan view showing the electrode voltage st1 being high and the carrier 101 being transferred is illustrated in figure 7F.
[00178] Figure 7D illustrates that at time t7, the voltage at electrode st0 can be eliminated, thus confining the captured carrier (if any) in the corresponding compartment (bin2, in this example). The voltage at electrode b6 can be increased at time t8 to reestablish the potential gradient in the carrier / capture area 106. A plan view illustrating voltage electrode st1 being lowered and carrier 101 being captured in bin2 is illustrated in the figure 7G.
[00179] Figure 7H illustrates the characteristics of the electrodes of a load carrier segregation structure, according to some modalities. Figure 7H specifies, for each electrode, the voltage during the gradient phase, the voltage during the conditioning phase, the voltage during the transfer phase, the voltage during the high reading phase, and the type of voltage change. However, this is purely illustrative, and the techniques described here are not limited to the implementation details illustrated in figure 7H. Illustrative Measurement Sequence
[00180] The repetition of the photon absorption / carrier generation process and the time conditioning of photogenerated charge carriers can allow the collection of statistical information on the moments when the photons reach the photodetector, as discussed below.
[00181] In some modalities, a "measurement" may include the receipt of a photon, the capture of a charge carrier at a particular time and / or place and the transfer of the captured carrier to a charge storage node corresponding to a particular period of time or compartment. A measurement can be repeated several times to collect statistical information about the times when the photons reach the photodetector.
[00182] Figure 8A illustrates a flowchart of a method 700 that includes performing a plurality of measurements 720, according to some modalities. Such a method can be carried out at least partially by an integrated device as described here.
[00183] In step 702, a measurement 720 can be initiated by a trigger event. A trigger event can be an event that serves as a time reference for the arrival of conditioning in time for a photon. The triggering event can be an optical pulse or an electrical pulse, for example, and it can be a single event or a recurring periodic event. In the context of fluorescence life measurement, the trigger event can be the generation of a light excitation pulse to excite a fluorophore. In the context of flight time imaging, the triggering event can be a pulse of light (e.g., from a flash) emitted by an image forming device comprising the integrated photodetector. The triggering event can be any event used as a reference for the photon or carrier arrival timing.
[00184] The generation of the light excitation pulse can produce a significant number of photons, some of which can reach pixel 100 and can produce charge carriers in the area of photon absorption / carrier generation 102 Since the measurement of the carriers photogenerated from the light excitation pulse is not desirable, they can flow downward through the electrical potential to drain 104 without being captured. Allowing the photogenerated carriers produced by an excitation pulse to flow into the drain 104 without being captured can reduce the amount of undesirable signal that would otherwise need to be prevented from reaching by complex optical components, such as the shutter or filter, which can add complexity to the design and / or additional cost. The timing of the elevation of one or more potential protections within the carrier travel / capture area 106 can be timed so that the photogenerated carriers caused by any undesirable optical signal flow flow into the drain 104. Furthermore, this technique can be used with any number of time slots, including modalities with only a single time slot. For example, a pixel may include a single time slot and a drain where the timing of the potential protections reduces the signal associated with the excitation pulse while capturing the desired optical signal within the carrier path / capture area 106.
[00185] Measurement 720 can then start at step 704, where the photons you want to detect can be absorbed and a charge carrier can be generated in region 102. In the context of fluorescence lifetime measurement or time imaging flight, step 704 can begin after the light excitation pulse is completed.
[00186] In step 706, cargo carriers moving through carrier route / capture area 106 can be captured at predetermined locations at selected times in relation to trigger event 702. In some embodiments, cargo carriers can be captured in one or more regions of the carrier path / capture area 106 by elevating one or more potential shields to trap a carrier in a location that depends on the moment at which it was generated by photon absorption, as discussed above.
[00187] In step 708, the captured cargo carriers, if present, can be transferred from the place where the captured cargo carriers were captured to a corresponding cargo storage compartment, "packing in time", thus, the carrier charge.
[00188] Following step 708, measurement 720 can be repeated n-1 times to obtain statistical information regarding the time periods in which photons tend to arrive after a 702 trigger event. Time-conditioned charge carriers can be aggregated in the corresponding cargo storage compartments as measurement 720 is repeated. Repeating measurement 720 may allow for the aggregation of a sufficient number of load carriers into the load carrier storage compartments to provide statistically significant results. For example, in the context of fluorescence life measurement, a photon absorption event in response to a photon received from a fluorophore can be expected to occur relatively rarely. For example, such an event can be expected to occur once every 1,000 measurements. Accordingly, a large number of 720 measurements may need to be performed to aggregate a sufficient number of load carriers into the load carrier storage compartments so that the results are statistically significant. In some embodiments, the number of n measurements of a fluorophore that can be performed for measuring the fluorescence life can be 500,000 or more, or 1,000,000 or more, to allow the capture and storage of a sufficient number of carriers of cargo in each compartment (that is, tens or hundreds, or more, in some modalities).
[00189] Once the allocated number of measurements n has been taken, method 700 can proceed to step 710 of reading the time slots. Reading the time compartments may include converting the amount of charge added in each of the charge storage compartments to corresponding voltages, as will be discussed below.
[00190] Figure 8B is a diagram illustrating an excitation pulse being generated at time t0, and the bin0-bin3 time compartments. Note that in this example the time compartments for photo measurement do not start until t1, a period of time after t0, which allows the excitation light to end before the measurement of the signal photons.
[00191] Figure 8C illustrates a representation of the number of photons / charge carriers in each time slot for a set of fluorescence life measurements in which the probability that the fluorescence of the marker or matrix decreases exponentially with time. By repeating the excitation sequence, capturing charge, and transferring to respective compartments many times and reading the amount of charge carriers transferred into each compartment, a histogram of the number of photons recorded in different compartments can be produced allowing the determination or approaching the service life of a fluorophore.
[00192] Method 700 can be performed through any additional period of time in which photons must be captured. In the context of measuring fluorescence life, an appropriate period for performing the 700 method can be 10 milliseconds, for example. In some embodiments, steps 702 to 708 can be repeated at a frequency that is in the MHz range. In some embodiments, time slots may have a resolution in the scale of picoseconds or nanoseconds. Time Detection Multiplexing in Response to Different Trigger Events
[00193] In some modalities, measurements can be performed using a plurality of different types of trigger events. Trigger events can be multiplexed in time so that a pixel receives light in response to different types of trigger events at different time periods. For example, in the context of luminescence lifetime measurements, trigger events can be excitation light pulses (eg laser pulses) of different wavelengths XI and λ2, which can excite different luminescent molecules (eg , fluorophores). In some embodiments, fluorophores can be identified and / or discriminated from each other based on their response to different wavelengths λ1 and λ2 of the excitation light. The excitation of a sample with pulses of light excitation of wavelengths λ1 and λ2 at different times, and the analysis of the luminescence emitted by the sample in response, may allow the detection and / or identification of luminescent molecules based on the fact that luminescence is detected in a first period of time in response to excitation light of wavelength λ1, or in a second period of time in response to excitation light of wavelength λ2. In addition to, or as an alternative to such temporal multiplexing, luminescent molecules can be identified and / or determined based on the measurement of their luminescence life.
[00194] In some embodiments, a nucleic acid can be sequenced based on the detection of the light emitted by one or more fluorophores attached to the nucleotides of the nucleic acid. In some embodiments, such sequencing can be performed by temporal multiplexing of excitation light of different wavelengths, based on the measurement of luminescence useful lives, or based on a combination of such techniques.
[00195] For example, in some embodiments, four different fluorophores can be connected to the respective nucleotides (for example, A, C, G and T) of a nucleic acid. The four fluorophores can be distinguished from each other based on a combination of excitation wavelength and luminescence life, as illustrated in the graph below.

