Resonator networks for improved label detection, computation, analyte sensing and tunable random number generation

Abstract

To provide resonator networks adapted to a variety of applications.SOLUTION: The networks include fluorophores, quantum dots, dyes, plasmonic nanorods, or other optical resonators maintained in position relative to each other by a backbone (e.g., a backbone composed of DNA). The networks may exhibit optical absorption and re-emission according to specified temporal decay profiles, e.g., to provide temporally multiplexed labels for imaging or flow cytometry. The networks can include resonators exhibiting a dark state, so that behavior of the networks can be modified by inducing the dark state in one or more of the resonators.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 521,192, filed June 16, 2017, U.S. Provisional Application No. 62 / 527,451, filed June 30, 2017, and U.S. Provisional Application No. 62 / 551,616, filed August 29, 2017, which are incorporated herein by reference. [Background technology]

[0002] background A variety of fluorophores, quantum dots, Raman dyes, and other optically active substances can be incorporated into the labels. Such labels can be used to determine the presence, location, amount, or other properties of the labels and / or the analytes to which they are configured to bind in the sample. This can include illuminating the sample with one or more wavelengths of light and detecting light responsively reflected by the labels, fluorescently absorbed and re-emitted by the labels, or otherwise emitted from the labels. The timing, spectral content, intensity, degree of polarization, or some other property of the light detected from the sample in response to illuminating the sample can be used to detect the identity of the labels in the sample. For example, a library of labels that differ in terms of excitation spectrum, emission spectrum, susceptibility to photobleaching, or some other optical property can be applied to the sample to detect the presence, location, or other property of each of multiple analytes in the sample.

[0003] In some examples, a label may contain multiple fluorophores in sufficient proximity to allow energy to pass from the absorbing donor fluorophore of the label to the emitting acceptor fluorophore of the label. In such examples, the binding state to a target analyte or some other state of such a label may be related to the distance between the donor and the acceptor. That is, binding of the label to an instance of an analyte may cause a conformational change in the label such that the distance between the donor and the acceptor increases (or decreases) to the extent that energy is less (or more) easily transferred from the donor to the acceptor. In such examples, the overall fluorescence of the label, or some other optical property of the label, may be detected and used to determine the presence, location, amount, isoform, or some other property of the analyte in the sample. Summary of the Invention [Means for solving the problem]

[0004] Abstract One aspect of the present disclosure provides a label that includes (i) two or more input resonators, each of which includes at least one of a fluorophore, a quantum dot, or a dye, (ii) an output resonator, each of which includes at least one of a fluorophore or a quantum dot, and (iii) an organic scaffold. The two or more input resonators and the output resonators are coupled to the scaffold, which maintains the relative positions of the input and output resonators such that energy can be transferred from each of the input resonators to the output resonators.

[0005] Another aspect of the present disclosure provides a label including (i) an input resonator, (ii) one or more intermediary resonators, where a first of the one or more intermediary resonators is positioned proximate to the input resonator so that the first intermediary resonator can receive energy from the input resonator, (iii) an output resonator, where at least one of the one or more intermediary resonators is positioned proximate to the output resonator within the label so that the output resonator can receive energy from at least one of the one or more intermediary resonators, and (iv) a scaffold, where the input resonator, the output resonator, and the one or more intermediary resonators are coupled to the scaffold, and the scaffold maintains the relative positions of the input resonator, the output resonator, and the one or more intermediary resonators such that energy can be transmitted from the input resonator to the output resonator via the one or more intermediary resonators.

[0006] Another aspect of the present disclosure provides a system including: (i) a sample container; (ii) a light source; (iii) a photodetector; and (iv) a controller. The controller is programmed to perform operations including: (a) illuminating the sample container using the light source; (b) detecting a timing of emission of a plurality of photons from the sample container within a detection wavelength range relative to the illumination of the sample container using the photodetector; and (c) determining an identity of a label based on the detected timing of the emission of the plurality of photons. Determining the identity of the label includes selecting the identity of the label from a set of known labels. The label includes: (1) an input resonator; (2) an output resonator characterized by an emission wavelength, the detection wavelength range including the emission wavelength of the output resonator; and (3) a network of one or more intermediary resonators, the relative positions of the input resonator, the output resonator, and the intermediary resonator(s) within the label being such that energy can be transferred from the input resonator to the output resonator via the intermediary resonator(s) in response to the input resonator being excited by illumination.

[0007] Yet another aspect of the present disclosure provides a non-transitory computer-readable medium having stored thereon instructions executable by at least one processor to perform functions, including: (i) illuminating a sample including a label; (ii) detecting a timing of emission of a plurality of photons from the sample within a detection wavelength range relative to the illumination of the sample, the detection wavelength range including an emission wavelength of an output resonator of the label; and (iii) determining an identity of the label based on the detected timing of the emission of the plurality of photons. The label includes (a) an input resonator, (b) an output resonator characterized by an emission wavelength, and (c) a network of one or more intermediary resonators, the relative positions of the input resonator, the output resonator, and the one or more intermediary resonators within the label are such that energy can be transferred from the input resonator to the output resonator through the network of one or more intermediary resonators in response to the input resonator being excited by the illumination. Determining the identity of the label includes selecting the identity of the label from a set of known labels.

[0008] Yet another aspect of the present disclosure provides an imaging agent including (i) a first label and (ii) a second label, the first label including (a) a first receptor that selectively interacts with a first analyte of interest, (b) at least two first input resonators, (c) at least one first output resonator, where a ratio of the plurality of first input resonators in the first label to the plurality of first output resonators in the first label has a first value, and (d) a first scaffold, where the first receptor, the at least two first input resonators, and the at least one first output resonator are coupled to the first scaffold, and the first scaffold maintains relative positions of the at least two first input resonators and the at least one first output resonator such that the first scaffold can transmit energy from each of the first input resonators to the at least one first output resonator. The second label includes (a) a second receptor that selectively interacts with a second analyte of interest, (b) at least two second input resonators, (c) at least one second output resonator, where a ratio of the plurality of second input resonators in the second label to the plurality of second output resonators in the second label has a second value, and (d) a second scaffold, where the second receptor, the at least two second input resonators, and the at least one second output resonator are coupled to the second scaffold, and the second scaffold maintains relative positions of the at least two second input resonators and the at least one second output resonator such that the second scaffold can transmit energy from each of the second input resonators to the at least one second output resonator. Further, the first value and the second value are different.

[0009] Yet another aspect of the present disclosure provides a method that includes (i) illuminating a sample containing a label, (ii) detecting a timing of emission of a plurality of photons from the sample within a detection wavelength range relative to the illumination of the sample, the detection wavelength range including an emission wavelength of an output resonator of the label, and (iii) determining an identity of the label based on the detected timing of the emission of the plurality of photons. The label includes (a) an input resonator, (b) an output resonator characterized by an emission wavelength, and (c) a network of one or more intermediary resonators, where the relative positions of the input resonator, the output resonator, and the one or more intermediary resonators within the label are such that energy can be transferred from the input resonator to the output resonator via the network of one or more intermediary resonators in response to the input resonator being excited by the illumination. Determining the identity of the label includes selecting the identity of the label from a set of known labels.

[0010] Yet another aspect of the present disclosure provides a system including (i) a sample container, (ii) a light source, (iii) a photodetector, and (iv) a controller. The controller is programmed to perform operations including: (a) illuminating the sample container using the light source; (b) detecting, using the photodetector, a timing of emission of a plurality of photons from the sample container within a detection wavelength range relative to the illumination of the sample container; and (c) determining an identity of the label based on the detected timing of the emission of the plurality of photons. Determining the identity of the label includes selecting the identity of the label from a set of known labels. The label includes an input resonator characterized by an emission wavelength, the detection wavelength range including the emission wavelength of the input resonator, and (b) a modulation resonator, the relative positions of the input resonator and the modulation resonator within the label being such that energy can be transferred between the input resonator and the modulation resonator in response to the input resonator being excited by the illumination.

[0011] Yet another aspect of the present disclosure provides a resonator network including: (i) a first input resonator having a dark state, the first input resonator capable of entering the dark state in response to receiving irradiation at a first input excitation wavelength, (ii) a readout resonator capable of receiving energy from irradiation at a readout wavelength, (iii) an output resonator, and (iv) a scaffold. The first input resonator, the readout resonator, and the output resonator are coupled to the scaffold, and the scaffold maintains the relative positions of the first input resonator, the readout resonator, and the output resonator such that energy can be transferred from the readout resonator to the output resonator and such that the probability of energy being transferred from the readout resonator to the output resonator is related to whether the first input resonator is in the dark state.

[0012] Yet another aspect of the present disclosure provides a method of detecting an analyte, the method including: (i) illuminating a resonator network with light at a first input wavelength for a first time period, (ii) illuminating the resonator network with light at a readout wavelength for the first time period, and (iii) detecting an intensity of light emitted from an output resonator of the resonator network for the first time period. The resonator network includes: (a) a first input resonator having a dark state, the first input resonator capable of entering the dark state in response to receiving irradiation at the first input excitation wavelength, (b) a readout resonator capable of receiving energy from irradiation at the readout wavelength, (c) a mediator resonator, (d) an output resonator, (e) a sensor including a receptor that preferentially binds to the analyte, and (f) a scaffold. The first input resonator, the readout resonator, the sensing element, and the output resonator are coupled to a scaffold, which maintains the relative positions of the first input resonator, the readout resonator, the mediator resonator, the sensing element, and the output resonator so that energy can be transmitted from the readout resonator to the output resonator via the mediator resonator and such that the probability of energy being transmitted from the readout resonator to the output resonator when the first input resonator is in a dark state is related to whether the receptor is bound to an instance of the analyte.

[0013] Yet another aspect of the present disclosure provides a method that includes (i) illuminating a plurality of resonator networks with light at a first input wavelength for a first time period, (ii) illuminating the plurality of resonator networks with light at a readout wavelength for the first time period, and (iii) detecting timing of emission of a plurality of photons from an output resonator of the plurality of resonator networks relative to the illumination of the resonator network, wherein each resonator network of the plurality of resonator networks includes (a) a first input resonator having a dark state, the first input resonator capable of entering the dark state in response to receiving illumination at the first input excitation wavelength, (b) a readout resonator capable of receiving energy from illumination at the readout wavelength, (c) two or more mediator resonators, (d) an output resonator, and (e) a scaffold. The first input resonator, the readout resonator, the two or more mediator resonators, and the output resonator are coupled to a scaffold that maintains relative positions of the first input resonator, the readout resonator, the two or more mediator resonators, and the output resonator such that energy can be transferred from the readout resonator to the output resonator via the mediator resonator, and such that the resonator network emits photons from the output resonators in response to the readout resonator receiving illumination at the readout wavelength according to a time-dependent probability density function, the detectable characteristic of which is related to whether the first input resonator is in a dark state.