[00196] In some embodiments, the integrated photodetector can temporally multiplex the detection of photons produced by a sample in response to excitation pulses of light of different wavelengths. For example, in a first period of time, the light produced by a sample in response to the excitation light of the wavelength λi can be detected. Subsequently, in a second period of time, the light produced by a sample in response to the excitation light of wavelength λ2 can be detected. To do this, a pixel having a plurality of time slots can use a first subset of time slots to detect the arrival of photons in the first period of time and a second subset of time slots to detect the arrival of photons in the second period of time. By examining whether light arrives at a pixel during the first period of time or the second period of time, it can be determined whether a fluorophore is fluorescent in response to light of wavelength λi or light of wavelength λ2.
[00197] In some modalities, the information regarding the photon arrival moments in response to a light excitation pulse can be used to determine and / or discriminate the fluorescence useful life and, thus, identify a fluorophore. In some embodiments, a first excitation pulse of a first wavelength can be emitted, then a first subset of one pixel time compartments can be used to condition the arrival of incident photons in time in a first time interval. Then, a second excitation pulse of a second wavelength can be emitted, and a second subset of pixel time compartments can be used to condition the arrival of incident photons in time in a second time interval. Accordingly, if the photons are received in the first time interval and / or the second time interval, information about the useful life of the fluorophore that produced the photons can be obtained. The repetition of the time multiplexing process of the light excitation pulses together with the measurement information regarding the fluorescence useful lives can provide enough information to allow the identification of the fluorophore. Accordingly, the nucleotide to which the fluorophore is attached can be identified. As a sequencing reaction progresses, additional nucleotides can be incorporated into a polymerase over time. The performance and repetition of the time multiplexing process of pulses of light excitation with measurements of fluorescence useful lives can provide sufficient information to allow the identification of such fluorophores. Accordingly, the sequence of nucleotides in a nucleic acid can be determined.
[00198] Figure 8D illustrates a method of operating the integrated photodetector according to some modalities in which light is received in the integrated photodetector in response to a plurality of different triggering events. Figure 8E illustrates electrode voltages of the load carrier segregation structure when performing the method of figure 8D.
[00199] In step 802, a measurement 820 can be initiated by a triggering event A. Triggering event A can be an event that serves as a time reference for the arrival of a photon packaged time. The triggering event can be an optical pulse or an electrical pulse, for example, and it can be a single event or a recurring periodic event. In the context of fluorescence life measurement, trigger event A can be the generation of a pulse of light excitation at a first wavelength to excite a first type of fluorophore.
[00200] The generation of the light excitation pulse can produce a significant number of photons, some of which can reach pixel 100 and can produce charge carriers in the area of photon absorption / carrier generation 102. Since the photogenerated carriers from the light excitation pulse they must not be measured, they can flow downwardly through the electrical potential to drain 104 without being captured, as discussed above. The elevation of one or more potential protections within the carrier capture / travel area 106 can be timed so that the photogenerated carriers caused by any unwanted optical signal flow flow to the drain 104.
[00201] Measurement 820 can then proceed to step 804, where the photons to be detected can be absorbed and a charge carrier can be generated in region 102. In the context of fluorescence life measurement, step 804 can begin after the light excitation pulse is completed.
[00202] In step 806, cargo carriers moving through the carrier route / capture area 106 can be captured at predetermined locations at selected times in relation to the 802 trigger event. In some embodiments, cargo carriers can be captured in one or more regions of the carrier path / capture area 106 by elevating one or more potential shields to trap a carrier in a location that depends on the moment at which it was generated by photon absorption, as discussed above. In some embodiments, step 806 may include raising the potential protections 501, 503 and 503 in success, thus capturing the load (if present) corresponding to the bin0 and / or bin1 time compartments.
[00203] In step 808, the captured cargo carriers, if present, can be transferred from the place where they were captured to a corresponding cargo storage compartment, "packing in time", in this way, the cargo carrier. For example, any captured charge corresponding to bin0 and / or bin1 time compartments can be transferred to bin0 and / or bin1 compartments in step 808 using a technique illustrated in figures 7A to 7D, for example.
[00204] In step 810, a second measurement 821 can be initiated by a triggering event B. The triggering event B can be an event that serves as a time reference for conditioning in time of the arrival of a photon. The triggering event can be an optical pulse or an electrical pulse, for example, and it can be a single event or a recurring periodic event. In the context of fluorescence life measurement, trigger event B can be the generation of a light-excitation pulse at a second wavelength to excite a second type of fluorophore.
[00205] The generation of the light excitation pulse can produce a significant number of photons, some of which can reach pixel 100 and can produce charge carriers in the area of photon absorption / carrier generation 102. Whereas carriers Photogenerated from the light excitation pulse should not be measured, they can flow downward through the electrical potential to drain 104 without being captured, as discussed above. The elevation of one or more potential protections within the carrier travel / capture area 106 can be timed so that the photogenerated carriers caused by any undesirable optical signal flow flow to the drain 104.
[00206] The second measurement 821 can then proceed to step 812, where the photons you want to detect can be absorbed and a charge carrier can be generated in region 102. In the context of fluorescence life measurement, step 812 can start after the second light excitation pulse is completed.
[00207] In step 814, cargo carriers moving through carrier route / capture area 106 can be captured at predetermined locations at selected times in relation to trigger event 810. In some embodiments, cargo carriers can be captured in one or more regions of the carrier path / capture area 106 by elevating one or more potential shields to trap a carrier in a location that depends on the moment at which it was generated by photon absorption, as discussed above. In some embodiments, step 814 may include raising potential protections 503, 504 and 505 in succession, thereby capturing the load (if present) corresponding to the bin2 and / or bin3 time compartments.
[00208] In step 816, the captured cargo carriers, if present, can be transferred from the place where they were captured to a corresponding cargo storage compartment, "packing in time", in this way, the cargo carrier. For example, any captured load corresponding to the bin2 and / or bin3 time compartments can be transferred to the bin2 and / or bin3 compartments in step 816 using a technique illustrated in figures 7A to 7D, for example.
[00209] Although an example has been described in which a pixel has four time compartments, and two compartments are allocated to measure the arrival times of light produced in response to each of the respective pulses of light excitation, the techniques described here they are not limited in that respect. For example, the pixel may have a greater or lesser number of compartments, which can be allocated in any suitable way by measuring light in response to different excitation pulses. In addition, the techniques described here are not limited to pulses of light excitation of two different wavelengths, since pulses of light excitation of either wavelength can be used, and multiplexed accordingly.
[00210] Following step 816, measurements 820 and 821 can be repeated n-1 times to obtain statistical information regarding the time periods in which photons tend to arrive after a triggering event. Time-conditioned cargo carriers can be aggregated into corresponding cargo storage compartments as measurements are repeated.
[00211] Once the allocated number of measurements n has been taken, method 800 can proceed to step 710 of reading the time slots. Reading the time compartments may include converting the amount of charge added in each of the charge storage compartments to corresponding voltages, as will be discussed below. Set of Reading Circuits and Illustrative Sequences
[00212] As illustrated in figures 2A and 2B, pixel 100 may include a set of reading circuits 110 that allows reading of the charge stored in the charge storage compartments of the charge carrier storage region 108. Pixel 100 may be an active pixel, so that the reading circuitry 110 includes a reading amplifier, or a passive pixel in which the reading circuitry 110 does not include a reading amplifier. Any suitable type of active or passive pixel reading circuitry can be used.
[00213] If the reading circuit set 110 includes a reading amplifier, any suitable type of amplifier can be used. Examples of suitable amplifiers include amplifiers based on a common source configuration and amplifiers based on a source follower configuration. However, the techniques described here are not limited to any particular amplifier configuration.
[00214] If the reading circuit set 110 includes a reading amplifier, the reading amplifier can collect the accumulated load in a load storage compartment (for example bin0, bin1, bin2 or bin3) as an input and produce a voltage representative of the load in the cargo storage compartment as an output.
[00215] An example of the reading circuit set 110 based on a source follower configuration is illustrated in figure 4. The example of reading circuit set 110 illustrated in figure 4 is a "4T" configuration having four transistors: rt, sf, rs and one of the transfer ports tx0-tx3. Since three rt, sf and rs transistors are shared between each load storage compartment, the illustrative circuitry illustrated in figure 4 for all four compartments is a "1.75T" configuration (4 transfer ports + 3 transistors) / 4 compartments. However, the techniques described here are not limited to the use of a set of reading circuits 110 having a 1.75T configuration, since any other type of reading configuration can be used.
[00216] Additionally, any of the suitable reading techniques can be used, including noise reduction techniques. In some embodiments, the reading circuit set 110 can read the load carrier storage compartments using correlated double sampling. Correlated double sampling is the technique in which a first sample can be taken from a node at a reconfiguration voltage level that includes an undetermined amount of noise, and a second sample can be taken from a signal level at the node including the same undetermined noise. The noise can be subtracted by subtracting the sampled reconfiguration level from the sampled signal level.
[00217] The reading circuit set 110 can read the load storage compartments sequentially or in parallel. An example of a timing diagram for reading bin0-bin3 compartment sequence with reading circuit set 110 illustrated in figure 4 using correlated double sampling is illustrated in figure 9A. As illustrated in figure 9A, initially the reconfiguration transistor rt can be connected to configure the floating diffuse node fd for a reconfiguration voltage ct. During the period of time in which the voltage of the floating diffusion node is reset, the transfer ports tx0-tx3 are turned off to keep the load carriers stored in their respective compartments. After the floating diffusion node fd is reconfigured the reconfiguration voltage can be sampled by turning off transistor rt and turning on transistor rs to produce an output voltage cb. The reset voltage represented by the output voltage cb can be stored in an analog format (for example, in a capacitor) or in a digital format (for example, for A / D conversion and storage). Then, the transfer port tx0 can be connected to allow the bin0 load to flow to the floating diff fd. The signal voltage can be sampled by connecting the transistor rs to produce an output voltage cb based on the load stored in bin0. The signal voltage represented by the output voltage cb can be stored in an analog format (for example, in a capacitor) or in a digital format (for example, by A / D conversion and storage).
[00218] Then, the transistor rt can be connected to configure the floating diffusion fd for a reconfiguration voltage ct. During the time period in which the voltage of the floating diffusion node fd is reset, the transfer ports tx0-tx3 are turned off to keep the load carriers stored in their respective compartments. After the floating diffusion node fd is reconfigured, the reconfiguration voltage can be sampled by turning off transistor rt and turning on transistor rs to produce an output voltage cb. Again, the reconfiguration voltage represented by the output voltage cb can be stored in an analog format (for example, in a capacitor) or in a digital format (for example, by A / D conversion and storage). Then, the transfer port tx1 can be connected to allow the load from bin1 to flow into the floating diffusion. The signal voltage can be sampled by connecting the transistor rs to produce an output voltage cb based on the load stored in bin1. Again, the signal voltage represented by the output voltage cb can be stored in an analog format (for example, in a capacitor) or in a digital format (for example, by A / D conversion or storage).
[00219] The same process can then be performed for bin2 and bin3 by performing a reconfiguration, reconfiguration voltage sampling, load transfer from a compartment to the floating diffusion node fd, and signal sampling. Accordingly, in the reading sequence illustrated in figure 9A, eight samples can be collected representing the reconfigured value and signal values for the four compartments. The reconfigured value stored for each compartment can be subtracted from the stored signal value to obtain an indicator result of stored load in each compartment, thus completing the correlated double sampling process.
[00220] Optionally, as discussed above, the reconfiguration voltage level sampled for one compartment can be stored in a first capacitor and the signal sampled for the compartment can be stored in a second capacitor. Optionally, before sampling the reconfiguration level and signal level on the capacitors, the capacitors can be released by configuring them for the same voltage.
[00221] Figure 9B illustrates a reading sequence for performing correlated double sampling that does not require measurement of a reconfigured value for each signal value, according to some modalities. In the example in figure 9B, a single reconfigured value is measured for all compartments of the pixel. To obtain the signal for the first compartment, a reconfigured value can be subtracted from the measured signal value, as discussed above. Instead of reconfiguring the floating diffusion at that time, the charge can be transferred to the floating diffusion from the second compartment, thus adding the charge to the first and second compartments. The signal for the second compartment can be obtained by subtracting the signal for the first compartment from the aggregate signal for the first and second compartments. Since both the signal for the first compartment and the aggregate signal for the first and second compartments include the same reconfiguration noise, the result is that the reconfiguration noise is subtracted. The process can continue for the remaining compartments, with the aggregate signal for the previous compartment being subtracted from the aggregate signal for the next compartment. The aggregation of the stored load for the compartments in this way can allow the reading of larger signals that would be the case if each compartment were read individually, and can reduce the noise, since the sampled signals will be higher above the noise floor than would be the case. if each compartment was read individually. In the example with four time slots, five samples can be collected - a reset value and four samples representing the cumulative load stored in the cargo storage compartments. This process will be described in more detail with reference to figure 9B.
[00222] As illustrated in figure 9B, initially the reconfiguration transistor rt can be connected to configure the floating diffusion node fd for a reconfigured voltage ct. During the period of time in which the voltage of the floating diffusion node is reset, the transfer ports tx0-tx3 are turned off to keep the load carriers stored in their respective compartments. After the floating diffusion node fd is reconfigured the reconfigured voltage can be sampled by turning off transistor rt and turning on transistor rs to produce an output voltage cb. The reconfigured voltage represented by the output voltage cb can be stored in an analog format (for example, in a capacitor) or in a digital format (for example, by A / D conversion and storage). Then, the transfer port tx0 can be connected to allow the bin0 load to flow into the floating diffusion. The signal voltage for bin0 can be sampled by connecting transistor rs to produce an output voltage cb based on the load stored in bin0.
[00223] Then, the transfer port tx1 can be connected to allow the load from bin1 to flow into the floating diffusion. The signal voltage for bin1 + bin0 can be sampled by connecting the transistor rs to produce a source voltage cb based on the charge stored in bin1 plus the charge stored in bin0. The output signal value for bin0 can be subtracted from the output signal value for bin0 + bin1 to produce a signal indicative of the load stored in bin1.
[00224] A similar process can then be performed for bin2 and bin3 by subtracting the measured signal level for bin na from the measured signal level for bin n + 1. Accordingly, using such technique, the number of samples that may need to be collected can be reduced.
[00225] The following formulas illustrate how to calculate the "corrected" signal (using correlated double sampling) for each compartment using only a single measured reset value. corrected signal bin0 = measured signal bin0 - reconfigured level corrected signal bin1 = measured signal to (bin0 + bin1) - measured signal bin2 corrected signal = measured signal to (bin0 + bin1 + bin2) - measured signal to ( bin0 + bin1) corrected signal bin3 = signal measured for (bin0 + bin1 + bin2 + bin3) - signal measured for (bin0 + bin1 + bin2).
[00226] In some modalities, excessive sampling of the reading of a pixel can be performed. Over-sampling involves reading the same signal from the pixel a plurality of times. Each time a signal is read from the pixel, there may be slight variations in the signal that are read due to noise. Over-sampling a signal reading and averaging samples can reduce noise (for example, white noise) in measurements. In some embodiments, multiple samples can be collected (for example, from 4 to 8 samples) to read a single nominal signal value from the pixel (for example, a single reconfigured level or signal level). In some embodiments, each of the signal samples can be read by changing the reading signal and converted to digital values (for example, digital words). The average of the samples can then be calculated, and the average used as a signal measured from the pixel. For example, if 8x over-sampling is used, eight samples can be collected for each reset and signal value, for a total of 64 samples in the case of measuring 4 time compartments and 4 reset levels, or 40 samples in the case of 1 level reconfigured and 4 levels of aggregate signal. Pixel Set Reading Circuit Set Parallel Reading, Sequential Reading, and Reading with a Combination of Parallel Readings and Sequences
[00227] As discussed above, the pixel set can include a plurality of pixels arranged in rows and columns. In some modalities, reading can be done row by row. In some embodiments, a row of the pixel set can be selected, and a reading process can be performed for the selected row of pixels. The set of reading circuits for a column of pixels can be common to the pixels in the column, so that reading can be performed by the set of reading circuits for respective pixels in the column as different rows are selected. Reading to a selected row can be done in parallel (called "column parallel"), sequentially or in a combination of parallel and sequential (called "semicolumn parallel").
[00228] In order to read the pixels of a selected row in parallel to the column, the set of individual reading circuits can be provided for each column so that the pixels of each column in the selected row can be read at the same time, as illustrated in figure 10A. Figure 10A illustrates a set of pixels having a plurality of columns C1 to Cn and a plurality of rows, with a selected row Ri being illustrated by way of illustration. In the embodiment of figure 10A, each column of pixels has an associated reading circuit 905. Since each column of pixels has an associated reading circuit 905, the signals of each pixel in row Ri can be read at the same time.
[00229] In order to read the pixels of a selected row in sequence, the set of individual reading circuits does not need to be provided for each column. For example, in some embodiments, a common reading circuit can be provided, and each pixel in the selected row can be read sequentially. Figure 10B illustrates an embodiment in which a common reading circuit 905 can be provided for a plurality of columns. The common reading circuit can be selectively connected to a column by a 906 switching network under the control of the appropriate control circuitry. For example, in some embodiments, the switching network 906 can sequentially connect individual columns of pixels to the reading circuit 905.
[00230] In order to read the pixels in semicolumn parallel, a plurality of reading circuits 905 can be provided, less than the number of columns, as illustrated in figure 10C. In such a semicolumn parallel architecture, each reading circuit 905 can be shared by a subset of columns. Each reading circuit 905 can be read sequentially from a subset of columns in the set. As illustrated in figure 10C, the 905A readout circuit can be selectively connected to its respective columns by a 906A switching network. The 905B reading circuit can be selectively connected to its respective speakers via a 906B switching network.
[00231] In some embodiments, a reading circuit 905 may include one or more amplifiers to amplify a signal from one pixel and an analog to digital converter to convert the amplified signal into a digital value. Examples of 905 reading circuit configurations according to various modalities are described below. Circuit and Sampling and Retention
[00232] In some embodiments, the set of reading circuits for a column may include one or more sampling and retention circuits. Figure 10D illustrates a circuit diagram illustrating the column reading circuit set 905C, which includes the sampling and holding circuit set 907, the amplifier circuit set 901, and an analog to digital converter (A / D) 902. The sampling and retention circuit 907 can sample the output voltage of a pixel (for example, at node cb) on a capacitive element (for example, a capacitor), and then retain the voltage on the capacitor while being read by a amplifier. As discussed above, the output voltage of the pixel can represent the number of charge carriers captured during one or more time intervals.