[0014] These and other aspects, advantages, and alternatives will become apparent to those skilled in the art from a reading of the following detailed description, where appropriate taken in conjunction with the accompanying drawings. In an embodiment of the present invention, for example, the following items are provided: (Item 1) two or more input resonators including at least one of a fluorophore, a quantum dot, or a dye; an output resonator comprising at least one of a fluorophore or a quantum dot; an organic framework, wherein the two or more input resonators and the output resonators are coupled to the framework, and the framework maintains the relative positions of the input resonators and the output resonators such that energy can be transferred from each of the input resonators to the output resonators. sign. (Item 2) 2. The label of claim 1, wherein the two or more input resonators include a first input resonator and a second input resonator, and the scaffold maintains a relative position of the input resonator and the output resonator such that energy can be transmitted from the second input resonator to the output resonator via the first input resonator. (Item 3) 3. The label of claim 2, capable of transferring energy from the first input resonator to the second input resonator. (Item 4) 4. The label of item 2 or 3, wherein the input resonators all comprise the same fluorophore. (Item 5) 4. The label of claim 3, wherein each of the input resonators is coupled to the backbone via a respective linker, the linkers having a characteristic linker length, the input resonators are characterized by a Förster radius, the linkers are coupled to the backbone at respective coupling positions, and the coupling positions are separated from each other by a distance that is smaller than the Förster radius and greater than twice the characteristic linker length. (Item 6) 6. The label according to any of items 2 to 5, wherein the two or more input resonators comprise more than four input resonators. (Item 7) 6. The label according to any of items 2 to 5, wherein the two or more input resonators comprise more than 30 input resonators. (Item 8) an additional output resonator; and two or more additional input resonators, wherein the two or more additional input resonators and the additional output resonators are coupled to the scaffold, and the scaffold maintains a relative position of the additional input resonators and the additional output resonators such that the scaffold can transmit energy from each of the additional input resonators to the additional output resonators. The label according to any one of items 1 to 7. (Item 9) 9. The label of claim 8, wherein the scaffold maintains the relative positions of the additional input resonators and the output resonators such that energy can be transferred from at least one of the additional input resonators to the output resonator. (Item 10) one or more intermediary resonators, at least one of which is disposed in the label proximate to the output resonator such that the output resonator can receive energy from the at least one of the one or more intermediary resonators, and the scaffold maintains the relative positions of the input resonator and the output resonator such that the output resonator can receive energy from the at least one of the one or more intermediary resonators and can transmit energy from each of the input resonators to the output resonator, the scaffold maintaining the relative positions of the input resonator, the output resonator, and the one or more intermediary resonators such that energy can be transmitted from each of the input resonators to the output resonator via the one or more intermediary resonators. The label according to any one of items 1 to 9. (Item 11) Item 11. The label of item 10, wherein the input resonator absorbs light at an excitation wavelength and the output resonator emits light at an emission wavelength, the emission wavelength being different from the excitation wavelength, the one or more intermediary resonators are characterized by respective emission wavelengths, and the emission wavelengths of the one or more intermediary resonators are intermediate between the excitation wavelength of the input resonator and the emission wavelength of the output resonator. (Item 12) 12. The sign of claim 10 or 11, wherein the one or more mediator resonators are arranged as resonator wires within the sign between the input resonator and the output resonator. (Item 13) 13. The label according to any one of items 10 to 12, wherein the intermediary resonators all contain the same fluorophore. (Item 14) 14. The label according to any one of items 10 to 13, further comprising a facilitation resonator coupled to the scaffold, wherein the scaffold maintains relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the facilitation resonator such that the facilitation resonator is in a dark state to facilitate the transfer of energy from the input resonator to the output resonator via the one or more mediator resonators. (Item 15) 15. The label according to any one of items 10 to 14, further comprising an inhibitory resonator coupled to the scaffold, wherein the scaffold maintains relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the inhibitory resonator such that the inhibitory resonator is in a dark state to inhibit transmission of energy from the input resonator to the output resonator via the one or more mediator resonators. (Item 16) and further comprising a receptor, said receptor selectively interacting with an analyte of interest, said receptor being linked to said scaffold. The label according to any one of items 1 to 15. (Item 17) A sign, An input resonator; one or more intermediary resonators, a first of the one or more intermediary resonators being disposed in proximity to the input resonator such that the first intermediary resonator can receive energy from the input resonator; an output resonator, wherein at least one of the one or more mediator resonators is disposed in the label proximate to the output resonator such that the output resonator can receive energy from the at least one of the one or more mediator resonators; a scaffold, wherein the input resonators, the output resonators, and the one or more intermediary resonators are coupled to the scaffold, and the scaffold maintains relative positions of the input resonators, the output resonators, and the one or more intermediary resonators such that the scaffold can transmit energy from the input resonators to the output resonators via the one or more intermediary resonators. sign. (Item 18) 18. The label according to item 17, wherein the backbone is two at least partially complementary DNA strands. (Item 19) 19. The label of item 17 or 18, wherein at least one of the mediator resonator, the input resonator, or the output resonator comprises a fluorophore. (Item 20) 20. The marker according to any one of items 17 to 19, wherein the one or more intermediate resonators are arranged as resonator wires between the input resonator and the output resonator within the marker. (Item 21) 21. The label according to any one of items 17 to 20, wherein the intermediary resonators all contain the same fluorophore. (Item 22) 22. The label according to any one of items 17 to 21, wherein the input resonator is a first input resonator, the label further includes a second input resonator, and at least one of the one or more mediator resonators is disposed in the vicinity of the second input resonator such that the at least one of the one or more mediator resonators can receive energy from the second input resonator. (Item 23) 23. The label of item 22, wherein the first input resonator is characterized by a first excitation wavelength and the second input resonator is characterized by a second excitation wavelength different from the first excitation wavelength. (Item 24) 24. The label according to any one of items 17 to 23, wherein the output resonator is a first output resonator, the label further includes a second output resonator, and at least one of the one or more mediator resonators is disposed in the label in the vicinity of the second output resonator, such that the second output resonator can receive energy from the at least one of the one or more mediator resonators. (Item 25) 25. The label of claim 24, wherein the second power resonator is characterized by a second emission wavelength different from the emission wavelength of the first power resonator. (Item 26) 26. The label according to any of items 17 to 25, wherein the input resonator absorbs light at an excitation wavelength and the output resonator emits light at an emission wavelength, the emission wavelength being different from the excitation wavelength. (Item 27) 27. The label of claim 26, wherein the one or more intermediary resonators are characterized by a respective emission wavelength, and the emission wavelength of the one or more intermediary resonators is intermediate between the excitation wavelength of the input resonator and the emission wavelength of the output resonator. (Item 28) 28. The label according to any one of items 17 to 27, further comprising a facilitation resonator coupled to the scaffold, wherein the scaffold maintains relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the facilitation resonator such that the facilitation resonator is in a dark state to facilitate the transfer of energy from the input resonator to the output resonator via the one or more mediator resonators. (Item 29) 29. The label according to any one of items 17 to 28, further comprising an inhibitory resonator coupled to the scaffold, wherein the scaffold maintains relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the inhibitory resonator such that the inhibitory resonator is in a dark state to inhibit transmission of energy from the input resonator to the output resonator via the one or more mediator resonators. (Item 30) and further comprising a receptor, said receptor selectively interacting with an analyte of interest, said receptor being linked to said scaffold. 30. The label according to any one of items 17 to 29. (Item 31) A sample container; A light source; A photodetector; and a controller, the controller comprising: illuminating the sample vessel using the light source; detecting a timing of emission of a plurality of photons from the sample vessel within a detection wavelength range relative to the illumination of the sample vessel using the photodetector; and determining an identity of a sign based on the detected timing of the emission of the plurality of photons, wherein determining the identity of the sign includes selecting the identity of the sign from a set of known signs, the sign being: An input resonator; an output resonator characterized by an emission wavelength, the detection wavelength range including the emission wavelength of the output resonator; and a network of one or more intermediary resonators, wherein the relative positions of the input resonators, the output resonators, and the one or more intermediary resonators within the label are such that, in response to the input resonators being excited by the irradiation, energy can be transferred from the input resonators to the output resonators via the one or more intermediary resonators. system. (Item 32) The operation, 32. The system of claim 31, further comprising classifying the contents of the sample container into one or more locations based on the determined identity of the label. (Item 33) determining the identity of the indicia; determining a probability density function for the timing of emission of photons from the sample container in response to illuminating the sample container based on the detected timing of the emission of the plurality of photons; 33. The system of claim 31 or 32, further comprising: comparing the determined probability density function with a set of known temporal decay profiles, each marker in the set of known temporal decay profiles corresponding to a respective one of the temporal decay profiles in the set of known temporal decay profiles. (Item 34) Item 34. The system of item 33, wherein comparing the determined probability density function with a set of known temporal decay profiles includes determining a measure of statistical divergence between the determined probability density function and each of the temporal decay profiles in the set of known temporal decay profiles. (Item 35) the indicator is a first indicator, and the action is and determining an identity of a second label based on the detected timing of the emission of the plurality of photons, wherein determining the identity of the second label comprises selecting the identity of the second label from the set of known labels, the second label being: A second input resonator; and a second output resonator, wherein the detection wavelength range includes an emission wavelength of the second output resonator; and and a second network of one or more intermediary resonators, wherein relative positions of the second input resonator, the second output resonator, and an intermediary resonator among the second network of one or more intermediary resonators within the second label are such that, in response to the second input resonator being excited by the irradiation, energy can be transferred from the second input resonator to the second output resonator via the second network of one or more intermediary resonators; 35. The system according to any one of items 31 to 34, wherein the network of one or more mediator resonators of the first label is different from the second network of one or more mediator resonators. (Item 36) The operation, 36. The system of claim 35, further comprising identifying the contents of the sample container based on the determined identity of the first label and the determined identity of the second label. (Item 37) 37. The system of claim 35 or 36, wherein the input resonator of the first label is the same as the second input resonator and the output resonator of the first label is the same as the second output resonator. (Item 38) The operation, 38. The system of any of items 35-37, further comprising determining an amount of the first label in the sample vessel relative to an amount of the second label in the sample vessel based on the detected timing of the emission of the plurality of photons. (Item 39) Determining the amount of the first label in the sample vessel relative to the amount of the second label in the sample vessel, determining a probability density function for the timing of emission of photons from the sample container in response to illuminating the sample container based on the detected timing of the emission of the plurality of photons; and determining an amount of the amount of the first label in the sample vessel relative to an amount of the second label in the sample vessel based on the determined probability density function, a first known temporal decay profile corresponding to the first label, and a second known temporal decay profile corresponding to the second label. (Item 40) a first intermediary resonator of the network of intermediary resonators is characterized by a further emission wavelength, and the system further comprises: 40. The system of any one of items 31 to 39, further comprising a second photodetector, wherein the operations further include detecting a timing of an emission of a further plurality of photons from the sample container within a further detection wavelength range relative to the illumination of the sample container using the second photodetector, the further detection wavelength range including the further emission wavelength of the first intermediary resonator, and determining the identity of the label includes determining the identity of the label based on the detected timing of the emission of the further plurality of photons. (Item 41) 41. The system of any one of items 31 to 40, wherein the photodetector comprises a single-photon avalanche diode. (Item 42) 42. The system of any one of items 31 to 41, wherein the sample vessel comprises a flow channel, illuminating the sample vessel comprises illuminating a portion of the flow channel, and detecting timing of emission of a plurality of photons from the sample vessel comprises detecting timing of emission of a plurality of photons from the flow channel. (Item 43) 43. The system of any one of items 31 to 42, wherein the input resonator is a first input resonator, the label further includes a second input resonator, and the relative positions of the second input resonator, the output resonator, and the one or more intermediary resonators within the label are such that energy can be transferred from the second input resonator to the output resonator via the one or more intermediary resonators in response to the second input resonator being excited by the irradiation. (Item 44) the first input resonator is characterized by a first excitation wavelength and the second input resonator is characterized by a second excitation wavelength different from the first excitation wavelength, and irradiating the sample container using the light source; providing a first illumination comprising light at the first excitation wavelength to the sample container for a first period of time; and providing a second illumination comprising light at the second excitation wavelength to the sample container for a second period of time. (Item 45) 45. The system of any one of items 31 to 44, wherein the output resonator is a first output resonator and the label further includes a second output resonator, and the relative positions of the input resonator, the second output resonator, and the one or more intermediary resonators within the label are such that energy can be transferred from the input resonator to the second output resonator via the one or more intermediary resonators in response to the input resonator being excited by the irradiation. (Item 46) the second output resonator is characterized by a second emission wavelength different from the emission wavelength of the first output resonator, and the operation comprises: 46. ​​The system of claim 45, further comprising: using the photodetector to detect a timing of an emission of a second plurality of photons from the sample container within a second detection wavelength range relative to the illumination of the sample container, the second detection wavelength range including the second emission wavelength, and determining the identity of the label comprises determining the identity of the label based on the detected timing of the emission of the second plurality of photons. (Item 47) Further equipped with a further light source, the label further comprises a facilitation resonator coupled to a scaffold, the scaffold maintaining relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the facilitation resonator such that the facilitation resonator is in a dark state to facilitate the transfer of energy from the input resonator to the output resonator via the one or more mediator resonators; The operation, using the additional light source to illuminate the sample container with radiation such that the facilitating resonator enters the dark state. The system according to any one of items 31 to 46. (Item 48) Further equipped with a further light source, the label further comprises an inhibitory resonator coupled to a scaffold, the scaffold maintaining relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the inhibitory resonator such that the inhibitory resonator is in a dark state to inhibit transmission of energy from the input resonator to the output resonator via the one or more mediator resonators; The operation, using the additional light source to illuminate the sample vessel with radiation such that the suppression resonators enter the dark state. The system according to any one of items 31 to 46. (Item 49) A non-transitory computer readable medium having stored thereon instructions executable by at least one processor to perform functions, the functions comprising: irradiating a sample, the sample comprising a label, the label comprising: An input resonator, an output resonator characterized by an emission wavelength; irradiating a label including a network of one or more intermediary resonators, the relative positions of the input resonators, the output resonators, and the one or more intermediary resonators within the label being such that, in response to the input resonators being excited by the irradiation, energy can be transferred from the input resonators to the output resonators via the network of one or more intermediary resonators; detecting a timing of emission of a plurality of photons from the sample within a detection wavelength range relative to the illumination of the sample, the detection wavelength range including the emission wavelength of the output resonator; and determining an identity of the label based on the detected timing of the emission of the plurality of photons, wherein determining the identity of the label comprises selecting the identity of the label from a set of known labels. (Item 50) A first sign, a first receptor that selectively interacts with a first analyte of interest; at least two first input resonators; at least one first output resonator, wherein a ratio of a plurality of first input resonators in the first label to a plurality of first output resonators in the first label has a first value; and a first label comprising a first scaffold, the first receptor, the at least two first input resonators, and the at least one first output resonator being coupled to the first scaffold, the first scaffold maintaining a relative position of the at least two first input resonators and the at least one first output resonator such that the first scaffold can transmit energy from each of the first input resonators to the at least one first output resonator; A second sign, a second receptor that selectively interacts with a second analyte of interest; at least two second input resonators; at least one second output resonator, wherein a ratio of a plurality of second input resonators in the second label to a plurality of second output resonators in the second label has a second value; and a second scaffold, wherein the second receptor, the at least two second input resonators, and the at least one second output resonator are coupled to the second scaffold, and the second scaffold maintains a relative position of the at least two second input resonators and the at least one second output resonator such that the second scaffold can transmit energy from each of the second input resonators to at least one second output resonator; the first value and the second value are different; Contrast agent. (Item 51) 51. The contrast agent of claim 50, wherein the first input resonator and the second input resonator differ in terms of absorption wavelength. (Item 52) 52. The contrast agent of claim 50 or 51, wherein the first power resonator and the second power resonator differ with respect to emission wavelength. (Item 53) The first label is 53. The imaging agent according to any one of items 50 to 52, further comprising one or more intermediary resonators, wherein a first intermediary resonator of the one or more intermediary resonators is disposed in the first label in the vicinity of the at least two first input resonators, such that the first intermediary resonator can receive energy from each of the at least two first input resonators, and at least one of the one or more intermediary resonators is disposed in the first label in the vicinity of at least one first output resonator, such that the at least one first output resonator can receive energy from the at least one of the one or more intermediary resonators, and the first skeleton maintains the relative positions of the at least two first input resonators and the at least one output resonator so that the at least one first output resonator can receive energy from the at least one of the one or more intermediary resonators, and the first skeleton maintains the relative positions of the first input resonator, the at least one first output resonator, and the one or more intermediary resonators so that the first input resonator can transmit energy from each of the first input resonators to the at least one first output resonator via the one or more intermediary resonators. (Item 54) Irradiating a sample containing a label, the label comprising: An input resonator, an output resonator characterized by an emission wavelength; irradiating a label including a network of one or more intermediary resonators, the relative positions of the input resonators, the output resonators, and the one or more intermediary resonators within the label being such that, in response to the input resonators being excited by the irradiation, energy can be transferred from the input resonators to the output resonators via the network of one or more intermediary resonators; detecting a timing of emission of a plurality of photons from the sample within a detection wavelength range relative to the illumination of the sample, the