[00233] The sampling and retention circuit can operate in a plurality of phases, called a "sampling" phase and a "retention" phase. In the "sampling" phase, the pixel voltage value can be sampled on a capacitive element. The voltage to be read is thus stored in the capacitive element. Following the "sampling" phase, the capacitor voltage is read in the "retention" phase. During the "hold" phase, the capacitor voltage can be read from the capacitive element and processed by one or more amplifiers and then converted into digital form by an analog to digital (A / D) converter. As illustrated in figure 10D, during the sampling phase (9I), switch s1 is turned on (configured in its conductive state) and switch s2 is turned off (configured in its non-conductive state), thus sampling the voltage from of the pixel reading terminal cb in a capacitive element, for example, capacitor C1. The retention phase (^ 2) follows the sampling phase. During the holding phase, switch s1 is turned off and switch s2 is turned on, thus connecting capacitor C1 to amplifier circuitry 901. By switching off switch S1, the voltage of the capacitor can be kept substantially constant as long as the voltage is read, as the amplifier circuitry 901 can have a high input impedance. The signal amplified from the amplifier circuitry 901 can be supplied to an A / D converter 902 to convert the amplified voltage into a digital value.
[00234] In some modalities, energy consumption and / or cost can be reduced by reducing or minimizing the number of circuits (for example, amplifiers, analog to digital converters) used. In some embodiments, to reduce or minimize the number of circuits in the reading stream, one or more circuits of the reading stream may be shared by more than one column of the pixel set. Multiplexing of Reading Circuit Assembly Components
[00235] In some modalities, one or more components of the set of reading circuits can be shared by two or more columns of the set of pixels. For example, as illustrated in figure 10E, all or a part of the amplifier circuitry 901, the A / D converter 902, or both, can be shared by two or more columns of the pixel set. Figure 10E illustrates an embodiment of the reading circuit set 905D where both the amplifier circuit set 901 and the A / D converter 902 are shared by two columns of the pixel set. In the embodiment of figure 10E, the respective column lines are connected to the respective pixel nodes cb1 and cb2. Each column line is connected to a respective sampling and holding circuit 907A, 907B. The amplifier circuit pack 901 and the A / D converter 902 can be shared by both speakers. The input for circuit set 901 can be multiplexed between sampling and holding circuits 907A and 907B so that its outputs are connected to amplifier circuit set 901 at different times (for example, sequentially). By using shared reading circuit components such as amplifier circuit set 901 and / or AD 902 converter, the number of components in the reading circuit set can be reduced, which can reduce the cost and / or consumption of power of the reading circuitry.
[00236] In some embodiments, the sampling and retention phases for the speakers sharing the 901 amplifier circuit set can be switched, so that when a column is in the sampling phase and not connected to the 901 amplifier circuit set, the other column is in the holding phase and its sampling and holding circuit is connected to the amplifier circuit set 901 to amplify the voltage it sampled previously. In the embodiment of figure 10F, the sampling and reading phases are alternated between the two columns, with the upper column being in the sampling phase during phase 1 and in the holding phase during phase 2, and the lower column being in the sampling during phase 2 and in the holding phase during phase 1. During phase 1 (^ 1), the signal from node cb 1 is sampled on capacitor C1 by switching on switch s1, and switch s2 is turned off, the switch s3 is turned off, and capacitor C2 is connected to amplifier 901 via switch s4, which is switched on. During phase 2 (^ 2), the signal from node cb2 is sampled on capacitor C2 by switching on switch s3, switch s4 is switched off, switch s1 is switched off, and capacitor C1 is connected to amplifier 901 via switch s2, which is connected. Sharing the 901 amplifier circuitry over more than one column can reduce the turnaround time of the 901 amplifier circuitry, as it does not need to remain inactive during a sampling phase for a column.
[00237] In some embodiments, more than two columns of the pixel set can share the set of reading circuits 901 and / or A / D converter 902. Figure 10F illustrates a mode in which n columns of the set of pixels share the set of reading circuit 901 and / or the A / D converter 902. Capacitors C1-Cn can be connected sequentially to the reading circuit set 901 in any suitable order. The sampling phase of the sampling and retention circuits for each column can be timed to occur during a period in which the sampling and retention circuit is not being read by the amplifier circuit set 901. In some embodiments, and as discussed above, the sampling phases can be timed to occur during a time interval in which the amplifier circuitry 901 is reading a different row, to limit the amount of time that the amplifier circuitry 901 remains inactive. For example, as discussed above, the voltage of node cb1 can be sampled on capacitor C1 during phase 1. During phase 2, the voltage of capacitor C1 can be read by amplifier circuitry 901 and the voltage of node cb2 can be sampled on capacitor C2. During phase 3, the voltage of capacitor C2 can be read by amplifier circuitry 901 and the voltage of a third node cb3 can be sampled on a third capacitor C3, etc. The process can then begin again with phase 1 beginning during the time when the last column (row n) was read by amplifier circuitry 901, or after the last column was read by amplifier circuitry 901. Any A suitable number of speakers can share the amplifier circuitry 901, such as 2, 4, 8, 16, 32, 64, 128, etc., or any other suitable number (which need not be a power of 2).
[00238] Figure 10G illustrates a diagram of the reading circuit set including the amplifier circuit set 901. In the embodiment of figure 10G, the amplifier circuit set 901 includes a plurality of amplifiers 910 and 911. Using a plurality of cascading amplifiers 910 and 911 it is possible to reduce energy consumption, since achieving the desired signal gain can be achieved with less energy dissipation when a plurality of amplifiers 910 and 911 is used as opposed to the use of an amplifier singular to achieve the same gain.
[00239] Figure 10H illustrates a diagram of the reading circuit set including amplifier circuit set 901 having first stage amplifiers 910A and 910B for the desired speakers and a second stage amplifier 911 that is shared by the two columns. A 912 multiplexer connects the 910A and 910B first stage amplifiers to the 911 second stage amplifier at different times. In some embodiments, amplifiers 910A, 910B and 911 may be different amplifiers.
[00240] Figure 10I illustrates a diagram of the reading circuit assembly including 910A and 910B first stage amplifiers, a 911 second stage amplifier and a 912 third stage amplifier. As discussed above, the use of an additional amplifier stage to achieve a desired gain value you can reduce energy consumption with respect to using less amplifier stages to achieve the desired gain value. In some embodiments, amplifiers 910A, 910B, 911 and 912 can be differential amplifiers.
[00241] In some modalities, the gain can be applied to the signal current in a plurality of stages. In some embodiments, the first stage amplifier (for example, 910A, 910B) may have a gain of 2 or more, the second stage amplifier (for example, 911) may have a gain of 1 to 8 or more, and the third-stage amplifier (eg 912) can have a gain of 1 to 2 or more, for an overall three-stage gain of 2 to 32 or more.
[00242] In some modalities, the amplifiers can have a digitally programmable gain. The gain of one or more stages can be changed depending on the characteristics of the light being received. For example, if more than one wavelength of the light excitation pulse (for example, laser pulse) is used and produces different pixel responses, the gain of one or more amplifiers in the reading current can be changed depending on which wavelength of light is currently being detected. If a wavelength results in fewer load carriers being produced, the gain can be increased to accommodate the reduced signal level. If another wavelength results in more load carriers being produced, the gain can be reduced. In some embodiments, read current gains for different wavelengths can be normalized with each other to produce the same output levels in response to different wavelengths. Reading Circuit Assembly Design Considerations
[00243] Since in some modalities the number of charge carriers captured for each time slot can be relatively small, for example, in the order of hundreds of charge carriers, the signal to be detected from each pixel can be relatively little. Accordingly, in some embodiments, the signal stream running from one pixel to (and including) an analog to digital converter may include a set of low-noise reading circuits. The techniques and circuits for limiting noise in the reading current will be discussed below.
[00244] In some modalities, differential signal processing can reduce or minimize noise in the reading stream. Differential signal processing can reject common-mode noise that can be injected into the reading stream. The readout circuitry may include one or more differential components, such as a differential sample and holding circuit, differential amplifiers and / or a differential A / D converter. In some embodiments, differential signal processing can be used as early as possible in the reading stream (for example, as close as possible to the pixel output), to avoid injecting common mode noise into the reading stream. In some embodiments, the entire reading current from a pixel output to a digital word can be carried out by differential circuit components. However, the techniques described here are not limited in this regard, since, in some embodiments, one or more single-ended reading circuitry components can be used.
[00245] Figure 10J illustrates the set of reading circuits shared by two columns including a sampling and differential retention circuit 908 and a differential amplifier 909. The sampling and differential retention circuit 908 includes Cin1 capacitors for a first column of the set of pixels and Cin2 capacitors for a second column of the pixel set. The differential amplifier 909 includes capacitors Cf1 for a first column of the pixel set and capacitors Cf2 for a second column of the pixel set.
[00246] Figure 10K illustrates a diagram of the differential sampling and retention circuit 908 and a differential amplifier 909 when the first column is in the sampling phase and the second column is in the holding phase, with Cin2 capacitors being connected to the amplifier input differential 909. Figure 10L illustrates a diagram of the differential sampling and retention circuit 908 and a differential amplifier 909 when the second column is in the sampling phase and the first column is in the holding phase, with Cin1 capacitors being connected to the amplifier input. differential 909.
[00247] Figure 10M illustrates the set of reading circuits shared by more than two columns including a sampling and differential retention circuit 908 and a differential amplifier 909. Figure 10M is similar to figure 10F since a differential amplifier 901 is shared for more than two columns, using a 908 differential sampling and retention circuit and a 909 differential amplifier. Dark Current Sampling
[00248] As understood by those skilled in the art, "dark current" is the current that is produced and a photodetector when no light is being detected by the photodetector. The design of a photodetector to correct the effect of dark current can improve the quality of photodetection.
[00249] In some embodiments of the integrated device described here, one or more of the cargo storage compartments can be used to sample the dark current. For example, a cargo storage compartment can sample dark current by aggregating carriers that arrive during a period of time in which no light or a very low level of light is received by the photodetector. In some modalities, such as those referring to the fluorescence lifetime measurements, the last compartment (for example, bin3) can be used to sample the dark current if the timing is such that it occurs once the probability of light emission falls for a negligible amount. The sampling of the scrubbing current may allow subtraction of the dark current from samples in other compartments, thus correcting the effect of the dark current. Number and Timing of Time Slots
[00250] Any suitable number of time slots can be used. In figures 3A and 3B, an example of a pixel with four time slots has been illustrated. Figure 8C illustrates a representation in which eight compartments are used. However, a pixel having any suitable number of time slots can be produced based on the desired temporal resolution and other factors. Increasing the number of compartments can increase the area occupied by each pixel, and can be achieved by reducing the total number of pixels or by using a manufacturing process having a smaller accessory size. The use of a small number of compartments can increase the number of pixels that can fit on a chip. In some embodiments, a single compartment can be used to determine the number of photons that arrive within a particular period of time. The number of compartments can be increased or reduced at least in part by increasing or reducing the number of extensions of the load carrier confinement region manufactured on the chip extending from the carrier travel / capture region 106. The number of electrodes b0- bm-1, transfer electrodes, etc. it can be increased or reduced according to the number of compartments to be included in a pixel.
[00251] The timing of the time compartments can be chosen in any suitable way. In some modalities, the timing can be selected by configuring the start and end moments for the time compartments, as illustrated in figure 6K. For example, the timing for bin0 can be configured by selecting the moments at which t1 and t2 occur, and the timing of the remaining compartments can be configured in a similar way.
[00252] In some modalities, the timing for the time compartments can be fixed so that the timing is the same in each measurement period. The timing can be configured based on a global timing signal. For example, a timing signal can establish the start of a measurement period, and time slots can be controlled to start and end based on a predetermined amount of time having passed from the timing signal. In the context of fluorescence lifetime measurement, the timing for the time compartments can be configured with respect to the timing of an excitation pulse based on the possible range of fluorescence lifetimes to be detected. In the context of flight time imaging, the timing of the time compartments can be configured based on an expected distance range for the scene that should be imaged. However, in some modalities, the timing of the time compartments can be variable and programmable.
[00253] In some embodiments, the timing for the time slots can be configured based on the timing of a trigger event 702 that starts a measurement period for a 720 measurement. In the context of fluorescence life measurement, the timing for time compartments it can be configured in response to the detection of the timing of an excitation pulse that excites a fluorophore. For example, when a light excitation pulse reaches pixel 100, a wave of carriers can travel from the region of photon absorption / carrier generation 102 to drain 104. The accumulation of photogenerated carriers in drain 104 in response to the pulse of excitation can cause a change in drain voltage 104. Accordingly, in some modalities the excitation pulse can be detected by detecting drain voltage 104. For example, a comparator can compare drain voltage 104 with a limit, and can produce a pulse when drain voltage 104 exceeds the limit. The pulse timing can indicate the timing of the triggering event 702 and the timing of time compartments (eg, t1, t2, etc.) can be configured based on this timing. However, the techniques described here are not limited in this regard, as any suitable technique can be used to detect the start of a 720 measurement.
[00254] In some embodiments, the integrated device can be programmable to allow the timing compartments to change. In some embodiments, the timing of the time compartments can be programmed for a particular set of measurements to be performed. For example, if the integrated device is used for a first type of test using a first set of markers having useful lives within a first range, time slots can be programmed to values suitable for discriminating the useful lives of markers within that range . However, if the integrated device is used for another type of test that uses different markers having different useful lives, the time compartments can be changed by programming them so that they correspond to the different time intervals suitable for the markers used in the second test type.
[00255] In some modalities, the timing of time compartments can be adaptively controlled between measurements based on the results of a set of measurements. For example, as illustrated in figure 11, a first set of measurements (Measurement Set A) can be performed using a first set of time slots that span a relatively large time span. The number of photons arriving at each compartment can be analyzed to determine whether a change should be made to the selected timing for the time compartments to improve or optimize the temporal information obtained. In some embodiments, the number of photons reaching each compartment can be analyzed to determine a narrower time span. For example, after taking a set of measurements with time compartments as shown in Measurement Set A of figure 11, it can be determined that a significant number of photons arrived in the time period corresponding to bin2 and no photons arrived in the time periods corresponding to other compartments. A second set of time compartments can then be selected for a second set of measurements (Measurement Set B) that focuses on the narrowest period of time corresponding to bin2 of Measurement Set A. As shown in figure 11, the Measurement Set B has four time slots within the time period corresponding to bin2 of Measurement Set A. By performing measurements with time slots according to Measurement Set B, additional details about the photon arrival timing can be obtained. For example, as illustrated in figure 11, a higher temporal resolution over the incident photon arrival timing can be achieved within a selected time interval. Such an adaptive time slot determination process can allow you to achieve a level of time resolution using a relatively small number of bays (for example, 4 bays) that might otherwise need a large number of bays (for example, 16 compartments).
[00256] In some modalities, the timing for the time compartments can be the same for all pixels in the set. In some embodiments, the timing may be different for different pixels so that the different pixels capture the carriers in different time slots. For example, a first set of pixels can capture carriers in a first set of time slots, and a second set of pixels can capture carriers in a second set of time slots that are at least partially different from the first set of time slots. time. For example, one row of pixels may have a time delay for its time slots and another row of pixels may have a different time delay for its time slots. In some embodiments, a first set of rows of pixels (for example, four rows) may have the same timing for their time slots, and another set of rows of pixels (for example, another four rows) may have a different timing for their time compartments. The pixels can be configured and / or programmed individually and / or as a group. Pixels with Subpixels Wavelength Breakdown
[00257] In some modalities, a pixel from a set of pixels may include a plurality of subpixels that are each capable of carrying out different types of measurements. Any number of subpixels can be included in a pixel.
[00258] Figure 12 illustrates an example of an 1100 pixel that includes four 100A subpixels. In some embodiments, each 100A subpixel in pixel 1100 can be configured to receive light of a different wavelength. For example, filters can be formed above subpixels 100A that allow photons of different wavelengths to be transmitted to subpixels 100A. For example, a first wavelength can be transmitted to a first subpixel 100A, a second wavelength can be transmitted to a second subpixel 100A, a third wavelength can be transmitted to a third subpixel 100A, and a fourth length of wave can be transmitted to a fourth 100A subpixel. A 1100 pixel having subpixels configured to receive light of different wavelengths can allow both temporal and spectral discrimination of incident light. In the context of fluorescent life measurement, the provision of temporal or spectral discrimination capability may allow discrimination of markers having different useful lives, different spectral characteristics, or markers having different useful lives and different spectral characteristics. Time Discrimination
[00259] In some embodiments, different subpixels 100A can be controlled to sample time slots for different time intervals. For example, a first subpixel 100A can be configured to sample a first set of time slots and a second subpixel can be configured to sample a second set of time slots. Similar structures in different subpixels 100A can sample time slots for different time intervals by controlling the timing of the load carrier segregation structure so that it is different in different subpixels. Pixel Set / Chip Architecture
[00260] Figure 13 illustrates a diagram of the chip architecture, according to some modalities. As illustrated in Figure 13, an integrated circuit or chip 1300 can include a pixel array 1302 including a plurality of pixel 100, a control circuit 1304 that includes a timing circuit 1306, voltage / current guidance generation circuits 1305 and a 1308 interface.
[00261] Pixel set 1302 includes a set of pixels 101 presented in any suitable pattern, such as a rectangular pattern, for example. Pixel set 1302 can have any suitable number of pixels. In some embodiments, the pixel set may have a 64 x 64 set of 4096 pixels 101, each including four sub-pixels 101A. However, the techniques described here are not limited to the number or arrangement of pixels and subpixels included in pixel set 1302. The pixel set may have row and / or column conductors for reading rows or columns of pixel set 1302. The pixels can be read in parallel, in series, or in a combination of both. For example, in some embodiments, a row of pixels can be read in parallel, and each row in the set of pixels can be read sequentially. However, the techniques described here are not limited in this respect, since the pixels can be read in any suitable way.
[00262] The pixel set 1302 is controlled by a control circuit 1304. The control circuit 1304 can be any suitable type of control circuit to control the operations on the 1300 chip, including the operations of the 1302 pixel set. In some The control circuit 1304 may include a microprocessor programmed to control the operations of the 1032 pixel set and any other operation on the 1300 chip. The control circuit may include a computer-readable medium (for example, memory) storing readable instructions computer (for example, code) to make the microprocessor perform such operations. For example, control circuit 1304 can control the production voltages to be applied to the electrodes of the charge carrier segregation structure at each pixel. The control circuit 1304 can change the voltages of one or more electrodes, as discussed above, to capture the carriers, transfer carriers and read the pixels in the array. The control circuit can configure the timing of the operations of the load carrier segregation structure based on a stored timing scheme. The stored timing scheme can be fixed, programmable and / or adaptive, as discussed above.