detection wavelength range including the emission wavelength of the output resonator; and determining an identity of the label based on the detected timing of the emission of the plurality of photons, wherein determining the identity of the label comprises selecting the identity of the label from a set of known labels. method. (Item 55) The sample comprises one or more particles, and the method comprises: 55. The method of claim 54, further comprising sorting the one or more particles into one or more locations based on the determined identity of the label. (Item 56) determining the identity of the indicia; determining a probability density function for the timing of emission of photons from the sample in response to irradiating the sample based on the detected timing of the emission of the plurality of photons; 56. The method of claim 54 or 55, comprising comparing the determined probability density function with a set of known temporal decay profiles, wherein each marker in the set of known temporal decay profiles corresponds to a respective one of the temporal decay profiles in the set of known temporal decay profiles. (Item 57) 57. The method of claim 56, wherein comparing the determined probability density function with a set of known temporal decay profiles includes determining a measure of statistical divergence between the determined probability density function and each of the temporal decay profiles in the set of known temporal decay profiles. (Item 58) the label is a first label, the sample comprises a second label, and the second label is A second input resonator; and a second output resonator, wherein the detection wavelength range includes an emission wavelength of the second output resonator; and and a second network of one or more intermediary resonators, wherein relative positions of the second input resonator, the second output resonator, and an intermediary resonator among the second network of one or more intermediary resonators within the second label are such that, in response to the second input resonator being excited by the irradiation, energy can be transferred from the second input resonator to the second output resonator via the second network of one or more intermediary resonators; the network of one or more mediator resonators of the first label is different from the second network of one or more mediator resonators, the method comprising: 58. The method of any of items 54 to 57, further comprising determining an identity of the second label based on the detected timing of the emission of the plurality of photons, wherein determining the identity of the second label comprises selecting the identity of the second label from the set of known labels. (Item 59) further comprising identifying particles in the sample based on the determined identity of the first label and the determined identity of the second label. Item 58. The method according to item 58. (Item 60) 60. The method of claim 58 or 59, wherein the input resonator of the first label is the same as the second input resonator and the output resonator of the first label is the same as the second output resonator. (Item 61) determining an amount of the first label in the sample relative to an amount of the second label in the sample based on the detected timing of the emission of the plurality of photons. The method according to any one of items 58 to 60. (Item 62) Determining the amount of the first label in the sample relative to the amount of the second label in the sample; determining a probability density function for the timing of emission of photons from the sample in response to irradiating the sample based on the detected timing of the emission of the plurality of photons; and determining the amount of the first label in the sample relative to the amount of the second label in the sample based on the determined probability density function, a first known temporal decay profile corresponding to the first label, and a second known temporal decay profile corresponding to the second label. (Item 63) A first intermediary resonator of the network of intermediary resonators is characterized by a further emission wavelength, and the method further comprises: 63. The method of any of items 54 to 62, further comprising detecting a timing of emission of a further plurality of photons from the sample within a further detection wavelength range relative to the illumination of the sample, the further detection wavelength range including the further emission wavelength of the first intermediary resonator, and determining the identity of the label comprises determining the identity of the label based on the detected timing of the emission of the further plurality of photons. (Item 64) 64. The method of any one of items 54 to 63, wherein the input resonator is a first input resonator, the label further comprises a second input resonator, and the relative positions of the second input resonator, the output resonator, and the one or more intermediary resonators within the label are such that energy can be transferred from the second input resonator to the output resonator via the one or more intermediary resonators in response to the second input resonator being excited by the irradiation. (Item 65) the first input resonator is characterized by a first excitation wavelength and the second input resonator is characterized by a second excitation wavelength different from the first excitation wavelength, and irradiating the sample; providing a first illumination comprising light at the first excitation wavelength to the sample for a first period of time; and providing a second illumination comprising light at the second excitation wavelength to the sample for a second period of time. (Item 66) 66. The method of any of items 54 to 65, wherein the output resonator is a first output resonator, the label further comprises a second output resonator, and the relative positions of the input resonator, the second output resonator, and the one or more intermediary resonators within the label are such that energy can be transferred from the input resonator to the second output resonator via the one or more intermediary resonators in response to the input resonator being excited by the irradiation. (Item 67) the second power resonator is characterized by a second emission wavelength different from the emission wavelength of the first power resonator, and the method further comprises: 67. The method of claim 66, further comprising detecting a timing of an emission of a second plurality of photons from the sample within a second detection wavelength range relative to the illumination of the sample, the second detection wavelength range including the second emission wavelength, and determining the identity of the label comprises determining the identity of the label based on the detected timing of the emission of the second plurality of photons. (Item 68) the label further comprises a facilitation resonator coupled to a scaffold, the scaffold maintaining relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the facilitation resonator such that the facilitation resonator is in a dark state to facilitate the transfer of energy from the input resonator to the output resonator via the one or more mediator resonators, and the method further comprising: 68. The method of any of items 54 to 67, further comprising irradiating the sample with radiation such that the facilitating resonator enters the dark state. (Item 69) the label further comprises an inhibitory resonator coupled to a scaffold, the scaffold maintaining relative positions of the input resonator, the output resonator, the one or more mediator resonators, and the inhibitory resonator such that the inhibitory resonator is in a dark state to inhibit transmission of energy from the input resonator to the output resonator via the one or more mediator resonators, and the method further comprising: 69. The method of any of items 54 to 68, further comprising irradiating the sample with radiation such that the suppressor resonators enter the dark state. (Item 70) A sample container; A light source; A photodetector; and a controller, the controller comprising: illuminating the sample vessel using the light source; detecting a timing of emission of a plurality of photons from the sample vessel within a detection wavelength range relative to the illumination of the sample vessel using the photodetector; and determining an identity of a sign based on the detected timing of the emission of the plurality of photons, wherein determining the identity of the sign includes selecting the identity of the sign from a set of known signs, the sign being: an input resonator characterized by an emission wavelength, the detection wavelength range including the emission wavelength of the input resonator; a modulation resonator, the relative positions of the input resonator and the modulation resonator within the label being such that energy can be transferred between the input resonator and the modulation resonator in response to the input resonator being excited by the irradiation. system. (Item 71) a first input resonator having a dark state, the first input resonator being capable of entering the dark state in response to receiving illumination at a first input excitation wavelength; a readout resonator capable of receiving energy from radiation at a readout wavelength; an output resonator; a scaffold, the first input resonator, the readout resonator, and the output resonator being coupled to the scaffold, the scaffold maintaining relative positions of the first input resonator, the readout resonator, and the output resonator such that the scaffold can transmit energy from the readout resonator to the output resonator and such that a probability of energy transmission from the readout resonator to the output resonator is related to whether the first input resonator is in the dark state. Resonator network. (Item 72) Item 72. The resonator network of item 71, wherein the first input resonator in the dark state inhibits the transmission of energy from the readout resonator to the output resonator. (Item 73) 73. The resonator network of claim 72, wherein the scaffold maintains relative positions of the first input resonator, the readout resonator, and the output resonator such that the first input resonator is in the dark state to prevent transmission of energy from the readout resonator to the output resonator via the first input resonator, such that energy can be transmitted from the readout resonator to the output resonator via the first input resonator. (Item 74) a second input resonator coupled to the scaffold, the second input resonator having a dark state, the second input resonator being capable of entering the dark state in response to receiving irradiation at a second input excitation wavelength, the scaffold maintaining relative positions of the first input resonator, the second input resonator, the readout resonator, and the output resonator such that the second input resonator being in the dark state facilitates transfer of energy from the readout resonator to the output resonator. 74. The resonator network according to item 72 or 73. (Item 75) Item 75. The resonator network of item 74, wherein the first input wavelength and the second input wavelength differ by less than 10 nanometers. (Item 76) 75. The resonator network of claim 74, wherein the first input wavelength and the second input wavelength differ by more than 50 nanometers. (Item 77) a second input resonator coupled to the scaffold, the second input resonator having a dark state, the second input resonator being capable of entering the dark state in response to receiving irradiation at a second input excitation wavelength, the scaffold maintaining relative positions of the first input resonator, the second input resonator, the readout resonator, and the output resonator such that the second input resonator being in the dark state inhibits transmission of energy from the readout resonator to the output resonator. 74. The resonator network according to item 72 or 73. (Item 78) Item 78. The resonator network of item 77, wherein the first input wavelength and the second input wavelength differ by less than 10 nanometers. (Item 79) Item 78. The resonator network of item 77, wherein the first input wavelength and the second input wavelength differ by more than 50 nanometers. (Item 80) Item 72. The resonator network of item 71, wherein the first input resonator is in the dark state to facilitate transfer of energy from the readout resonator to the output resonator. (Item 81) 81. The resonator network of claim 80, wherein the framework maintains the relative positions of the first input resonator, the readout resonator, and the output resonator such that when the first input resonator is not in the dark state, energy is more likely to be transmitted from the readout resonator to the first input resonator and then dissipated by the first input resonator than to be transmitted to the output resonator. (Item 82) a second input resonator coupled to the scaffold, the second input resonator having a dark state, the second input resonator being capable of entering the dark state in response to receiving irradiation at a second input excitation wavelength, the scaffold maintaining relative positions of the first input resonator, the second input resonator, the readout resonator, and the output resonator such that the second input resonator being in the dark state facilitates transfer of energy from the readout resonator to the output resonator. 82. The resonator network according to item 80 or 81. (Item 83) Item 83. The resonator network of item 82, wherein the first input wavelength and the second input wavelength differ by less than 10 nanometers. (Item 84) Item 83. The resonator network of item 82, wherein the first input wavelength and the second input wavelength differ by more than 50 nanometers. (Item 85) the one or more intermediary resonators further comprising: a first intermediary resonator of the one or more intermediary resonators is disposed in the resonator network in proximity to the readout resonator such that the readout resonator is capable of exciting the first intermediary resonator in response to the excitation of the readout resonator by irradiation at the readout wavelength; and at least one of the one or more intermediary resonators is disposed in the resonator network in proximity to the output resonator such that the output resonator can be excited by the at least one of the one or more intermediary resonators. 85. The resonator network according to any one of Items 71 to 84. (Item 86) and a sensing element coupled to the framework, the sensing element having a state related to a characteristic of an environment of the resonator network, the probability of energy being transferred from the readout resonator to the output resonator being related to the state of the sensing element. Item 86. The resonator network according to item 85. (Item 87) 87. The resonator network according to claim 86, wherein the property of the environment of the resonator network is a pH of a fluid in the environment of the resonator network. (Item 88) and a sensor coupled to the scaffold, the sensor comprising a receptor that preferentially binds to an analyte, and wherein an instance of the analyte binds to the receptor, causing the sensor to quench at least one of the one or more mediator resonators. Item 86. The resonator network according to item 85. (Item 89) and a sensor coupled to the scaffold, the sensor comprising a receptor that preferentially binds to an analyte, the sensor quenching at least one of the one or more mediator resonators when the receptor is not bound to any instance of the analyte. Item 86. The resonator network according to item 85. (Item 90) and a sensor coupled to the scaffold, the sensor comprising a receptor that preferentially binds to an analyte, the receptor binding to an instance of the analyte causing the sensor to modify the position of at least one of the one or more intermediary resonators relative to the scaffold. Item 86. The resonator network according to item 85. (Item 91) 86. The resonator network of any of items 71 to 85, wherein the resonator network emits photons from the output resonators in response to the readout resonator receiving irradiation at the readout wavelength according to a time-dependent probability density function, a detectable characteristic of the time-dependent probability density function related to whether the first input resonator is in the dark state. (Item 92) 1. A method for detecting an analyte, comprising: illuminating a resonator network with light at a first input wavelength for a first period of time, the resonator network comprising: a first input resonator having a dark state and capable of entering said dark state in response to receiving illumination at a first input excitation wavelength; a readout resonator capable of receiving energy from radiation at a readout wavelength; mediating resonator, Output resonator, a sensor comprising a receptor that preferentially binds to the analyte; and irradiating a system including a scaffold, the first input resonator, the readout resonator, the sensing element, and the output resonator coupled to the scaffold such that the scaffold can transmit energy from the readout resonator to the output resonator via the intermediary resonator, and further maintaining relative positions of the first input resonator, the readout resonator, the intermediary resonator, the sensing element, and the output resonator such that a probability of energy transmission from the readout resonator to the output resonator when the first input resonator is in the dark state is related to whether the receptor is bound to an instance of the analyte; illuminating the resonator network with light at the readout wavelength during the first period of time; and detecting an intensity of light emitted from said output resonator during said first period of time. (Item 93) 93. The method of claim 92, wherein the sensing entity quenches the mediator resonator upon binding of the analyte instance to the receptor. (Item 94) 93. The method of claim 92, wherein the receptor is not bound to any instance of the analyte, thereby causing the sensor to quench the mediator resonator. (Item 95) 93. The method of claim 92, wherein the receptor binds to an instance of the analyte, thereby modifying the position of the intermediary resonator relative to the backbone. (Item 96) The resonator network comprises: a second input resonator coupled to the backbone, the second input resonator having a dark state and capable of entering the dark state in response to receiving irradiation at a second input excitation wavelength; a second sensor coupled to the scaffold, the second sensor comprising a second receptor that preferentially binds to a second analyte; and a second mediator resonator, maintaining relative positions of the second input resonator, the readout resonator, the second mediator resonator, the second sensing element, and the output resonator such that the scaffold can transmit energy from the readout resonator to the output resonator via the second mediator resonator, and such that a probability of energy being transmitted from the readout resonator to the output resonator when the second input resonator is in the dark state and the first input resonator is not in the dark state is related to whether the second receptor is bound to an instance of the second analyte; The method further comprising: illuminating the resonator network with light at the second input wavelength for a second time period after the first time period; illuminating the resonator network with light at the readout wavelength during the second period of time; Item 96. The method of any one of items 92 to 95, further comprising detecting an intensity of light emitted from the output resonator during the second time period. (Item 97) determining a presence or amount of the first analyte in an environment of the resonator network based on the intensity of light emitted from the output resonators during the first time period. The method according to any one of items 92 to 96. (Item 98) illuminating a plurality of resonator networks with light at a first input wavelength during a first time period, wherein each resonator network of the plurality of resonator networks: a first input resonator having a dark state and capable of entering said dark state in response to receiving illumination at a first input excitation wavelength; a readout resonator capable of receiving energy from radiation at a readout wavelength; Two or more intermediary resonators, an output resonator; and a scaffold comprising: the first input resonator, the readout resonator, the two or more intermediary resonators, and the output resonator coupled to the scaffold; and wherein the scaffold is capable of transmitting energy from the readout resonator to the output resonator via the intermediary resonator; and wherein the resonator network maintains relative positions of the first input resonator, the readout resonator, the two or more intermediary resonators, and the output resonator such that the scaffold can transmit energy from the readout resonator to the output resonator via the intermediary resonator, and such that the resonator network emits photons from the output resonators in response to the readout resonator receiving illumination at the readout wavelength according to a time-dependent probability density function, a detectable characteristic of the time-dependent probability density function being related to whether the first input resonator is in the dark state; illuminating the plurality of resonator networks with light at the readout wavelength during the first period of time; and detecting a timing of emission of a plurality of photons from the output resonators of the plurality of resonator networks relative to the illumination of the resonator network. method. (Item 99) each resonator network of the plurality of resonator networks further includes a second input resonator, the second input resonator having a dark state and capable of entering the dark state in response to receiving illumination at a second input excitation wavelength, the detectable characteristic of the time-dependent probability density function relating to whether the second input resonator is in the dark state, the method further comprising: illuminating the plurality of resonator networks with light at the second input wavelength for a second time period after the first time period; illuminating the plurality of resonator networks with light at the readout wavelength during the second period of time; 99. The method of claim 98, further comprising detecting a timing of emission of a plurality of photons from the output resonators of the plurality of resonator networks relative to the illumination of the resonator network during the second time period. (Item 100) each resonator network of the plurality of resonator networks further includes a second input resonator, the second input resonator having a dark state and capable of entering the dark state in response to receiving illumination at a second input excitation wavelength, the detectable characteristic of the time-dependent probability density function relating to whether the second input resonator is in the dark state, the method further comprising: illuminating the plurality of resonator networks with light at the first input wavelength and light at the second input wavelength for a second time period after the first time period; illuminating the plurality of resonator networks with light at the readout wavelength during the second period of time; 99. The method of claim 98, further comprising detecting a timing of emission of a plurality of photons from the output resonators of the plurality of resonator networks relative to the illumination of the resonator network during the second time period. (Item 101) generating a sample of a random variable based on the detected timing of the emission of the plurality of photons during the first time period. The method according to any one of items 98 to 100, further comprising: (Item 102) illuminating the plurality of resonator networks with light at the readout wavelength for a second time period after the first time period; Detecting a timing of emission of a plurality of photons from the output resonators of the plurality of resonator networks relative to the illumination of the resonator network during the second time period; generating a sample of a second random variable based on the detected timing of the emission of the plurality of photons during the second time period; and Item 102. The method of item 101, further comprising: (Item 103) a light source configured to provide illumination at a first input wavelength and a readout wavelength; A light sensor; A resonator network; A controller configured to operate the light source and the light sensor to perform any one of the methods described in items 92 to 102. A system comprising: [Brief description of the drawings]

[0015] [Figure 1A] FIG. 1A is a schematic diagram of a resonator within a label.

[0016] [Figure 1B] FIG. 1B is a state transition diagram of the indicator shown generally in FIG. 1A.

[0017] [Figure 2A] FIG. 2A illustrates the cumulative probability over time of the occurrence of various terminal states of a sign.

[0018] [Figure 2B] FIG. 2B illustrates the probability of a label emitting a photon as a function of time after excitation of the label.

[0019] [Figure 3A] FIG. 3A is a schematic diagram of a resonator within a label.

[0020] [Figure 3B] FIG. 3B is a schematic diagram of a resonator within the label.

[0021] [Figure 3C] FIG. 3C is a schematic diagram of a resonator within the label.

[0022] [Figure 3D] FIG. 3D is a schematic diagram of a resonator within the label.

[0023] [Figure 3E] FIG. 3E is a schematic diagram of a resonator within the label.

[0024] [Figure 3F] FIG. 3F is a schematic diagram of a resonator within the label.

[0025] [Figure 4A] FIG. 4A illustrates the probability of various different labels emitting a photon as a function of time following excitation of the label.

[0026] [Figure 4B] FIG. 4B shows photon counts received from samples of two different labels as a function of time after excitation of the labels.

[0027] [Diagram 5] FIG. 5 is a schematic diagram of an exemplary label.

[0028] [Figure 6A] FIG. 6A is a schematic diagram of a resonator within a label.

[0029] [Figure 6B] FIG. 6B is a schematic diagram of a resonator within the label.

[0030] [Figure 6C] FIG. 6C is a schematic diagram of a resonator within the label.

[0031] [Figure 6D] FIG. 6D is a schematic diagram of a resonator within the label.

[0032] [Figure 6E] FIG. 6E is a schematic diagram of a resonator within the label.

[0033] [Figure 6F] FIG. 6F is a schematic diagram of a resonator within the label.

[0034] [Figure 6G] FIG. 6G is a schematic diagram of a resonator within the label.