[00263] The control circuit 1304 can include a timing circuit 1306 for timing operations of the pixel load carrier segregation structures or other chip operations. In some embodiments, timing circuit 1306 may allow the production of signals to accurately control the timing of voltage changes in load carrier segregation structures to accurately time compartment load carriers. In some embodiments, the timing circuit 1306 may include an external reference clock and / or a delayed latched circuit (DLL) for the precise configuration of the timing of the signals provided to the load carrier segregation structures. In some embodiments, two single-ended delay lines can be used, each with half the number of stages aligned 180 degrees out of phase. However, any suitable technique can be used to control the timing of signals on the chip.
[00264] The 1300 chip may include an interface 1308 to send signals from the 1300 chip, receive signals on the 1300 chip, or both. The interface 1308 can allow the reading of the signals perceived by the set of pixels 1302. The reading from the chip 1300 can be performed using an analog interface and / or a digital interface. If the reading from the 1300 chip is performed using a digital interface, the 1300 chip can have one or more analog to digital converters to convert the signals read from the 1302 pixel set into digital signals. In some embodiments, the reading circuit may include a Programmable Gain Amplifier. One or more control signals can be provided to the 1300 chip from an external source via interface 1308. For example, such control signals can control the type of measurements to be performed, which may include configuring the timing of the control compartments. time.
[00265] The analysis of the signals read from the set of pixels 1302 can be performed by the set of circuits on chip or off chip. For example, in the context of fluorescence life measurement, the analysis of the photon arrival timing may include the approximation of a fluorophore fluorescence life. Any type of analysis can be performed. If the analysis of the signals read from the pixel set 1302 is performed on the chip, the chip 1300 can have any suitable processing circuit set to perform the analysis. For example, the 1300 chip may have a microprocessor to perform the analysis that is part of or separate from the 1304 control circuit. If the analysis is performed on the chip, in some embodiments the analysis result can be sent to an external device or provided otherwise off-chip via interface 1308. In some embodiments, all or part of the analysis can be performed off-chip. If the analysis is performed outside the chip, the signals read from the pixel set 1302 and / or the result of any analysis performed by the chip 1300, can be supplied to an external device via the interface 1308.
[00266] In some embodiments, the 1300 chip may include one or more of the following: 1) digitally controlled on-chip pixel orientation generators (DACs). 2) digitally programmable chip gain amplifiers that convert the single-ended pixel output voltage signal into a differential signal and apply the gain to the signal 3) digitally controlled amplifier orientation generators that allow scaling of power dissipation with the exit rate.
[00267] Figure 14A illustrates a diagram of a modality of a 1300A chip, which is an example of the 1300 chip having a set of 64 x 64 quad pixels, according to some modalities. In the embodiment of figure 14A, half of the pixel output signals are provided through the upper side of the chip and the other half of the pixel output signals are provided through the lower side of the chip. Guidance circuits are included for setting the voltage of the electrodes of the load carrier segregation structures.
[00268] Figure 14B illustrates a diagram of a modality of a 1300B chip, which is an example of a 1300 chip and includes sets of 2 x 2, with each set having a set of 256 x 64 octal pixels of quad pixels, according to with some modalities. Band space and guidance circuits are included. Digital-to-analog converters (DACs), including Vhigh DACs and Vlow DACs are included for setting high and low voltages of the pixel set electrodes. Figure 14B also illustrates the 1320 light monitoring sensors. Each light monitoring sensor can include a photodetector, such as a photodiode. In some embodiments, each light monitoring sensor may include a quad set of photodetectors (for example, photodiodes) to align the 1300B chip with a light source. In a modality in which the 1300B chip is configured to detect molecules, light monitoring sensors can allow the 1300B chip to be aligned with a waveguide that receives light from one or more locations in which the molecules are positioned. The diode reading circuits and a diode selection register are also illustrated in figure 14B.
[00269] Examples of set sizes, dimensions, number of compartments and accessory sizes are described above and illustrated in the figures merely by way of illustration, since any suitable set size, dimensions, number of compartments and accessory sizes can be used. Realization of Illustrative Integrated Circuit and Integrated Photodetector Training Method
[00270] In some embodiments, the 1300 chip can be formed on a silicon substrate using a standard CMOS (Complementary Metal Oxide Semiconductor) process. However, the techniques described here are not limited in this regard, as any suitable substrate or manufacturing process can be used.
[00271] Figures 15 to 22 illustrate a process of forming a 1300 chip, according to some modalities.
[00272] Figure 15A illustrates a perspective view of load confinement regions 103 that can be formed on a semiconductor substrate. Figure 15B shows a plan view corresponding to figure 15A. In some embodiments, the load confinement regions 103 can be formed on a semiconductor substrate of volume 1500. However, the techniques described here are not limited to the use of a semiconductor substrate of volume, since any suitable type of semiconductor substrate can be used. In some embodiments, substrate 1500 and cargo containment regions 103 can be formed from monocrystalline silicon. However, the techniques described here may not be limited in this regard, since any suitable type of semiconductor material can be used. In some embodiments, the use of a silicon substrate may allow the use of an industry-standard CMOS process. However, any suitable manufacturing process can be used. In some embodiments, a bulk silicon substrate having a p-type coating can be used. However, any suitable type of coating can be used, including a n-type coating or a p-type coating. [00273] As shown in figure 15A, the load containment regions 103 can be an elevated part of the substrate 1500. The load containment regions 103 can be formed by engraving regions of the substrate 1500 in the pattern shown in figures 15A and 15B thus leaving elevated load confinement regions 103 extending above the substrate. An insulating layer can then be formed on and to the side of the load containment regions 103. For example, in some embodiments, an insulating layer of silicon oxide can be formed in the load containment regions 103 by thermal growth. However, any suitable technique can be used to form the insulating layer, and the insulating layer can include any suitable insulating material.
[00274] As illustrated in figure 16, electrodes as illustrated in figure 3B can be formed through the insulating layer by forming a standardized polysilicon layer 1601. The electrodes can be spaced from each other to allow different electrodes to be at different voltages. The electrodes can be formed from any suitable conductive material. In some embodiments, the electrodes can be formed of coated polysilicon. However, the techniques described here are not limited to the formation of polysilicon electrodes, since any suitable conductive material can be used to form the electrodes (for example, a metal). Conductive paths 1701 can be formed through the standard polysilicon layer 1601 to contact the polysilicon layer 1601 through an insulating layer (not shown) superimposed on the standard polysilicon layer 1601. Conductive paths 1701 can be formed from any suitable conductor.
[00275] In some embodiments, one or more electrodes (for example, from the polysilicon layer 1601) can be coated and divided electrodes having both p and n type coatings. A coated and divided electrode can allow the formation of a potential well to capture a carrier, as illustrated in figure 17. Figure 17 illustrates a coated and divided electrode 2302 having a p + region and an n + region. The n + region and the p + region produce different potential levels in the underlying semiconductor. As illustrated in figure 17, the n + region of the coated and divided electrode 2302 can produce a potential well under the n + region that can confine charge carriers (for example, electrons). Figure 17 illustrates that maintaining the voltage of the 2302 high coated and split electrode can produce a potential gradient as illustrated by dashed lines, which can confine charge carriers (for example, electrons) in a 2304 potential well. of the voltage of the coated and divided element 2302 can raise the electrical potential under the coated and divided electrode 2302 to allow the transfer of charge trapped in the potential well 2304 to a charge storage compartment, for example.
[00276] The coatings can be formed in the semiconductor material to allow the formation of transistors of the reading circuit set 110. In some embodiments, a mask can be arranged over the load confinement region 103 to avoid coating the confinement region load 103 during the formation of the transistors of the reading circuit set 110, since the load confinement region 103 can form unwanted potential wells in the load confinement regions 103.
[00277] Figure 18 illustrates the formation of a metallic layer 1801 (for example, metal 1) through the standardized polysilicon layer 1601 to connect to tracks 1701. Figure 19 illustrates the metallic layer 1801 superimposed on the polysilicon layer 1601 and regions load containment system 103.
[00278] Figure 20 illustrates the formation of pathways 1901 to contact metallic layer 1801. The conductive pathways 1901 can be formed through metallic layer 1801 to contact metallic layer 1801 through an insulating layer (not shown) overlapping the metallic layer 1801. Figure 20 also illustrates the formation of a second metallic layer 2001 (for example, metal 2) through metallic layer 1801 and tracks 1901.
[00279] Figure 21 illustrates the second metallic layer 2001 in addition to the formation of paths 2101 through the metallic layer 2001 to contact the metallic layer 2001 through an insulating layer (not shown) overlapping the metallic layer 2001.
[00280] Figure 22 illustrates the formation of a third metallic layer 2201 (for example, metal 3) through metallic layer 2001 and tracks 2101 to contact tracks 2101.
[00281] The above process is described by way of illustration, since the techniques described here are not limited to any particular manufacturing process. In addition, the techniques described here are not limited to the particular illustrated presentation. Set of Drive Circuits for Load Carrier Segregation Structure
[00282] The electrodes of the charge carrier segregation structure that overlap the substrate may have a substantial parasitic capacitance. Changing the voltage at the electrodes requires charging or discharging the parasitic capacitance. The speed with which the current can be supplied to charge or discharge the parasitic capacitance limits the speed at which the voltage of an electrode can be changed. As discussed above, in some modalities, charge carriers can be captured and transferred into time compartments with resolution of nanoseconds or picoseconds. The inventors recognized and appreciated that the timing with which charge carriers can be captured can be more accurate if the voltage of the b0-bm-1 electrodes changes too quickly, thereby raising potential protections at precise times. However, the rate of change in voltage at the b0-bm-1 electrodes is limited due to the parasitic inductance and equivalent series resistance (ESR) of the connection between the voltage supply and the b0-bm-1 electrodes.
[00283] Additionally, the charging and discharging of the parasitic capacitances of the electrodes can consume a significant amount of energy. The energy dissipated by charging and discharging an electrode is Pdiss = (1/2) √ * C »V2, where C is the capacitance between the electrode and the substrate, V is the voltage difference between the electrode and the substrate, ef is the frequency with which the voltage is switched.
[00284] Figure 23 illustrates an example of a driving circuit 2300 to drive an electrode 2301 of the load carrier segregation structure, according to some modalities. Electrode 2301 is illustrated as a capacitor in figure 23. As discussed above, electrode 2301 can be switched to a relatively low voltage Vlow and a relatively high voltage Vhigh at selected times. The driver circuit 2300 includes a VdacH 2302 generator that produces the high Vhigh voltage and a VdacL 2304 generator that produces the low Vlow voltage. In some modalities, the difference between Vlow and Vhigh can be made as small as possible for the electrode to influence charge carriers in the designed way, thus reducing or minimizing energy dissipation. In some embodiments, the VdacH 2302 generator and / or VdacL 2304 generator can be programmable voltage generators that can produce the desired Vlow and / or Vhigh voltages, and can allow for the change of Vlow and / or Vhigh.
[00285] The drive circuit 2300 also includes the generator Bclk 2306, which can produce a timing signal to time the voltage transitions of electrode 2301. The generator Bclk 2306 can be programmable, and can allow digital selection when the edges of the timing signal occur, based on a registered digital word. In some embodiments, the Bclk 2306 generator can be implemented using a delayed circuit (DLL), as discussed above. The timing signal from the generator Bclk 2306 is supplied to the input of the driver Bclk 2312 that drives the electrode 2301.
[00286] The drive circuit 2300 also includes a VdacH 2308 amplifier and a VdacL 2310 amplifier. The VdacH 2308 amplifier receives a signal from the VdacH generator and controls transistor 2314 using the feedback to supply the VdacH voltage to the high supply terminal. Bclk 2312 trigger power. The VdacH 2308 amplifier also charges the 1312A capacitor to the VdacH voltage. The VdacL 2310 amplifier receives a signal from the VdacL generator and controls transistor 2316 using the feedback to supply the VdacL voltage to the low power supply terminal of the Bclk 2312 driver. The VdacL 2310 amplifier also charges the 1312B capacitor to the VdacL voltage.
[00287] As discussed above, electrode 2301 can have substantial capacitance. To supply sufficient current to charge the 2301 electrode at high speed, decoupling capacitors 1312A and 1312B can be provided to supply current to the Bclk 2312 actuator's low power supply terminal or Bclk 2312 actuator's high power supply terminal during transitions.
[00288] Decoupling capacitors can be positioned in close proximity to the electrode to limit parasitic inductance and equivalent series resistance (ESR) between the electrode and the decoupling capacitor. When the voltage of an electrode is changed to a new voltage, the electrode is connected to the decoupling capacitor at the new voltage to supply current to the electrode through a current path having low parasitic inductance and / or equivalent series resistance (ESR) , so that the electrode voltage can be changed quickly. In some embodiments, the decoupling capacitor can be positioned close enough to the electrode so that the parasitic inductance between the decoupling capacitor and the electrode is less than 3nH, less than 2 nH, or less than 1nH. In some embodiments, the equivalent series resistance (ESR) of the current path between the decoupling capacitor and the electrode is less than 70 ohms, less than 35 ohms, or less than 5 ohms. However, these values are provided by way of example only, since the techniques described here are not limited to specific values of inductance and resistance.
[00289] In some modalities, the b0-bm-1 electrodes can be connected to one or more decoupling capacitors. In some embodiments, each b0-bm-1 electrode may have its own decoupling capacitor. For example, in some embodiments, an electrode may have a single decoupling capacitor coupled between the high and low voltage supplies of the electrode, or two decoupling capacitors coupled respectively to the high voltage supply and the low voltage supply. However, the techniques described here are not limited in this regard. Any or all of the electrodes of the charge carrier segregation structure can be connected to the decoupling capacitors.
[00290] Decoupling capacitors can have any suitable capacitance value. In some embodiments, the capacitance value of a decoupling capacitor is ten to one hundred times the capacitance of the electrode to which it is connected. In some embodiments, the capacitance of a decoupling capacitor can be at least 150 pF, at least 300 pF, or at least 3 nF or more. However, these values are provided merely by way of example, since the techniques described here are not limited to specific capacitance values.
[00291] A decoupling capacitor can be on-chip or off-chip. Figure 24 illustrates a modality in which chip 1300 is affixed to a printed circuit board 1310, which can be called a "panel chip" or "panel matrix" implementation. Wired connections can connect the 1300 chip to one or more decoupling capacitors 1312 on the printed circuit board 1310, thus providing a current path having low parasitic inductance and / or equivalent series resistance (ESR) between a chip electrode 1300 and a 1312 decoupling capacitor. In some embodiments, off-chip decoupling capacitors can be positioned 1 cm, or 5 mm from the 1300 chip or less. However, the techniques described here are not limited in this regard. As mentioned above, decoupling capacitors can be formed on the 1300 chip.
[00292] As discussed above, the charging and discharging of electrodes from the charge carrier segregation structure can dissipate significant energy. In some embodiments, one or more rows of pixels on the 1300 chip and their corresponding electrodes can be deactivated, which can limit the power consumption of the 1300 chip. The 1300 chip can be programmable in this regard, and can allow you to select which rows will be enabled or disabled. The rows that will be activated and deactivated can be changed over time.
[00293] Figure 25 illustrates the activation of 32 rows in a central region of the chip and the deactivation of 48 rows at the edges of the chip. Deactivating one or more rows of chips can allow you to reduce power consumption in situations or applications where not all rows of the chip are required. Additional Aspects
[00294] In some modalities, the techniques described can be performed using one or more devices. The modalities are not limited to operation with any particular type of computing device.
[00295] Figure 26 is a block diagram of an illustrative computing device 1000 that can be used to implement a control circuit to control the set of pixels or to perform data analysis from the pixels. Computing device 1000 may include one or more processors 1001 and one or more non-transitory and tangible computer-readable storage media (e.g., memory 1003). Memory 1003 can store, in a non-transitory and tangible computer-writable medium, computer program instructions that, when executed, implement any of the functionality described above. Processors 1001 can be coupled to memory 1003 and can execute such computer program instructions to make functionality work.
[00296] The computing device 1000 may also include a network input / output (I / O) interface 1005 through which the computing device can communicate with other computing devices (for example, over a network), and it can also include one or more I / O interfaces 1007, through which the computing device can output to and receive input from a user. I / O user interfaces can include devices such as a keyboard, mouse, microphone, a display device (for example, a monitor or touch screen), speakers, a camera, and / or various other types of I / O devices O.
[00297] The modalities described above can be implemented in any one of several ways. For example, the modalities can be implemented using hardware, software, or a combination of them. When implemented in software, the software code can be run on any suitable processor (for example, a microprocessor) or collection of processors, whether provided in a single computing device or distributed among multiple computing devices. It should be appreciated that any component or collection of components that performs the functions described above can generally be considered as one or more controllers that control the functions discussed above. One or more controllers can be implemented in several ways, such as dedicated hardware, or with general purpose hardware (for example, one or more processors) that is programmed using the microcode or software to perform the functions mentioned above.
[00298] In this regard, it should be appreciated that an implementation of the modalities described here comprises at least one computer-readable storage medium (for example, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, disks digital versatile (DVD) or other optical disk storage, magnetic tapes, magnetic disk storage or other magnetic storage devices, or other non-transitory, tangible, computer-readable storage medium encoded with a computer program (that is, a plurality of executable instructions) that, when executed on one or more processors, perform the functions discussed above in one or more modalities. The computer-readable medium can be transported so that the program stored therein can be loaded onto any computing device to implement aspects of the techniques discussed here. Additionally, it should be appreciated that the reference to a computer program that, when executed, performs any of the functions discussed above, is not limited to an application program running on a host computer. Instead, the terms computer program and software are used here in a generic sense to refer to any type of computer code (for example, application software, firmware, microcode or any other form of computer instruction) that may be employed to program one or more processors to implement aspects of the techniques discussed here.
[00299] Various aspects of the present invention can be used alone, in combination, or in a variety of provisions not specifically discussed in the modalities described above and are therefore not limited in that application to the details and provisions of the components presented in the description above or illustrated in the drawings. For example, aspects described in one modality can be combined in any way with aspects described in other modalities.
[00300] In addition, the invention can be embodied as a method, of which an example has been provided. The acts performed as part of the method can be ordered in any appropriate way. Accordingly, the modalities can be constructed in which the acts are performed in a different order from that illustrated, which may include the performance of some acts simultaneously, despite being illustrated as sequential acts in the illustrative modalities.
[00301] The use of ordinal terms such as "first", "second", "third", etc., in claims to modify one claim element alone does not connote any property, precedence, or order of one claim element over another or temporal order in which the acts of a method are performed, but are used merely as labels to distinguish an element of claim having a particular name from another element having the same name (but, for use of the term ordinal) to distinguish elements of claim.
[00302] In addition, the phraseology and terminology used here serve the purpose of description and should not be considered limiting. The use of "including", "comprising", or "possessing", "containing", "involving" and its variations, should encompass the items listed later and their equivalents as additional items.