[0035] [Figure 6H] FIG. 6H is a schematic diagram of a resonator within the label.

[0036] [Figure 7A] FIG. 7A shows a schematic diagram of a resonator in a network.

[0037] [Figure 7B] FIG. 7B is a schematic diagram of a resonator within a network.

[0038] [Figure 7C] FIG. 7C is a schematic diagram of a resonator within a network.

[0039] [Figure 7D] FIG. 7D is a schematic diagram of a resonator within a network.

[0040] [Figure 8A] FIG. 8A is a schematic diagram of a resonator within a network.

[0041] [Figure 8B] FIG. 8B is a schematic diagram of a resonator within a network.

[0042] [Figure 8C] FIG. 8C is a schematic diagram of a resonator within a network.

[0043] [Figure 8D] FIG. 8D is a schematic diagram of a resonator within a network.

[0044] [Figure 8E] FIG. 8E is a schematic diagram of a resonator within a network.

[0045] [Figure 8F] FIG. 8F is a schematic diagram of a resonator within a network.

[0046] [Figure 9A] FIG. 9A is a schematic diagram of a resonator within a network.

[0047] [Figure 9B] FIG. 9B is a schematic diagram of a resonator within a network.

[0048] [Figure 10A] FIG. 10A is a schematic diagram of a resonator within a network.

[0049] [Figure 10B] FIG. 10B is a schematic diagram of a resonator within a network.

[0050] [Figure 11] FIG. 11 is a flow diagram of an exemplary method.

[0051] [Figure 12] FIG. 12 is a flow diagram of an exemplary method.

[0052] [Figure 13] FIG. 13 is a flow diagram of an exemplary method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In these drawings, similar symbols typically identify similar components unless the context dictates otherwise. The exemplary embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure as generally described and illustrated in the figures herein can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated herein. I. Overview

[0054] DNA self-assembly and other emerging nanoscale fabrication techniques allow for the precise fabrication of many instances of a specified structure at the nanoscale. Such precision can allow fluorophores, quantum dots, dye molecules, plasmonic nanorods, or other optical resonators to be positioned in precise positions and / or orientations relative to one another to create a variety of optical resonator networks. Such resonator networks can be specified to facilitate a variety of different applications. In some examples, the resonator networks can be designed to exhibit a pre-specified time relationship between optical excitation (e.g., by an illumination pulse) and re-emission, which can enable time-multiplexed labels and taggants that can be detected using a single excitation wavelength and a single detection wavelength. Additionally or alternatively, the stochastic nature of the timing of excitation of optical re-emission by these resonator networks can be exploited to generate samples of random variables. These resonator networks can include one or more "input resonators" that exhibit a dark state, and the resonator networks including such input resonators can be configured to implement logic gates or other structures to control the flow of excitons or other energy through the resonator network. Such structures can then be used, for example, to enable detection of a variety of different analytes with a single resonator network, to control the distribution of random variables generated using the resonator network, to further multiplex a set of labels used to image a biological sample, or to facilitate some other application.

[0055] These resonator networks include networks of fluorophores, quantum dots, dyes, Raman dyes, conductive nanorods, chromophores, or other optical resonator structures. The networks may further include antibodies, aptamers, strands of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), or other receptors configured to allow selective binding to an analyte of interest (e.g., a surface protein, a molecular epitope, a unique base sequence, or other unique feature of the analyte of interest). These labels may be used to observe a sample, to identify components of the sample (e.g., to identify cells, proteins, or other particles or substances within the sample), to classify such components based on the identification (e.g., to classify cells in a flow cytometer according to identified cell types or other characteristics), or to facilitate some other application.

[0056] In this exemplary application, such a resonator network can be applied to detect the presence of, distinguish between, or otherwise observe a number of different labels in a biological or material sample or other environment of interest (e.g., by linking the resonator network to antibodies, aptamers, or analyte-specific receptors). Such labels can enable detection of the presence, amount, or location of one or more analytes of interest in a sample (e.g., in a channel of a flow cytometry device). Having access to a large library of distinguishable labels can enable simultaneous detection of a number of different analytes. Additionally or alternatively, access to a large library of distinguishable labels can enable more precise detection of a particular analyte (e.g., a cell type or subtype of interest) by using multiple labels to bind to the same analyte, e.g., different epitopes, surface proteins, or other features of that analyte. Furthermore, access to such a large library of labels can enable selection of labels according to the estimated density or number of corresponding analytes of interest, e.g., to ensure that when optically interrogating such a sample, the effective brightness of different labels corresponding to analytes with different concentrations in the sample will be approximately the same.

[0057] Such labels can be distinguishable by differing in excitation spectra, emission spectra, fluorescence lifetimes, fluorescence intensity, susceptibility to photobleaching, dependence of fluorescence on binding to the analyte or some other environmental factor, polarization of the re-emitted light, or some other optical property. However, when relying on differences in emission or excitation spectra, it can be difficult to create large libraries of distinguishable labels due to limitations on available fluorophores or other optically distinguishable substances, and limitations on wavelength transparency / compatibility of common sample materials of interest.

[0058] The present disclosure provides methods for specifying, fabricating, detecting, and identifying optical labels that differ in terms of their temporal decay profiles and / or excitation and emission spectra. Additionally or alternatively, the provided labels can have enhanced brightness compared to existing labels (e.g., fluorophore-based labels) and can have configurable brightness to facilitate panel design or to allow for the relative brightness of different labels to facilitate some other consideration. Such labels can differ in terms of the time-dependent probability of re-emission of light by the label after excitation of the label (e.g., by an ultrafast laser pulse). Additionally or alternatively, such labels can include a network of resonators that increases the difference between the excitation wavelength of the label and the emission wavelength of the label (e.g., by interposing multiple intermediary resonators between the input and output resonators to allow exciton transmission between the input and output resonators where direct energy transfer is not favored). Furthermore, such labels can include logic gates or other optically controllable structures to allow further multiplexing when detecting and identifying the labels.

[0059] Because such labels can differ with respect to their temporal decay profiles, such labels can be detected and identified in a sample by illuminating the sample with a single wavelength of illumination and / or by detecting light responsively emitted from the sample within a narrow band of wavelengths. In such detection examples, the apparatus used to interrogate samples containing such labels can be simplified and / or the interrogation of multiple labels in sample media with stringent optical requirements (e.g., exhibiting significant autofluorescence, having a particular susceptibility to photobleaching or other deleterious optical effects, having a narrow band of transparency) can be facilitated.

[0060] Each label (or other resonator network described herein) includes at least one input resonator capable of receiving optical energy (e.g., energy from an interrogation laser pulse) to excite the network, and at least one output resonator capable of emitting photons in response to receiving energy from the input resonator through the resonator network (e.g., as excitons transmitted via Förster resonance energy transfer (FRET) and / or some other mechanism). The relative positions of the input resonator(s), output resonator(s), and one or more additional intermediary resonators allow for the transfer of excitons, electric fields, surface plasmons, or other energy from the resonator to the resonator, such that when a particular resonator of the network is excited (e.g., an input resonator), that resonator has the opportunity to transfer its excitation energy to one or more other resonators (e.g., an output resonator). The number and arrangement of resonators present within each instance of such a label (e.g., multiple input resonators of each instance of a label) can be specified to set the brightness of the label (e.g., to normalize the intensity of light emitted from the sample by different labels that may be bound to analytes present in the sample).

[0061] Thus, the temporal decay profile of a particular label can be related to the properties of the resonator network, such as the identity and properties of the resonators (e.g., probability of non-radiative decay, probability of resonance energy transfer to another resonator, or probability of radiative emission), as well as the relative position and orientation of the resonators within the network. For example, a number of intermediate resonators can be placed in series between an input resonator and an output resonator to form a resonator wire. The temporal decay profile of such a resonator network can be related to the length of the wire, e.g., a longer wire can exhibit a decay profile with a broader peak located later in time. A library of distinguishable labels can be created by varying the properties of the resonator network for each of the labels such that the corresponding decay profiles of the labels are distinguishable. Thus, by illuminating the sample and detecting the timing of the emission of photons from the sample relative to the illumination, the presence, identity, or other properties of such labels in the sample can be detected.

[0062] Additionally or alternatively, the stochastic nature of the excitation and re-emission of light from such a resonator network and the time difference can be exploited to generate samples of random variables. The temporal decay profile of such a resonator network can be static (i.e., set by the structure of the network and not easily modified or controlled), and in such an example, the timing of photon re-emission from such a network (or a population of such networks) can be used to generate samples of a single random variable related to the static temporal decay profile of the network. Alternatively, such a network can include one or more input resonators that, when appropriately optically stimulated, assume a dark state (i.e., can be disabled in terms of the ability to transmit and / or receive energy to and from other resonators in the network). Such input resonators can be used to tune the temporal decay profile of the network over time, for example, allowing the resonator network to be used to generate samples of a variety of different random variables related to the different optically controllable temporal decay profiles of each of the networks.

[0063] Such resonators exhibiting a dark state can be incorporated into a network such that their dark state inhibits and / or promotes the transmission of energy between different parts of the network (e.g., between an input and an output). For example, such an input resonator can be located between two other resonators such that when the input resonator is in the dark state, energy transmission between the two other resonators via the input resonator is impeded. In another example, an input resonator can be positioned in a network such that when the input resonator is not in the dark state, it preferentially receives energy from one or more other resonators in the network. Thus, putting the input resonator in the dark state can act to prevent the input resonator from "sinking" energy from the network.

[0064] Thus, a resonator exhibiting its dark state can be incorporated into a resonator network to provide a logic function within the network. For example, such a resonator network can be configured to perform a logic operation, where an input is "programmed" into the network by inducing an associated input resonator to a dark state (e.g., by illuminating the associated input resonator with radiation at the excitation wavelength of the input resonator(s). This logic operation can then be "read out" by optically exciting additional resonators ("readout resonators") of the network and detecting photons emitted in response from an output resonator of the network.

[0065] Such resonator networks can also be used to sense properties of a sample or another environment of interest, for example to detect the presence or amount of one or more analytes of interest in a biological sample. One or more resonators of the network can have an intrinsic sensitivity to a variable of interest (e.g., the resonators can be quenched when the pH of the environment is within a particular range). Additionally or alternatively, the network can include a sensor configured to alter one or more detectable properties of the resonator network (e.g., the probability of reemission in response to excitation, the temporal decay profile of excitation and reemission). For example, the network can include a receptor (e.g., an antibody, an aptamer, a strand of complementary DNA or RNA) that quenches the resonators of the network when bound to the analyte, quenches the resonators of the network when not bound to the analyte, modifies the relative position of one or more resonators of the network when bound to the analyte, or otherwise modifies the configuration and / or behavior of the resonator network depending on whether it is bound to an instance of the analyte. Such resonator networks can include logic elements (e.g., resonators that exhibit one or more dark states), and a single resonator network can be used to detect multiple different analytes (e.g., by controlling input resonators in the dark state to "address" specific receptors among various different receptors in the network).

[0066] Such a resonator network of labels can be created through a variety of techniques. In some examples, DNA self-assembly can be used to ensure that the relative positions of the resonators in the label correspond to designated positions according to the desired temporal decay profile. For example, each resonator of the network can be linked to a respective designated DNA strand. Each DNA strand can include one or more moieties that complement portions of one or more other DNA strands such that the DNA strands self-assemble into a nanostructure that maintains the resonators at the designated relative positions. II. Labeling using directed resonator networks for time multiplexing

[0067] The labels described herein can be made to be distinguishably different in terms of their temporal decay profiles in response to irradiation. This can be achieved by specifying the identity, number, relative position and / or orientation, topology, or other properties of the network of resonators of the label. These properties of the resonators can be specified such that the resulting temporal decay profile corresponds to a desired temporal decay profile. For example, the resonator network of the label can be specified such that the temporal decay profile of the label includes one or more peaks having respective specified widths, normalized amplitudes, mean delay times, or other properties or characteristics, such that the temporal decay profile of the label is distinguishable from one or more other labels and / or background materials (e.g., fluorescent proteins of cells or other biological samples) present in the sample or environment of interest.

[0068] In general, the resonator network of such labels includes at least one input resonator, one or more intermediate resonators, and at least one output resonator. The resonators may be fluorophores, Raman dyes, quantum dots, dyes, pigments, conductive nanorods, or other nanostructures, chromophores, or other materials, and may receive energy from and / or transmit energy to one or more other resonators in the network in the form of excitons, electric fields, surface plasmons, or some other form of energy that can be transferred as a unit from one resonator to another.

[0069] At least one input resonator of the network can receive energy into the network as a result of a label being irradiated (e.g., by a laser pulse having a wavelength corresponding to the excitation wavelength of the input resonator). At least one output resonator of the network can transmit energy from the network in the form of photons whose timing of emission relative to the irradiation of the label can be detected and used to identify the label, along with multiple additional photons detected from the sample (e.g., additional instances of the label in the sample, or specific instances of the label resulting from repeated irradiation of the sample). The input resonators, output resonators, and one or more intermediary resonators are arranged to form a resonator network such that energy (e.g., excitons) received into the network via the input resonator(s) can be transmitted through the network to the output resonator(s).

[0070] It should be noted that the labeling of any particular resonator in a network as "input", "intermediate", or "output" is meant to be non-limiting. A particular resonator in a network can act as an intermediary resonator for one or more other resonators, and can also act as an input resonator and / or an output resonator for the network. Furthermore, a label as described herein can include only two resonators (e.g., an "input" resonator and a "modulation" resonator), which can be queried by exposing the label to radiation capable of exciting at least the input resonator as described herein, and detecting the timing of the emission of multiple photons emitted in response from at least one of the input resonator or the modulation resonator relative to the radiation. The input resonator (e.g., a fluorophore, a conductive nanorod, or other nanoparticle, a quantum dot) can be positioned within the label such that energy (e.g., excitons, electric field) can be transferred from the input resonator to the modulation resonator (e.g., a fluorophore, a conductive nanorod, or other nanoparticle, a quantum dot, a non-fluorescent light-absorbing molecule, or a substance) and / or back from the modulation resonator to the input resonator.

[0071] The identity of a label having such two resonators, or any other label described herein that can emit light from the same resonator and thereby receive energy from irradiation based on the detected relative timing of the emission of multiple photons, can then be determined. For example, the label can be identified by comparing the detected timing to a set of known temporal decay profiles, where the label corresponds to one of the temporal decay profiles of the set of known temporal decay profiles. In such an example, the temporal decay profile of the label can be tailored by specifying the identity of the resonator and precisely controlling the relative position and / or orientation of the resonators (e.g., using DNA self-assembly).

[0072] As a result of the particular configuration of the resonators and resonator network as a whole, the timing of the emission of photons from the output resonator (or the label's input resonator, mediator resonator, modulation resonator, or any other resonator) relative to the illumination of the label exhibits a unique time delay profile. Thus, the timing of the emission of multiple photons from the sample relative to the illumination of the sample (during one or more illumination periods) can be detected and used to identify a label in a sample based on the particular temporal decay profile(s) of the label(s) in the sample, or to identify one or more additional labels in the sample.

[0073] FIG. 1A shows a schematic diagram of resonators of an exemplary label 100 described herein and potential energy transfer between these resonators. The exemplary label 100 includes an input resonator 110a, an intermediary resonator 110b, and an output resonator 110c. The input resonator 110a can be excited by receiving irradiation 101 from the environment of the label 100. After being excited, the input resonator 110a can radiate a photon 140a, non-radiative decay 130a as energy is lost to the environment (e.g., as heat), or transfer energy 120a (e.g., via a Forster resonance energy transfer process) to the intermediary resonator 110b. In response to being excited, the intermediary resonator 110b can radiate a photon 140b, non-radiative decay 130b, transfer energy 120b to the output resonator 110c, or transfer energy 125a to the input resonator 110a. In response to being excited, the output resonator 110c can radiate a photon 140c, non-radiatively decay 130c, or transfer energy 125b to the mediator resonator 110b.

[0074] By way of example, the relative probabilities of different energy transitions / transfers are illustrated in Figure 1A by the relative line thicknesses of the representative arrows. Thus, for the exemplary label 100, input resonator 110a most likely transfers energy to intermediate resonator 110b, which in turn transfers energy to output resonator 110c, which then radiates photon 140c.

[0075] The time dependence of each transition from a particular resonator can be represented over time by a random variable with a particular distribution. For example, the transfer of energy (e.g., excitons) by the mediator resonator 110b to the output resonator 110c can be done in response to a random variable that is exponentially distributed in the time domain. These random variables, together with the structure and other properties of the resonator network of the label 100, can be used to model the behavior of the label 100, for example, using a continuous-time Markov chain. Such a model can then be used to predict the overall temporal decay profile of the label 100 from the excitation of the input resonator 110a by the irradiation 101 to the emission of the photon 140c by the output resonator 110c.

[0076] FIG. 1B shows a state diagram that can be used to model the potential states of the label 100 depending on the excitation state of the resonators. The model assumes that only a single energy (e.g., a single exciton) is received from the illumination 101 through the input resonator 110a, and therefore only one of the resonators of the label 100 can be excited. This single energy can then be transferred between resonators and / or exit the resonator network (e.g., via emission of a photon or by a non-radiative decay process). The model includes states for excitation of the input resonator 110a ("excited input"), the intermediate resonator 110b ("excited intermediate"), and the output resonator 110c ("excited output"). The model also includes absorption states for non-radiative decay from each of the resonators ("attenuated input", "attenuated intermediate", and "attenuated output"), as well as radiative photon emission from each of the resonators ("emitted input", "emitted intermediate", and "emitted output").

[0077] The transition probabilities for each transition are also shown. These transition probabilities can be related to the identity of the resonators (e.g., the intrinsic fluorescence lifetime of the resonators, the Förster radius), the relative position, distance, and / or orientation of the resonators (e.g., the distance relative to the Förster radius of a pair of resonators), or some other property of the label 100. Thus, the relative positions and identities of the resonators within the resonator network can be specified to control the transition probabilities and topology of the model, and thus the predicted temporal decay profile of the label 100.

[0078] In one example, the label includes an Alexa Fluor448 dye as an input resonator and an Alexa Fluor594 dye as an output resonator, and the input and output resonators are located in close proximity to each other, such that the input resonator can transmit energy to the output resonator as an exciton in response to the input resonator being excited by irradiation (e.g., by a very short laser pulse). Figure 2A shows the probability over time that the input resonator emits a photon ("AF448 fluorescence"), the input resonator decays ("AF448 non-radiative decay"), the output resonator emits a photon ("AF594 fluorescence"), and the output resonator decays ("AF594 non-radiative decay"). Figure 2A shows the probability over time that at least one of these processes has occurred ("exciton relaxation").

[0079] From these probabilities, the temporal decay profile of this label can be determined. This is shown in FIG. 2B as "AF594 fluorescence." Thus, if multiple instances of the label are present in the sample and / or a sample containing a single instance of the label is irradiated multiple times, the timing of photon emission from the output resonator (e.g., emission wavelength of the Alexa Fluor594 dye) should exhibit a distribution over time, relative to the illumination of the sample, that corresponds to the temporal decay profile shown. Conversely, the timing of photon emission from the input resonator (e.g., emission wavelength of the Alexa Fluor488 dye) should exhibit a distribution over time, relative to the illumination of the sample, that corresponds to the other temporal decay profile shown in FIG. 2B ("AF488 fluorescence").

[0080] The temporal decay profile of a particular label at a particular wavelength (e.g., the emission wavelength of the output resonator of the label) can be controlled by specifying the topology, structure, resonator type, or other characteristics of the resonator network of the label. Thus, a library of different distinguishable labels can be created by specifying the respective resonator networks such that the temporal decay profiles are distinguishable from each other and / or background processes (e.g., fluorescence) within a sample or other environment of interest (e.g., by a particular detection device having a particular time resolution for detection of photons from a sample containing such labels). This can include specifying the temporal decay profiles to maximize or increase a measure of statistical divergence (e.g., Kullback-Leibler divergence, Jensen-Shannon divergence, Bregman divergence, or Fisher information) between the temporal decay profiles. Additionally or alternatively, the temporal decay profiles can be specified to differ with respect to the timing, width, shape, number, or other characteristics of one or more peaks present in the temporal decay profiles.

[0081] A resonator network can be determined to provide a desired temporal decay profile using various methods. For example, heuristic methods can be used to vary the number of resonators in the resonator wires of the network, the number of parallel resonator wires in the network between the input and output of the network, the identity of the resonators of the network (e.g., with respect to the excitation and / or emission spectra of the resonators), or other characteristics of the network to provide associated changes in the number, width, or delay of peaks in the temporal decay profile, the average delay of the temporal decay profile, or other characteristics of the temporal decay profile. Additionally or alternatively, automated methods such as genetic algorithms, machine learning, or other techniques can be used to specify the configuration of one or more resonator networks such that the temporal decay profiles are distinguishable or provide some other benefit. The temporal decay profiles of such labels can then be experimentally verified, and the experimentally determined temporal decay profiles can be used to identify labels present in a sample or other environment of interest.

[0082] FIG. 3A shows a schematic diagram of the resonators of an exemplary label 300a described herein and the potential energy transfer between these resonators. The exemplary label 300a includes an input resonator ("IN"), two intermediate resonators ("M1" and "M2"), and an output resonator ("OUT"). These input resonators can be excited by receiving radiation from the environment of the label 300a (e.g., radiation at the excitation wavelength of the input resonators). The two intermediate resonators are arranged as a resonator wire between the input resonator and the output resonator. That is, the two intermediate resonators are arranged such that each resonator in the wire can receive energy from and / or transmit energy to two adjacent resonators. The number of resonators in such a resonator wire can be specified to adjust the temporal decay profile of the label 300a, for example to adjust the delay or width of a peak in the decay profile, to increase the average decay of the decay profile, or to adjust some other characteristic of the temporal decay profile.

[0083] By way of example, the relative probability of different energy transfers between resonators is illustrated in FIG. 3A by the relative line thickness of the representative arrows. Thus, for the exemplary label 300a, the input resonator is more likely to transfer energy to the first mediator resonator (M1) than vice versa. Also, the second mediator resonator (M2) is more likely to transfer energy to the output resonator than vice versa. The first mediator resonator is approximately as likely to transfer energy to the second mediator resonator as the second mediator resonator is to transfer energy to the first mediator resonator. Thus, energy generally travels in one direction, from the input resonator to the mediator resonator and from the mediator resonator to the output resonator. Conversely, energy can travel in both directions between the mediator resonators before being emitted from the output resonator (or one of the mediator resonators) as photons or before being lost via non-radiative processes.

[0084] Label 300a in FIG. 3A illustrates a label incorporating a two-element resonator wire, where energy can be transferred bidirectionally between adjacent resonators in the wire. Such bidirectional energy transfer can be achieved by selecting the resonators in the wire such that the emission spectrum of the first mediator resonator largely overlaps with the excitation spectrum of the second mediator resonator, and vice versa. This can be achieved by selecting the same fluorophore (e.g., Alexa Fluor 594) for both mediator resonators in the wire.

[0085] Alternatively, one or more pairs of mediator resonators in a resonator network (e.g., adjacent resonators in a resonator wire) can be specified such that energy generally travels in one direction between such paired resonators. FIG. 3B shows a schematic diagram of an exemplary label 300b including such a resonator pair. The exemplary label 300b includes an input resonator ("IN"), two mediator resonators ("M1" and "M2"), and an output resonator ("OUT"). The relative probabilities of different energy transfers between these resonators are indicated in FIG. 3B by the relative line thickness of the representative arrows. Thus, for the exemplary label 300b, the input resonator is more likely to transfer energy to the first mediator resonator (M1) than vice versa. Also, the first mediator resonator (M1) is more likely to transfer energy to the second mediator resonator (M2) than vice versa, and the second mediator resonator (M2) is more likely to transfer energy to the output resonator than vice versa. Thus, energy generally travels in one direction from the input resonator through the intermediate resonator to the output resonator. The temporal decay profile of such a label 300b may exhibit narrower and / or less delayed peaks and / or an overall reduced average delay compared to the temporal decay profile of the first exemplary label 300a.