权利要求:
Claims (24)
[0001]
1. Integrated circuit (1300) characterized by the fact that it comprises: a photodetection region (102A) configured to receive incident photons, the photodetection region (102A) being configured to produce a plurality of charge carriers in response to incident photons; at least one cargo carrier storage region (108); a load carrier segregation structure configured to selectively target load carriers from the plurality of load carriers to at least one load carrier storage region (108) based on the times at which load carriers are produced; a control circuit (1304) configured to control the load carrier segregation structure to perform a measurement, the measurement comprising: - a load carrier capture phase in which the load carrier segregation structure forms at least one potential protection; and - after the charge carrier capture phase, a charge carrier transfer phase in which a charge carrier, if captured during the charge carrier capture phase, is transferred to at least one carrier storage region loading (108).
[0002]
2. Integrated circuit (1300), according to claim 1, characterized in that the control circuit (1304) is configured to control the load carrier segregation structure to measure a plurality of moments to add carrier of loads in at least one load carrier storage region (108).
[0003]
3. Integrated circuit (1300), according to claim 2, characterized by the fact that the plurality of moments is at least a thousand moments.
[0004]
4. Integrated circuit (1300), according to claim 3, characterized by the fact that the plurality of moments is at least one million moments.
[0005]
5. Integrated circuit (1300), according to claim 4, characterized by the fact that the plurality of measurements is performed in less than 50 milliseconds.
[0006]
6. Integrated circuit (1300), according to claim 5, characterized by the fact that the plurality of measurements is performed in more than one millisecond.
[0007]
7. Integrated circuit (1300), according to claim 1, characterized in that the control circuit (1304) is configured to perform the measurement based on a timing of an excitation light pulse.
[0008]
8. Integrated circuit (1300), according to claim 7, characterized in that the control circuit (1304) is configured to control the charge carrier segregation structure to discard the charge carriers produced in response to the photons of the excitation light pulse.
[0009]
Integrated circuit (1300) according to claim 8, characterized in that the excitation light pulse is a first excitation light pulse, in which at least one load-bearing storage region (108) comprises a plurality of cargo carrier storage regions, and wherein the cargo carrier segregation structure is configured to direct cargo carriers to respective cargo carrier storage regions of the plurality of cargo carrier storage regions based on the moments at which load carriers are produced, where the measurement is a first measurement, the load carrier capture phase is a first load carrier capture phase, and the load carrier transfer phase is a first load carrier transfer phase, in which the first load carrier transfer phase transfers a carrier captured in the first load carrier capture phase for a corresponding first storage region among the plurality of load carrier storage regions, wherein the control circuit (1304) is configured to control the load carrier segregation structure to perform a second measurement, the second measurement comprising : a second load carrier capture phase in which the load carrier segregation structure forms at least a second potential protection; and after the second charge carrier capture phase, a second charge carrier transfer phase in which a charge carrier is transferred to at least one charge carrier storage region (108); wherein the second charge carrier transfer phase transfers a carrier captured in the second charge carrier capture phase to a corresponding second storage region among the plurality of charge carrier storage regions, where the control circuit ( 1304) is configured to perform the second measurement based on a timing of a second excitation light pulse.
[0010]
10. Integrated circuit (1300), according to claim 9, characterized in that the control circuit (1304) is configured to control the load carrier segregation structure to perform each of the first and second measurements a plurality of moments to add cargo carriers to the plurality of cargo carrier storage regions.
[0011]
11. Integrated circuit (1300), according to claim 10, characterized by the fact that the control circuit (1304) is configured to switch between the control of the load carrier segregation structure to perform the first measurement and the control of the load carrier segregation structure to perform the second measurement.
[0012]
12. Integrated circuit (1300), according to claim 10, characterized by the fact that the plurality of moments is at least a thousand moments.
[0013]
13. Integrated circuit (1300), according to claim 2, characterized by the fact that it comprises: a reading circuit configured to read a signal from at least one load carrier storage region (108), in which the control circuit (1304) is configured to control the reading circuit to read a signal from at least one load carrier storage region (108) after performing the measurement a plurality of moments.
[0014]
14. Integrated circuit (1300) according to claim 13, characterized in that the at least one load carrier storage region (108) comprises a plurality of load carrier storage regions, and in which the structure load carrier segregation is configured to target load carriers to the respective load carrier storage regions within the plurality of load carrier storage regions based on the times at which load carriers are produced, and the control circuit (1304) is configured to control the reading circuit to read signals from the plurality of charge carrier storage regions after the measurement has taken a plurality of moments.
[0015]
15. Integrated circuit (1300), according to claim 1, characterized in that the control circuit (1304) is configured to control the load carrier segregation structure to change a timing, duration and / or number of compartments corresponding to at least one load carrier storage region (108).
[0016]
16. Integrated circuit (1300) according to claim 15, characterized in that at least one load carrier storage region (108) comprises a plurality of load carrier storage regions, and in which the load structure load carrier segregation is configured to direct load carriers to respective load carrier storage regions among the plurality of load carrier storage regions based on the times at which load carriers are produced, in which the circuit control (1304) is configured to control the load carrier segregation structure so that the plurality of load carrier storage regions corresponds to a first plurality of time slots during a first plurality of measurements and the plurality of regions load carrier storage corresponding to a second plurality of time slots during a second plurality of measurements.
[0017]
17. Integrated circuit (1300) according to claim 16, characterized in that the second plurality of measurements takes place after the first plurality of measurements and the second plurality of time compartments has a higher time resolution than that of the first plurality of time compartments.
[0018]
18. Integrated circuit (1300), according to claim 16, characterized by the fact that the control circuit (1304) is configured to analyze a number of load carriers collected during the first plurality of measurements and to configure a timing of the second plurality of time compartments based on the amount of cargo holders collected.
[0019]
19. Photodetection method, characterized by the fact that it comprises: (A) the receipt of incident photons; and (B) the selective targeting of charge carriers from a plurality of charge carriers produced in response to incident photons to at least one charge carrier storage region (108) based on the times at which charge carriers are produced ; wherein the at least one cargo carrier storage region (108) comprises a plurality of cargo carrier storage regions, and the selective targeting of cargo carriers comprises selectively targeting cargo carriers to the carrier storage regions respective cargo carriers among the plurality of cargo carrier storage regions, where (B) comprises capturing cargo carriers in a cargo carrier route region, and where the capture of cargo carriers comprises changing a voltage of at least one electrode overlapping the load carrier travel region.
[0020]
20. Photodetection method according to claim 19, characterized in that (B) it also comprises changing the voltage of at least one charge transfer electrode to transfer a captured charge carrier to charge carrier storage regions .
[0021]
21. Photodetection method, according to claim 20, characterized by the fact that it also comprises the reading of signals from the plurality of load carrier storage regions.
[0022]
22. Photodetection method, according to claim 19, characterized by the fact that (B) is performed through a plurality of measurements, the individual measurements among the plurality of measurements comprising: the change in the electrode voltages overlapping the path region cargo carrier; and changing the voltage of at least one charge transfer electrode to transfer any captured charge carrier to a charge carrier storage region (108) among the plurality of charge carrier storage regions, wherein the method comprises still reading signals from the plurality of load carrier storage regions after the plurality of measurements.
[0023]
23. Photodetection method according to claim 22, characterized in that the plurality of measurements comprises at least a thousand measurements.
[0024]
24. Photodetection method according to claim 23, characterized in that the plurality of measurements comprises at least one million measurements.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112017002485B1|2020-12-01|integrated circuit and photodetection method