[0086] The labels described herein may include multiple resonator wires of any length and / or composition (e.g., multiple resonator wires of similar or different composition connected between common input and output resonators). For example, FIG. 3C shows a schematic diagram of an exemplary label 300c including a resonator wire of any length (i.e., including "n" resonators). The exemplary label 300c includes an input resonator ("IN"), "n" mediator resonators ("M1", "M2", "M3", "M4", ..., and "Mn"), and an output resonator ("OUT"). As shown in FIG. 3C by the relative line thickness of the representative arrows, the energy transfer between adjacent mediator resonators in the resonator wire is bidirectional. However, one or more of the transitions between the resonators of such a pair of resonator wires may be unidirectional.

[0087] The resonator networks of the markers described herein can exhibit different topologies, such as branched topologies. Such branched topologies can include multiple different resonator wires, the ends of which are connected to input resonators, output resonators, intermediate resonators (e.g., terminal resonators of one or more other resonator wires), or connected in some other manner to provide markers exhibiting a desired temporal decay profile.

[0088] FIG. 3D shows a schematic diagram of an exemplary label 300d including two paths through which energy can travel through a resonator network to be emitted by an output resonator. The exemplary label 300d includes an input resonator ("IN"), a first intermediary resonator ("M1") that can receive energy from the input resonator and transmit energy to the output resonator, and three additional resonators ("M2", "M3", and "M4") arranged as resonator wires that can transmit energy from the input resonator to the output resonator. As shown by the relative line thickness of the representative arrows, energy transfer between adjacent intermediary resonators in the resonator wire is bidirectional. Such a resonator network can exhibit a temporal decay profile that is a mixture of other temporal decay profiles, for example, a first temporal decay profile of a label that includes only the input, output, and first resonator, and a second temporal decay profile of a label that includes only the input, output, and resonator wire (i.e., intermediary resonators "M2", "M3", and "M4"). A resonator network can include two- or three-dimensional regions of intermediate, input, and / or output resonators. Any such resonator network can be determined via a genetic algorithm or other automated process to provide a desired temporal decay profile or to meet some other criteria.

[0089] The resonator network of the labels described herein can include multiple input resonators and / or multiple output resonators. Such multiple input and / or output resonators can be provided to provide various benefits, such as tailoring the effective temporal decay profile of the label, increasing the probability that the label is excited in response to irradiation and / or increasing the effective brightness of the label, providing wavelength-dependent multiplexing for the excitation and / or detection of the label (e.g., by the label exhibiting different temporal decay profiles depending on which of the multiple spectrally distinct input resonators is excited), or providing some other benefit. The multiple input resonators can be the same (i.e., each can include the same fluorophore, quantum dot, or other optical element) or different (e.g., can be different fluorophores, such that the different input fluorophores are excited by respective different wavelengths of light). The multiple output resonators can be the same (i.e., each can include the same fluorophore, quantum dot, or other optical element) or different (e.g., can be different fluorophores, such that the different output fluorophores emit respective different wavelengths of light). Additionally or alternatively, a single instance of a label may include multiple separate or interconnected resonator networks (e.g., multiple copies of the same resonator network) to increase and / or control the effective brightness of the label, to reduce the time and / or number of light pulses required to identify the label, or to provide some other benefit.

[0090] FIG. 3E shows a schematic diagram of an exemplary label 300e including an input resonator ("IN"), two mediator resonators ("M1" and "M2"), and a first output resonator ("OUT1"). The label further includes a second output resonator ("OUT2") and a third output resonator ("OUT3"), as needed. The additional output resonators can be provided to adjust the temporal decay profile of the label 300e. For example, the second output resonator can be the same as the first output resonator (e.g., can have the same emission spectrum) and can be added to the label 300e to increase the probability that the label 300e will emit energy after the second mediator resonator is excited (e.g., by doubling the probability that energy from the second mediator resonator can be transferred from one of the first or second output resonators and then one of the output resonators can emit the received energy as photons).

[0091] Additionally or alternatively, the additional output resonators can be different in terms of emission wavelength or emission spectrum and can be provided to facilitate spectrally multiplexed detection of temporal decay profiles at different wavelengths corresponding to the different output resonators. For example, a third output resonator can be different from the first output resonator (e.g., can have a different emission spectrum) and this third output resonator can be added to the label 300e, so that the label 300e can emit photons from one or the other of the output resonators. Such photons, which differ in terms of wavelength, can be detected and used separately to determine two different temporal decay profiles for the label 300e (or from a sample containing the label), and such multiple detected temporal decay profiles can be used to identify the label 300e.

[0092] FIG. 3F shows a schematic diagram of an exemplary label 300f including a first input resonator ("IN1"), two intermediate resonators ("M1" and "M2"), and an output resonator ("OUT"). The label may further include a second input resonator ("IN2") and a third input resonator ("IN3"). The additional input resonators may be provided to adjust the temporal decay profile of the label 300f or to increase the probability that the label 300f is excited by exposure to irradiation. For example, the second input resonator may be the same as the first input resonator (e.g., may have the same excitation spectrum) and may be added to the label 300f to increase the probability that the label 300f receives energy in response to irradiation (e.g., by doubling the probability that a photon of the irradiation is absorbed by at least one of the first or second input resonators).

[0093] Additionally or alternatively, the additional input resonators can be provided to facilitate spectrally multiplexed excitation of the label 300f and thus spectrally multiplexed detection of the temporal decay profiles at different wavelengths corresponding to the different input resonators. For example, a third input resonator can be provided to the label 300f, which can be different from the first input resonator (e.g., can have a different excitation spectrum) and can be added to the label 300f to excite the label 300f during a first and second time period by first and second irradiations that are different in terms of wavelengths provided during the first and second time periods, respectively. Such excitation of the label 300f that differs with respect to the input resonator with which the label 300f is excited can be characterized by respective different temporal decay profiles and can thus be detected and used during separate time periods to determine two different temporal decay profiles for the label 300f (or from a sample containing the label), and such multiple detected temporal decay profiles can be used to identify the label 300f.

[0094] It should be noted that the resonator network of the label described herein can also be used to generate samples of random variables. The samples of random variables can be generated based on the time difference between the excitation of the resonator network / label and the timing of the detection of one or more photons emitted in response from the resonator network / label. The particular distribution of the random variable can be related to the temporal decay profile of the resonator network / label. For example, the value of the generated sample can be a function of the detected time difference between the timing of the irradiation of the resonator network(s) and the timing of the detection of one or more photons emitted in response from the resonator network(s). The distribution of the generated random variable can be related to the temporal decay profile of the resonator network(s) and the function applied to generate samples of the random variable from the detected time difference. The structure of the resonator network(s) can be specified such that the function for generating samples from the detected time difference is computationally tractable and / or efficient to compute (e.g., exhibits a particular temporal decay profile or other time-dependent probability density function). III. Exemplary Systems and Methods for Identifying a Label in a Sample

[0095] In various applications, it is beneficial to interrogate a sample (e.g., a biological sample, or a stream of cells in a flow cytometer) or some other environment of interest to detect the presence, identity, absolute or relative amount, or other property of a label described herein that may be present in the sample or other environment of interest. Such interrogation may facilitate imaging of the sample, for example to determine the location, concentration, or other information regarding one or more analytes present in the sample and to which one or more various labels are configured to bind. Such interrogation may facilitate identification of cells, proteins, RNA strands, or other components of the sample to classify such components or provide some other benefit. For example, a flow cytometry device may include a flow channel through which cells (or other particles of interest) flow. As described herein, such a flow channel may be interrogated to identify one or more labels and / or cell types or subtypes in the channel, to determine characteristics of the cells, or to determine some other information based on the identified labels. Such information may then be used to classify the cells, for example according to cell type.

[0096] Such methods of detecting and / or identifying labels in an environment of interest can include providing illumination (e.g., in the form of one or more very short pulses of illumination) to the environment of interest and detecting one or more characteristics of photons emitted from the environment in response to the illumination (e.g., the wavelength or spectrum of such photons, e.g., the timing of emission of such photons relative to the timing of the application of one or more pulses of illumination). This can include providing a single pulse of illumination and detecting responsively emitted photons from multiple instances of one or more labels in the environment. Additionally or alternatively, one or more instances of one or more labels can be illuminated multiple times with multiple pulses of illumination and the timing of responsively emitted photons relative to the illumination pulses can be detected. Information regarding the timing of the responsively emitted photons can then be used to identify one or more labels present in the environment, determine the binding state or other characteristics of such labels, determine the absolute or relative amount of the label(s) in the environment, or determine some other information related to one or more labels described herein present in the environment.

[0097] The illumination can be provided to the environment as one or more illumination pulses. The provided illumination can have a specified wavelength, e.g., an excitation wavelength of one or more input resonators of the labels. Such excitation wavelength can be common to some or all of the labels present in the environment of interest, e.g., because some or all of the labels include the same fluorophore, quantum dot, dye, or other optical substance or structure as an input resonator(s). Additionally or alternatively, multiple different wavelengths of light can be provided to excite, e.g., multiple different input resonators of multiple different labels. In some examples, such different wavelengths of light can be provided at different times (e.g., as part of different illumination pulses) to facilitate spectrally multiplexed detection of multiple different labels and / or multiple different sets of labels. In some examples, a single label can include multiple different input resonators, and the different input resonators can be excited by light of each different wavelength, e.g., as part of each different illumination pulse.

[0098] To improve identification of labels within an environment, the illumination pulses used to interrogate the environment can be ultrashort pulses (e.g., pulses having durations on the order of attoseconds to nanoseconds). Such ultrashort pulses can be provided as broadband pulses emitted from a mode-locked oscillator. In examples where the labels include resonators having long-lived states (e.g., lanthanide atoms or other lanthanide compounds or complexes), the illumination pulses can have longer durations, e.g., on the order of microseconds.

[0099] For such an illumination pulse, the timing of the emission of photons from the environment in response to the illumination pulse can be detected in a variety of ways. In some examples, the timing of individual photons can be detected using, for example, one or more single-photon avalanche diodes, photomultiplier tubes, or other single-photon detectors. The output of such detectors can be used as part of a time-correlated single-photon counter to determine a count of photons determined as a function of time after the illumination pulse is provided to the environment. The timing of such detected photons can be used to determine a probability density function for the timing of the emission of photons from the sample in response to illumination of the sample.

[0100] Additionally or alternatively, detecting the timing of photon emission from the environment may include detecting the timing of one or more peaks in the rate or intensity of emitted photons, or detecting some other aggregate characteristic of the timing of the emitted photons (e.g., determining a delayed timing of a peak in the photon emission rate that can be matched to the delay of a corresponding peak in a known temporal decay profile). Such detection may include applying a peak detector, a differentiator, a matched filter, or some other analog or digital signal processing technique to the output of a single-photon avalanche diode or other photodetector element configured to receive photons emitted from the environment of interest.

[0101] One or more known labels may be present in the environment of interest, and it is useful to determine the identity of such labels and / or some other information regarding the labels in the environment. As described above, such labels may be distinguished according to their temporal decay profiles, i.e., each known label may be characterized by a respective different temporal decay profile. Thus, the identity of one or more labels present in the environment may be determined by comparing the detected timing of the emission of photons from the environment with a dictionary of temporal decay profiles, each of which corresponds to a respective known label that may be present in the environment.