---

BR112019012540A2|2019-11-12|direct-pack pixel integrated photodetector

---

TWI734748B|2021-08-01|Sensor and device for lifetime imaging and detection applications

---

US20190391010A1|2019-12-26|Integrated photodetector with charge storage bin of varied detection time

---

TW202137577A|2021-10-01|Pixel with enhanced drain

---

TW202139919A|2021-11-01|Sensor and device for lifetime imaging and detection applications

同族专利:

---

公开号 | 公开日

---

US20160377543A1|2016-12-29|

---

BR112017002485A2|2017-12-05|

---

EP3194935B1|2018-10-31|

---

JP6707520B2|2020-06-10|

---

JP2017531356A|2017-10-19|

---

WO2016022998A2|2016-02-11|

---

JP6935541B2|2021-09-15|

---

AU2015300766B2|2021-02-04|

---

US9945779B2|2018-04-17|

---

AU2015300766A1|2017-03-16|

---

US20210025823A1|2021-01-28|

---

WO2016022998A3|2016-04-14|

---

CA2957540A1|2016-02-11|

---

US20180259456A1|2018-09-13|

---

CN107112333B|2020-07-10|

---

CN111710687A|2020-09-25|

---

US10775305B2|2020-09-15|

---

CN107112333A|2017-08-29|

---

US20160133668A1|2016-05-12|

---

US20170322153A1|2017-11-09|

---

MX2017001806A|2018-01-30|

---

JP2020162127A|2020-10-01|

---

EP3471402A1|2019-04-17|

---

US11209363B2|2021-12-28|

---

AU2021202729A1|2021-05-27|

---

US9606058B2|2017-03-28|

---

US9696258B2|2017-07-04|

---

US9759658B2|2017-09-12|

---

KR20170042663A|2017-04-19|

---

US20160380025A1|2016-12-29|

---

EP3194935A2|2017-07-26|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US5198543A|1989-03-24|1993-03-30|Consejo Superior Investigaciones Cientificas|PHI29 DNA polymerase|

---

US5302509A|1989-08-14|1994-04-12|Beckman Instruments, Inc.|Method for sequencing polynucleotides|

---

CA2044616A1|1989-10-26|1991-04-27|Pepi Ross|Dna sequencing|

---

US5355165A|1992-08-06|1994-10-11|Princeton Scientific Instruments, Inc.|Very high frame rate CCD imager|

---

EP0682671A4|1993-02-01|1998-01-14|Seq Ltd|Methods and apparatus for dna sequencing.|

---

US5471515A|1994-01-28|1995-11-28|California Institute Of Technology|Active pixel sensor with intra-pixel charge transfer|

---

US6570617B2|1994-01-28|2003-05-27|California Institute Of Technology|CMOS active pixel sensor type imaging system on a chip|

---

JPH10501616A|1994-05-27|1998-02-10|ノバルティスアクチエンゲゼルシャフト|Method for detecting decay-excited luminescence.|

---

US5912155A|1994-09-30|1999-06-15|Life Technologies, Inc.|Cloned DNA polymerases from Thermotoga neapolitana|

---

US5814565A|1995-02-23|1998-09-29|University Of Utah Research Foundation|Integrated optic waveguide immunosensor|

---

US6261797B1|1996-01-29|2001-07-17|Stratagene|Primer-mediated polynucleotide synthesis and manipulation techniques|

---

US5990506A|1996-03-20|1999-11-23|California Institute Of Technology|Active pixel sensors with substantially planarized color filtering elements|

---

WO1998022799A2|1996-11-18|1998-05-28|Novartis Ag|Measurement device and its use|

---

EP1009802B1|1997-02-12|2004-08-11|Eugene Y. Chan|Methods for analyzimg polymers|

---

WO1998040496A1|1997-03-12|1998-09-17|The Perkin-Elmer Corporation|Dna polymerases having improved labeled nucleotide incorporation properties|

---

US6327410B1|1997-03-14|2001-12-04|The Trustees Of Tufts College|Target analyte sensors utilizing Microspheres|

---

DE19748211A1|1997-10-31|1999-05-06|Zeiss Carl Fa|Optical array system and reader for microtiter plates|

---

EP0921196A1|1997-12-02|1999-06-09|Roche Diagnostics GmbH|Modified DNA-polymerase from carboxydothermus hydrogenoformans and its use for coupled reverse transcription and polymerase chain reaction|

---

DE19810879A1|1998-03-13|1999-09-16|Roche Diagnostics Gmbh|New chimeric polymerase with 5'-3'-polymerase activity, and optionally proofreading activity, used for polymerase chain reactions and sequencing|

---

WO1999049082A2|1998-03-23|1999-09-30|Invitrogen Corporation|Modified nucleotides and methods useful for nucleic acid sequencing|

---

JP3813818B2|1998-05-01|2006-08-23|アリゾナボードオブリージェンツ|Method for determining the nucleotide sequence of oligonucleotides and DNA molecules|

---

US7875440B2|1998-05-01|2011-01-25|Arizona Board Of Regents|Method of determining the nucleotide sequence of oligonucleotides and DNA molecules|

---

GB9810350D0|1998-05-14|1998-07-15|Ciba Geigy Ag|Organic compounds|

---

US6787308B2|1998-07-30|2004-09-07|Solexa Ltd.|Arrayed biomolecules and their use in sequencing|

---

US6716394B2|1998-08-11|2004-04-06|Caliper Technologies Corp.|DNA sequencing using multiple fluorescent labels being distinguishable by their decay times|

---

US6210896B1|1998-08-13|2001-04-03|Us Genomics|Molecular motors|

---

US6280939B1|1998-09-01|2001-08-28|Veeco Instruments, Inc.|Method and apparatus for DNA sequencing using a local sensitive force detector|

---

JP4326050B2|1998-09-22|2009-09-02|ハイスペック合資会社|High-speed image sensor|

---

JP4638043B2|1998-12-14|2011-02-23|パシフィックバイオサイエンシーズオブカリフォルニア，インコーポレイテッド|Systems and methods for sequencing single molecule nucleic acids by polymerase synthesis|

---

US6445491B2|1999-01-29|2002-09-03|Irma America, Inc.|Method and apparatus for optical sectioning and imaging using time-gated parametric image amplification|

---

JP2002537858A|1999-03-10|2002-11-12|エーエスエムサイエンティフィック，インコーポレイテッド|Methods for direct sequencing of nucleic acids|

---

US7056661B2|1999-05-19|2006-06-06|Cornell Research Foundation, Inc.|Method for sequencing nucleic acid molecules|

---

EP1681357A3|1999-05-19|2006-07-26|Cornell Research Foundation, Inc.|Method for sequencing nucleic acidmolecules|

---

US6137117A|1999-06-21|2000-10-24|The United States Of America As Represented By The Secretary Of The Navy|Integrating multi-waveguide sensor|

---

CN2433618Y|1999-10-29|2001-06-06|中国科学院上海原子核研究所|Gene chip detecting device|

---

US6825921B1|1999-11-10|2004-11-30|Molecular Devices Corporation|Multi-mode light detection system|

---

US6399335B1|1999-11-16|2002-06-04|Advanced Research And Technology Institute, Inc.|γ-phosphoester nucleoside triphosphates|

---

JP4433347B2|2000-01-17|2010-03-17|富士フイルム株式会社|Fluorescence imaging device|

---

JP2003532123A|2000-04-28|2003-10-28|エッジライトバイオサイエンシズインコーポレイテッド|Microarray evanescent wave fluorescence detector|

---

JP2004516810A|2000-06-07|2004-06-10|リ−コールインコーポレーティッド|Charge switch nucleotide|

---

US6936702B2|2000-06-07|2005-08-30|Li-Cor, Inc.|Charge-switch nucleotides|

---

US6975898B2|2000-06-19|2005-12-13|University Of Washington|Medical imaging, diagnosis, and therapy using a scanning single optical fiber system|

---

WO2002001194A1|2000-06-25|2002-01-03|Affymetrix, Inc.|Optically active substrates|

---

FR2813121A1|2000-08-21|2002-02-22|Claude Weisbuch|PERFECTED DEVICE FOR SUPPORTING CHROMOPHORIC ELEMENTS|

---

EP1320596A4|2000-08-30|2005-01-12|Univ Rochester|Method of performing reverse transcription reaction using reverse transcriptase encoded by non-ltr retrotransposable element|

---

US20020031836A1|2000-09-11|2002-03-14|Feldstein Mark J.|Fluidics system|

---

EP1207387A1|2000-11-20|2002-05-22|Institut Curie|Multi-photon imaging installation.|

---

WO2002086088A2|2001-04-24|2002-10-31|Li-Cor, Inc.|Polymerases with charge-switch activity and methods of generating such polymerases|

---

US7256019B2|2001-08-29|2007-08-14|Ge Healthcare Bio-Sciences Corp.|Terminal phosphate blocked nucleoside polyphosphates|

---

US7052839B2|2001-08-29|2006-05-30|Amersham Biosciences Corp|Terminal-phosphate-labeled nucleotides and methods of use|

---

US7244566B2|2001-08-29|2007-07-17|Ge Healthcare Bio-Sciences Corp.|Analyte detection|

---

AT458067T|2001-08-29|2010-03-15|Ge Healthcare Bio Sciences|LABELED NUCLEOSIDE POLYPHOSPHATES|

---

US7223541B2|2001-08-29|2007-05-29|Ge Healthcare Bio-Sciences Corp.|Terminal-phosphate-labeled nucleotides and methods of use|

---

US7727722B2|2001-08-29|2010-06-01|General Electric Company|Ligation amplification|

---

US7033762B2|2001-08-29|2006-04-25|Amersham Biosciences Corp|Single nucleotide amplification and detection by polymerase|

---

JP2005508630A|2001-09-14|2005-04-07|インヴィトロジェンコーポレーション|DNA polymerase and its variants|

---

US6917726B2|2001-09-27|2005-07-12|Cornell Research Foundation, Inc.|Zero-mode clad waveguides for performing spectroscopy with confined effective observation volumes|

---

US7057026B2|2001-12-04|2006-06-06|Solexa Limited|Labelled nucleotides|

---

GB2382648B|2001-12-11|2003-11-12|Amersham Pharm Biotech Uk Ltd|System and method for time correlated multi-photon counting measurements|

---

CN1138862C|2002-01-28|2004-02-18|国前|Collector for nucleic acid analysis and its application method|

---

US7179654B2|2002-03-18|2007-02-20|Agilent Technologies, Inc.|Biochemical assay with programmable array detection|

---

US6924887B2|2002-03-27|2005-08-02|Sarnoff Corporation|Method and apparatus for generating charge from a light pulse|

---

US8238993B2|2002-04-04|2012-08-07|Veralight, Inc.|Determination of a measure of a glycation end-product or disease state using tissue fluorescence lifetime|

---

US7595883B1|2002-09-16|2009-09-29|The Board Of Trustees Of The Leland Stanford Junior University|Biological analysis arrangement and approach therefor|

---

US20040106163A1|2002-11-12|2004-06-03|Workman Jerome James|Non-invasive measurement of analytes|

---

WO2004047353A2|2002-11-19|2004-06-03|Safetzone Technologies Corporation|Guest communication system and method|

---

US20040144927A1|2003-01-28|2004-07-29|Auner Gregory W.|Microsystems arrays for digital radiation imaging and signal processing and method for making microsystem arrays|

---

US7393640B2|2003-02-05|2008-07-01|Ge Healthcare Bio-Sciences Corp.|Terminal-phosphate-labeled nucleotides with new linkers|

---

WO2004092331A2|2003-04-08|2004-10-28|Li-Cor, Inc.|Composition and method for nucleic acid sequencing|

---

WO2005073407A1|2003-10-07|2005-08-11|Ut-Battelle, Llc|Advanced integrated circuit biochip|

---

DE10348949A1|2003-10-18|2005-05-19|Bayer Healthcare Ag|Quantitative determination of molecular modifications, e.g. in high throughput screening, comprises labeling molecules with fluorescent dye, change in lifetime of fluorescence with modification being measured|

---

JP2007509317A|2003-10-18|2007-04-12|バイエル・ヘルスケア・アクチェンゲゼルシャフト|Direct observation of molecular modifications by measuring fluorescence lifetime in biological test systems|

---

US7169560B2|2003-11-12|2007-01-30|Helicos Biosciences Corporation|Short cycle methods for sequencing polynucleotides|

---

US20070281288A1|2004-01-27|2007-12-06|Shimshon Belkin|Method and System for Detecting Analytes|

---

DE602005020421D1|2004-02-19|2010-05-20|Helicos Biosciences Corp|METHOD FOR THE ANALYSIS OF POLYNUCLEOTIDE SEQUENCES|

---

US20060019265A1|2004-04-30|2006-01-26|Kimberly-Clark Worldwide, Inc.|Transmission-based luminescent detection systems|

---

US7462452B2|2004-04-30|2008-12-09|Pacific Biosciences Of California, Inc.|Field-switch sequencing|

---

EP1622200A1|2004-07-26|2006-02-01|CSEM Centre Suisse d'Electronique et de Microtechnique SA|Solid-state photodetector pixel and photodetecting method|

---

US7302146B2|2004-09-17|2007-11-27|Pacific Biosciences Of California, Inc.|Apparatus and method for analysis of molecules|

---

US7170050B2|2004-09-17|2007-01-30|Pacific Biosciences Of California, Inc.|Apparatus and methods for optical analysis of molecules|

---

US7345764B2|2005-02-07|2008-03-18|Vladimir Bulovic|Apparatus and method for a slim format spectrometer|

---

US20060223067A1|2005-03-31|2006-10-05|Paolo Vatta|Mutant DNA polymerases and methods of use|

---

US7365299B2|2005-05-09|2008-04-29|Sensors Unlimited, Inc.|Method and apparatus for providing flexible photodetector binning|

---

US7738086B2|2005-05-09|2010-06-15|The Trustees Of Columbia University In The City Of New York|Active CMOS biosensor chip for fluorescent-based detection|

---

US7645866B2|2005-06-28|2010-01-12|Life Technologies Corporation|Methods of producing and sequencing modified polynucleotides|

---

WO2007026252A2|2005-07-01|2007-03-08|Dako Denmark A/S|In situ hybridization detection method|

---

US7426322B2|2005-07-20|2008-09-16|Searete Llc.|Plasmon photocatalysis|

---

US7405281B2|2005-09-29|2008-07-29|Pacific Biosciences Of California, Inc.|Fluorescent nucleotide analogs and uses therefor|

---

WO2007070572A2|2005-12-12|2007-06-21|The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services|Probe for nucleic acid sequencing and methods of use|

---

CN101365807A|2005-12-22|2009-02-11|加利福尼亚太平洋生物科学股份有限公司|Polymerases for nucleotide analogue incorporation|

---

AT518010T|2005-12-22|2011-08-15|Pacific Biosciences California|ACTIVE SURFACE COATED POLYMERASES|

---

US7668697B2|2006-02-06|2010-02-23|Andrei Volkov|Method for analyzing dynamic detectable events at the single molecule level|

---

US7995202B2|2006-02-13|2011-08-09|Pacific Biosciences Of California, Inc.|Methods and systems for simultaneous real-time monitoring of optical signals from multiple sources|

---

US7715001B2|2006-02-13|2010-05-11|Pacific Biosciences Of California, Inc.|Methods and systems for simultaneous real-time monitoring of optical signals from multiple sources|

---

US7692783B2|2006-02-13|2010-04-06|Pacific Biosciences Of California|Methods and systems for simultaneous real-time monitoring of optical signals from multiple sources|

---

US20080050747A1|2006-03-30|2008-02-28|Pacific Biosciences Of California, Inc.|Articles having localized molecules disposed thereon and methods of producing and using same|

---

US8975216B2|2006-03-30|2015-03-10|Pacific Biosciences Of California|Articles having localized molecules disposed thereon and methods of producing same|

---

DE102006030541B4|2006-06-23|2010-05-12|Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.|Optical arrangement|

---

US8207509B2|2006-09-01|2012-06-26|Pacific Biosciences Of California, Inc.|Substrates, systems and methods for analyzing materials|

---

AU2007289057C1|2006-09-01|2014-01-16|Pacific Biosciences Of California, Inc.|Substrates, systems and methods for analyzing materials|

---

EP2089517A4|2006-10-23|2010-10-20|Pacific Biosciences California|Polymerase enzymes and reagents for enhanced nucleic acid sequencing|

---

FR2908888B1|2006-11-21|2012-08-03|Centre Nat Rech Scient|DEVICE FOR EXACTLY DETECTING THE EMISSION OF A TARGET PARTICLE|

---

JP5270835B2|2006-12-29|2013-08-21|パナソニック株式会社|Photodetector, spatial information detector|

---

EP2132556B1|2007-03-22|2011-05-11|Universite De Strasbourg |Device for sorting and concentrating electromagnetic energy and apparatus comprising at least one such device|

---

US20080241866A1|2007-03-30|2008-10-02|Pacific Biosciences Of California, Inc.|Systems and methods for enhancing fluorescent signals|

---

US7873085B2|2007-10-23|2011-01-18|Andrei Babushkin|Method and device for controlling optical output of laser diode|

---

WO2009082706A1|2007-12-21|2009-07-02|The Trustees Of Columbia University In The City Of New York|Active cmos sensor array for electrochemical biomolecular detection|

---

WO2009091847A2|2008-01-14|2009-07-23|Life Technologies Corporation|Compositions, methods and systems for single molecule sequencing|

---

US8501922B2|2008-02-07|2013-08-06|Pacific Biosciences Of California, Inc.|CIS reactive oxygen quenchers integrated into linkers|

---

WO2010027484A2|2008-09-05|2010-03-11|Pacific Biosciences Of California, Inc.|Engineering polymerases and reaction conditions for modified incorporation properties|

---

US8652781B2|2008-02-12|2014-02-18|Pacific Biosciences Of California, Inc.|Cognate sampling kinetics|

---

CA2715385A1|2008-02-12|2009-08-20|Pacific Biosciences Of California, Inc.|Compositions and methods for use in analytical reactions|

---

AU2009223702B2|2008-03-13|2013-08-22|Pacific Biosciences Of California, Inc.|Labeled reactants and their uses|

---

US7973146B2|2008-03-26|2011-07-05|Pacific Biosciences Of California, Inc.|Engineered fluorescent dye labeled nucleotide analogs for DNA sequencing|

---

US8236499B2|2008-03-28|2012-08-07|Pacific Biosciences Of California, Inc.|Methods and compositions for nucleic acid sample preparation|

---

US8153375B2|2008-03-28|2012-04-10|Pacific Biosciences Of California, Inc.|Compositions and methods for nucleic acid sequencing|

---

WO2009145828A2|2008-03-31|2009-12-03|Pacific Biosciences Of California, Inc.|Two slow-step polymerase enzyme systems and methods|

---

CA2720247C|2008-03-31|2020-07-14|Pacific Biosciences Of California, Inc.|Single molecule loading methods and compositions|

---

US8999676B2|2008-03-31|2015-04-07|Pacific Biosciences Of California, Inc.|Recombinant polymerases for improved single molecule sequencing|

---

US9127259B2|2008-03-31|2015-09-08|Pacific Biosciences Of California, Inc.|Enzymes resistant to photodamage|

---

WO2009145820A2|2008-03-31|2009-12-03|Pacific Biosciences Of California, Inc.|Generation of modified polymerases for improved accuracy in single molecule sequencing|

---

US8420366B2|2008-03-31|2013-04-16|Pacific Biosciences Of California, Inc.|Generation of modified polymerases for improved accuracy in single molecule sequencing|

---

US8760549B2|2008-08-28|2014-06-24|Mesa Imaging Ag|Demodulation pixel with daisy chain charge storage sites and method of operation therefor|

---

WO2010033193A2|2008-09-16|2010-03-25|Pacific Biosciences Of California, Inc.|Substrates and optical systems and methods of use thereof|

---

US8481264B2|2008-09-19|2013-07-09|Pacific Biosciences Of California, Inc.|Immobilized nucleic acid complexes for sequence analysis|

---

US8921046B2|2008-09-19|2014-12-30|Pacific Biosciences Of California, Inc.|Nucleic acid sequence analysis|

---

US9156010B2|2008-09-23|2015-10-13|Bio-Rad Laboratories, Inc.|Droplet-based assay system|

---

WO2010036287A1|2008-09-24|2010-04-01|Pacific Biosciences Of California, Inc.|Intermittent detection during analytical reactions|

---

US8383369B2|2008-09-24|2013-02-26|Pacific Biosciences Of California, Inc.|Intermittent detection during analytical reactions|

---

CA2738626C|2008-09-30|2017-08-08|Pacific Biosciences Of California, Inc.|Ultra-high multiplex analytical systems and methods|

---

EP2182523B1|2008-10-31|2013-01-09|CSEM Centre Suisse d'Electronique et de Microtechnique SA -Recherche et Développement|Charge sampling device and method based on a MOS-transmission line|

---

WO2010057185A1|2008-11-17|2010-05-20|Pacific Biosciences Of California, Inc.|Phospholink nucleotides for sequencing applications|

---

US8519340B2|2008-12-22|2013-08-27|Koninklijke Philips N.V.|High dynamic range light sensor|

---

JP5688756B2|2008-12-25|2015-03-25|国立大学法人静岡大学|Semiconductor element and solid-state imaging device|

---

WO2010086602A1|2009-01-30|2010-08-05|Oxford Nanopore Technologies Limited|Hybridization linkers|

---

JP5519711B2|2009-03-12|2014-06-11|アールエスピーシステムズアクティーゼルスカブ|Optical probe for in vivo measurement of optical signals|

---

US20100255487A1|2009-03-27|2010-10-07|Life Technologies Corporation|Methods and apparatus for single molecule sequencing using energy transfer detection|

---

WO2010117420A2|2009-03-30|2010-10-14|Pacific Biosciences Of California, Inc.|Fret-labeled compounds and uses therefor|

---

JP5415805B2|2009-03-31|2014-02-12|オリンパスメディカルシステムズ株式会社|Diagnosis support device|

---

EP2419716B1|2009-04-15|2012-08-22|Koninklijke Philips Electronics N.V.|Device for time controlled fluorescence detection|

---

EP2443427B1|2009-06-17|2014-04-02|Ingeneron, Inc.|Method and apparatus for quantitative microimaging|

---

US8501406B1|2009-07-14|2013-08-06|Pacific Biosciences Of California, Inc.|Selectively functionalized arrays|

---

WO2011040971A2|2009-09-30|2011-04-07|Pacific Biosciences Of California, Inc.|Generation of modified polymerases for improved accuracy in single molecule sequencing|

---

EP2487897B1|2009-10-05|2016-09-14|National University Corporation Shizuoka University|Semiconductor element and solid-state imaging device|

---

US8278728B2|2009-10-17|2012-10-02|Florida Institute Of Technology|Array of concentric CMOS photodiodes for detection and de-multiplexing of spatially modulated optical channels|

---

WO2011068569A1|2009-12-04|2011-06-09|Biotium, Inc.|Heterocycle-substituted xanthene dyes|

---

JP6017107B2|2009-12-28|2016-10-26|ソニー株式会社|Image sensor, manufacturing method thereof, and sensor device|

---

WO2011090745A1|2009-12-29|2011-07-28|Life Technologies Corporation|Single molecule detection and sequencing using fluorescence lifetime imaging|

---

EP2362207A1|2010-01-28|2011-08-31|F. Hoffmann-La Roche AG|Measuring system and method, in particular for determining blood sugar|

---

US8994946B2|2010-02-19|2015-03-31|Pacific Biosciences Of California, Inc.|Integrated analytical system and method|

---

US9410891B2|2010-02-19|2016-08-09|Pacific Biosciences Of California, Inc.|Optics collection and detection system and method|

---

JP5881120B2|2010-02-19|2016-03-09|グリシュア リミテッド|Intravascular glucose sensor|

---

JP2013534614A|2010-03-25|2013-09-05|モコン・インコーポレーテッド|Analyte detection device and calibration technology based on luminescence lifetime|

---

US20130149734A1|2010-05-28|2013-06-13|The Regents Of The University Of Colorado, A Body Corporate|Multi-photon Tissue Imaging|

---

US8865078B2|2010-06-11|2014-10-21|Industrial Technology Research Institute|Apparatus for single-molecule detection|

---

US8865077B2|2010-06-11|2014-10-21|Industrial Technology Research Institute|Apparatus for single-molecule detection|

---

JP2012132741A|2010-12-21|2012-07-12|Fujifilm Corp|Time-resolved fluorescence measuring device and method|

---

EP2689028B1|2011-03-23|2017-08-30|Pacific Biosciences Of California, Inc.|Isolation of polymerase-nucleic acid complexes and loading onto substrates|

---

US9968258B2|2011-09-12|2018-05-15|Tufts University|Imaging fluorescence or luminescence lifetime|

---

US20130090537A1|2011-10-07|2013-04-11|2M Engineering Limited|Blood glucose sensor|

---

CA3003082C|2011-10-28|2020-12-15|Illumina, Inc.|Microarray fabrication system and method|

---

WO2013066959A1|2011-10-31|2013-05-10|The Trustees Of Columbia University In The City Of New York|Systems and methods for imaging using single photon avalanche diodes|

---

US9606060B2|2012-01-13|2017-03-28|California Institute Of Technology|Filterless time-domain detection of one or more fluorophores|

---

US8906660B2|2012-02-01|2014-12-09|Pacific Biosciences Of California, Inc.|Recombinant polymerases with increased phototolerance|

---

EP3222627B1|2012-02-15|2019-08-07|Pacific Biosciences of California, Inc.|Polymerase enzyme substrates with protein shield|

---

DE102012206089B4|2012-03-15|2017-02-02|Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.|SEMICONDUCTOR STRUCTURE, METHOD OF OPERATING THE SAME AND METHOD OF MANUFACTURING THE SAME|

---

CN102914525B|2012-04-10|2016-06-01|广东工业大学|The novel fluorescence life-span microscopic imaging device of optically-based addition heterodyne modulation and method|

---

WO2013171197A1|2012-05-15|2013-11-21|Ait Austrian Institute Of Technology Gmbh|Compact plasmon-enhanced fluorescence biosensor|

---

US9372308B1|2012-06-17|2016-06-21|Pacific Biosciences Of California, Inc.|Arrays of integrated analytical devices and methods for production|

---

CA2881823C|2012-08-20|2019-06-11|Illumina, Inc.|Method and system for fluorescence lifetime based sequencing|

---

EP3524964B1|2012-12-18|2020-07-15|Pacific Biosciences Of California, Inc.|An optical analytical device|

---

US9260251B2|2013-07-09|2016-02-16|Nd Industries, Inc.|Multi-row magnetic dial for the conveyance of workpieces and related method|

---

US20150042954A1|2013-08-08|2015-02-12|University Of Rochester|System and Method for Fluorescence Lifetime Imaging Aided by Adaptive Optics|

---

US9983135B2|2013-11-17|2018-05-29|Quantum-Si Incorporated|Active-source-pixel, integrated device for rapid analysis of biological and chemical specimens|

---

CN103728446B|2013-12-11|2016-02-24|天津大学|Photon counting-type hyperchannel time resolved fluoro-immunoassay system and method for counting|

---

US9736388B2|2013-12-13|2017-08-15|Bio-Rad Laboratories, Inc.|Non-destructive read operations with dynamically growing images|

---

EP3099232B1|2014-01-31|2021-08-18|The General Hospital Corporation|System and method for photoluminescence detection|

---

US9765395B2|2014-04-28|2017-09-19|Nanomedical Diagnostics, Inc.|System and method for DNA sequencing and blood chemistry analysis|

---

US10174363B2|2015-05-20|2019-01-08|Quantum-Si Incorporated|Methods for nucleic acid sequencing|

---

MX2017001806A|2014-08-08|2018-01-30|Quantum Si Inc|Integrated device for temporal binning of received photons.|

---

AU2016264753B2|2015-05-20|2021-09-09|Quantum-Si Incorporated|Method of determining the sequence of a nucleic acid using time resolved luminescence|

---

JP6930911B2|2014-08-08|2021-09-01|クアンタム−エスアイ インコーポレイテッドＱｕａｎｔｕｍ−Ｓｉ Ｉｎｃｏｒｐｏｒａｔｅｄ|Integrated device with external light source for molecular search, detection, and analysis|

---

JP6812341B2|2014-08-08|2021-01-13|クアンタム−エスアイ インコーポレイテッドＱｕａｎｔｕｍ−Ｓｉ Ｉｎｃｏｒｐｏｒａｔｅｄ|Optical systems and assay chips for molecular exploration, detection and analysis|

---

US9871065B2|2014-12-22|2018-01-16|Google Inc.|RGBZ pixel unit cell with first and second Z transfer gates|

---

US9666748B2|2015-01-14|2017-05-30|International Business Machines Corporation|Integrated on chip detector and zero waveguide module structure for use in DNA sequencing|

---

KR101828760B1|2015-02-09|2018-02-12|에스프로스 포토닉스 아게|Tof distance sensor|

---

CN113064236A|2015-03-16|2021-07-02|加利福尼亚太平洋生物科学股份有限公司|Integrated device and system for free space optical coupling|

---

US10976257B2|2015-06-08|2021-04-13|The Regents Of The University Of Michigan|Pixel circuit and method for optical sensing|

---

CN105300949B|2015-11-26|2019-06-11|浙江大学|A kind of fluorescence life measuring method and device|

---

CN108780044A|2016-02-17|2018-11-09|泰斯艾科特健康公司|The sensor and equipment of application are imaged and detected for the service life|

---

EP3465503B1|2016-06-01|2021-09-29|Quantum-Si Incorporated|Pulse caller and base caller|

---

KR20190095417A|2016-12-22|2019-08-14|퀀텀-에스아이 인코포레이티드|Integrated photodetector with direct binning pixels|

---

JP2021528905A|2018-06-22|2021-10-21|クアンタム−エスアイ インコーポレイテッドＱｕａｎｔｕｍ−Ｓｉ Ｉｎｃｏｒｐｏｒａｔｅｄ|Integrated photodetector with charge storage bins of various detection times|

---

KR20210046061A|2018-08-29|2021-04-27|퀀텀-에스아이 인코포레이티드|Systems and Methods for Detecting Lifetime Using Photon Counting Photodetectors|US9983135B2|2013-11-17|2018-05-29|Quantum-Si Incorporated|Active-source-pixel, integrated device for rapid analysis of biological and chemical specimens|

---

US10174363B2|2015-05-20|2019-01-08|Quantum-Si Incorporated|Methods for nucleic acid sequencing|

---

MX2017001806A|2014-08-08|2018-01-30|Quantum Si Inc|Integrated device for temporal binning of received photons.|

---

JP6930911B2|2014-08-08|2021-09-01|クアンタム−エスアイ インコーポレイテッドＱｕａｎｔｕｍ−Ｓｉ Ｉｎｃｏｒｐｏｒａｔｅｄ|Integrated device with external light source for molecular search, detection, and analysis|

---

JP6812341B2|2014-08-08|2021-01-13|クアンタム−エスアイ インコーポレイテッドＱｕａｎｔｕｍ−Ｓｉ Ｉｎｃｏｒｐｏｒａｔｅｄ|Optical systems and assay chips for molecular exploration, detection and analysis|

---

KR101725099B1|2014-12-05|2017-04-26|삼성전자주식회사|Computed tomography apparatus and control method for the same|

---

AU2015203591A1|2015-06-26|2017-01-19|Canon Kabushiki Kaisha|System and method for object matching|

---

JP2017098809A|2015-11-26|2017-06-01|キヤノン株式会社|Photoelectric conversion device and imaging system|

---

CN108780044A|2016-02-17|2018-11-09|泰斯艾科特健康公司|The sensor and equipment of application are imaged and detected for the service life|

---

EP3465503B1|2016-06-01|2021-09-29|Quantum-Si Incorporated|Pulse caller and base caller|

---

CN109155322A|2016-06-08|2019-01-04|因维萨热技术公司|Imaging sensor with electronic shutter|

---

JP6908819B2|2016-09-29|2021-07-28|ミツミ電機株式会社|Proximity sensor|

---

EP3305170B1|2016-10-04|2020-12-02|ams AG|Fluorescence lifetime sensor module and method of determining a fluorescence lifetime using a sensor module|

---

JP6808463B2|2016-11-30|2021-01-06|キヤノン株式会社|Photoelectric conversion device and photoelectric conversion system|

---

KR20190098184A|2016-12-19|2019-08-21|퀀텀-에스아이 인코포레이티드|Loading of molecules into sample wells for analysis|

---

KR20190095417A|2016-12-22|2019-08-14|퀀텀-에스아이 인코포레이티드|Integrated photodetector with direct binning pixels|

---

GB201622429D0|2016-12-30|2017-02-15|Univ Court Of The Univ Of Edinburgh The|Photon sensor apparatus|

---

WO2018204810A1|2017-05-05|2018-11-08|Quantum-Si Incorporated|Substrates having modified surface reactivity and antifouling properties in biological reactions|

---

CA3069974A1|2017-07-24|2019-01-31|Quantum-Si Incorporated|Optical rejection photonic structures|

---

EP3701568A4|2017-10-29|2021-08-04|Christopher J. Rourk|Electron transport gate circuits and methods of manufacture, operation and use|

---

US10817780B2|2017-10-29|2020-10-27|Christopher J. Rourk|Electron transport gate circuits and methods of manufacture, operation and use|

---

JP2021528905A|2018-06-22|2021-10-21|クアンタム−エスアイ インコーポレイテッドＱｕａｎｔｕｍ−Ｓｉ Ｉｎｃｏｒｐｏｒａｔｅｄ|Integrated photodetector with charge storage bins of various detection times|

---

EP3824553A1|2018-07-16|2021-05-26|Gigajot Technology, Inc.|High-sensitivity depth sensor with non-avalanche photodetector|

---

KR20210046061A|2018-08-29|2021-04-27|퀀텀-에스아이 인코포레이티드|Systems and Methods for Detecting Lifetime Using Photon Counting Photodetectors|

---

US20200187762A1|2018-12-17|2020-06-18|Qatar University|Fluorescence lifetime spectroscopy based capsule endoscopy|

---

CN114174858A|2019-07-12|2022-03-11|索尼半导体解决方案公司|Semiconductor device with a plurality of semiconductor chips|

---

WO2021178438A1|2020-03-02|2021-09-10|Quantum-Si Incorporated|Integrated sensor for multi-dimensional signal analysis|

---

US20210318242A1|2020-04-08|2021-10-14|Quantum-Si Incorporated|Integrated sensor with reduced skew|

---

US20210390705A1|2020-06-11|2021-12-16|Nautilus Biotechnology, Inc.|Methods and systems for computational decoding of biological, chemical, and physical entities|

法律状态:
2020-02-04| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-08-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2020-12-01| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/08/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201462035377P| true| 2014-08-08|2014-08-08|

---

US62/035,377|2014-08-08|

---

US201562164506P| true| 2015-05-20|2015-05-20|

---

US62/164,506|2015-05-20|

---

PCT/US2015/044360|WO2016022998A2|2014-08-08|2015-08-07|Integrated device for temporal binning of received photons|

---