[0102] FIG. 4A shows six different temporal decay profiles, each corresponding to one of six known labels. Each of the known labels is induced by the same input resonator (e.g., Alexa The known labels have a first resonator (e.g., Alexa Fluor 430) and an output resonator (e.g., Alexa Fluor 750) which together with one or more of the same intermediary resonators (e.g., Alexa Fluor 594) form a resonator wire. The known labels differ with respect to the number of intermediary resonators. Information regarding the timing of the photons received from the environment can be compared to the temporal decay profile and used to determine which, if any, of the known labels are present in the environment. This can include comparing the delay in the peak rate of emission of photons from the environment to the delay of the respective peaks of the known temporal decay profile.

[0103] Additionally or alternatively, the timing of the detected photon emissions can be used to determine a probability density function for the timing of photon emissions from the sample in response to illumination of the sample. The probability density function so determined can then be compared to the temporal decay profiles of known labels and used to identify one or more labels present in the environment. FIG. 4B shows the counts of detected photons over time from two different samples within multiple discrete time ranges relative to illumination of the sample (time 0). The first count (indicated by the black rectangle) is received from the first sample containing known label "6" from FIG. 4A, and the second count (indicated by the white rectangle) is received from the second sample containing known label "1" from FIG. 4A. These counts can be used to determine first and second probability density functions for the first and second samples, respectively, which can be compared to the six known temporal decay profiles to identify which of these known labels are present in each of the samples. Such a comparison can include determining a measure of statistical divergence (e.g., Kullback-Leibler divergence, Jensen-Shannon divergence, Bregman divergence, or Fisher information) between the determined probability density function and each of the known temporal decay profiles. The labels present in the sample can then be determined, for example, by selecting the known labels that correspond to the minimum of the determined statistical divergence measures.

[0104] Similar or different methods can be used to determine whether multiple labels are present in a sample and, if so, to identify such multiple labels. In some examples, the identity of cells or other components of an environment (e.g., a flow channel of a flow cytometry instrument) can then be determined based on the identity of the labels in the environment, e.g., based on a determination that all of a subset of known labels are simultaneously present in a flow channel or other environment of interest.

[0105] Various methods can be used to determine how many of a set of known labels are present in an environment and to identify the labels present. For example, an expectation maximization algorithm can be used in conjunction with a statistical mixture model to determine the most likely labels present in the environment based on a determined probability density function for the timing of photon emission from the environment in response to illumination of the environment. Such a mixture model can be based on a set of temporal decay functions corresponding to the set of known labels. Such expectation maximization algorithms and mixture models can also be used to determine the relative amounts of such multiple labels in a sample.

[0106] Interrogating the environment can include detecting the timing of emission of photons within a plurality of different wavelength ranges. This can be done to detect the timing of emission of photons from two different output resonators of the label. Additionally or alternatively, this can be done to detect the timing of emission of photons from the output resonator, one or more intermediary resonators, and / or the input resonator of the label.

[0107] Furthermore, one or more of the labels present in the environment may include resonators that exhibit a dark state, and thus the temporal decay profile of the label may depend on whether the resonators that exhibit a dark state are in their respective dark states. For example, the label may include a resonator that exhibits a first dark state, and may exhibit a first temporal decay profile when the resonators that exhibit the first dark state are in the dark state, and the label may exhibit a second temporal decay profile when the resonators that exhibit the first dark state are not in the dark state. In such an example, detecting and / or identifying the label may include detecting the timing of optical excitation and re-emission during a time period when the resonator(s) that exhibit a dark state are not in the dark state, and during a different time period, inducing the resonator(s) that exhibit a dark state to be in the dark state (e.g., by providing irradiation at an excitation wavelength of the resonator(s) that exhibit a dark state) and again detecting the timing of optical excitation and re-emission of the label. IV. Exemplary Resonator Networks

[0108] The resonator networks described herein (e.g., resonator networks included as part of a label) can be fabricated in a variety of ways such that one or more input and / or readout resonators, output resonators, "logic input" resonators exhibiting a dark state, and / or mediator resonators are arranged according to a specified network of resonators, and such that the network's temporal decay profile, network brightness, excitation spectrum, emission spectrum, Stokes shift, or any other optical property of the network, or any other detectable property of interest of the network (e.g., binding state to an analyte of interest) corresponds to that designation (e.g., a specified temporal decay profile, probability of emission in response to illumination). Such arrangement can include ensuring that the relative positions, distances, orientations, or other relationships between the resonators (e.g., between pairs of resonators) correspond to a specified position, distance, orientation, or other relationship between the resonators.

[0109] This can include using DNA self-assembly to fabricate multiple instances of one or more resonator networks. For example, multiple different DNA strands can be linked to each resonator (e.g., input resonator, output resonator, and / or intermediate resonator) of a resonator network (e.g., attaching N-hydroxysuccinimide (NHS) ester modified dye molecules via primary amino modifier groups on thymidines). Pairs of DNA strands can have at least partially complementary portions, such that when the DNA strands are mixed and exposed to specified conditions (e.g., a specified pH, or a specified temperature profile), the complementary portions of the DNA strands align and bond together to form a semi-rigid nanostructure that maintains the relative positions and / or orientations of the resonators of the resonator network.

[0110] FIG. 5 shows a schematic diagram of such a resonator network. An input resonator ("EMITTER ATTO488"), an output resonator ("EMITTER ATTO610"), and two mediator resonators ("MEDIATOR1 ATTO565" and "MEDIATOR2 ATTO565") are linked to respective DNA strands. The linked DNA strands then self-assemble with additional DNA strands into the nanostructure shown, such that the input resonator, mediator resonator, and output resonator form a resonator wire. In some instances, multiple separate identical or different networks can be formed as part of a single instance of a resonator network (e.g., increasing the brightness of the resonator network) through such methods or other techniques.

[0111] The distance between resonators in such a resonator network can be specified so that the resonator network exhibits one or more desired behaviors (e.g., excited by light of a particular excitation wavelength and responsively re-emits light of an emission wavelength according to a specified temporal decay profile). This can include specifying the distance between adjacent resonators so that they can transmit energy between each other (e.g., bidirectionally or unidirectionally) and do not quench each other or otherwise interfere with each other's optical properties. In examples where the resonators are linked to the backbone via linkers (e.g., to the DNA backbone via amide bonds (created by N-hydroxysuccinimide (NHS) ester molecules) or other linker structures), these linkers can be linked to positions on the background specified in consideration of the above as well as the length(s) of the linker. For example, the linking positions can be separated by a distance greater than twice the linker length (e.g., to prevent the resonators from contacting each other and thus quenching each other or otherwise interfering with each other's optical properties). Additionally or alternatively, the linking locations can be separated by a distance less than the maximum distance over which the resonators can transmit energy between one another, for example, the resonators can be fluorophores or some other optical resonators characterized by a Förster radius when transmitting energy via Förster resonance energy transfer, and the linking locations can be separated by a distance less than the Förster radius. V. Labels Using Designed Resonator Networks for Improved Brightness and / or Spectral Multiplexing

[0112] When designing or specifying a set of resonator networks and / or labels for flow cytometry, molecular imaging, optical computing, biosensing, analyte assays, optical random number generation, or any other application (e.g., through a process of panel design), it is beneficial to be able to arbitrarily select the excitation spectrum / wavelength, emission spectrum / wavelength, extinction coefficient, brightness, or other optical properties of one or more resonator networks. A combination of labels including such resonator networks (e.g., an imaging agent including two or more such labels) can then be added to a sample to detect, identify, image, or otherwise observe each analyte of interest in the sample (e.g., by mixing or otherwise adding an imaging agent with multiple labels to the sample). The ability to detect, distinguish, or otherwise observe such labels in a sample can be improved by selecting the respective excitation wavelengths, emission wavelengths, brightness, extinction coefficients, absorption cross sections, or other optical properties of the different labels added to the sample. Such labels can be made to differ in terms of excitation spectrum, emission spectrum, brightness, or other optical properties, as described herein. This can be accomplished by specifying the identity, number, relative position and / or orientation, topology, or other properties of the network of resonators of the label.

[0113] For example, it is beneficial to select and / or configure different labels to differ with respect to excitation wavelength, emission wavelength, Stokes shift, or other spectral properties to facilitate discrimination of such labels. Such discrimination can be based on the detected wavelength of light emitted from the labels as a function of the wavelength of light used to excite the labels, and / or the detected or determined brightness of light emitted from the labels. However, when using labels with a single resonator (e.g., labels with a single fluorophore), the selection of such optical properties may be constrained by the limited library of commercially or otherwise available resonators. Using labels with two resonators (e.g., labels with two fluorophores configured with one fluorophore acting as a donor and the other as an acceptor for Förster resonance energy transfer) can increase the space of potential labels and / or the range of their possible optical properties. However, such labels may still be limited by the availability of resonators with the desired optical properties (e.g., with respect to the magnitude of the effective Stokes shift or other properties of the labels) that are capable of participating in energy transfer between each other (e.g., to have sufficiently overlapping emission and excitation spectra).

[0114] To provide further freedom to specify such optical properties of the label and / or resonator network, the resonator network can include one or more intermediate resonators configured to allow energy to be transferred from the input resonator to the output resonator via one or more intermediate resonators. In such a resonator network, the input and output resonators can be selected (e.g., depending on the excitation spectrum / wavelength, emission spectrum / wavelength, brightness, compatibility with environmental conditions, tendency to photobleaching) without the output resonator being able to receive energy directly (e.g., via resonance energy transfer) from the input resonator. One or more intermediate resonators can then be selected and placed in the resonator network relative to the input and output resonators so that the energy received into the network as a result of the resonator network being irradiated can be transferred to the output resonator via the intermediate resonator(s).

[0115] FIG. 6A shows a schematic diagram of an exemplary resonator network 600a described herein. The exemplary resonator network 600a includes an input resonator ("IN"), an intermediate resonator ("M1"), and an output resonator ("OUT"). The input resonator can be excited by receiving radiation from the environment of the resonator network 600a (e.g., radiation at the excitation wavelength of the input resonator). The input resonators, the output resonators, and the intermediate resonators are arranged such that the intermediate resonators can receive energy from the input resonators and the output resonators can receive energy from the intermediate resonators. The intermediate resonators can be selected to be capable of receiving energy from the input resonators and providing energy to the output resonators (e.g., from a set of commercially available fluorophores). This can include selecting the intermediate resonators such that the emission spectrum of the input resonators overlaps with the excitation spectrum of the intermediate resonators and / or the emission spectrum of the intermediate resonators overlaps with the excitation spectrum of the output resonators.

[0116] To allow for a larger difference between the excitation spectrum / wavelength of the input resonators and the emission spectrum / wavelength of the output resonators of such a resonator network, the resonator network can include additional intermediate resonators (e.g., arranged as resonator wires within the sign). FIG. 6B shows a schematic diagram of an exemplary resonator network 600b described herein. The exemplary resonator network 600b includes an input resonator ("IN"), n intermediate resonators ("M1"-"M4" and "Mn"), and an output resonator ("OUT"). The input resonator can be excited by receiving radiation from the environment of the resonator network 600b (e.g., radiation at the excitation wavelength of the input resonator). The intermediate resonator is arranged as a resonator wire or any length between the input resonator and the output resonator. That is, the n intermediate resonators are arranged such that each resonator in the wire can receive energy from one adjacent resonator and transmit energy to another adjacent resonator. The number and identity of resonators in such a resonator wire can be specified to adjust the difference between the excitation spectrum of the input resonators and the emission spectrum of the output resonators, e.g., to adjust the difference between the excitation wavelength of the input resonators and the emission wavelength of the output resonators. In such an example, each intermediary resonator disposed between the input and output resonators can have an emission wavelength that is intermediate between the excitation wavelength of the input and the emission wavelength of the output resonator, such that, for example, the transfer of energy between each intermediary resonator allows for a controlled reduction in wavelength and / or magnitude of excitons (or other quanta) of energy from the input resonators to the output resonators.

[0117] Furthermore, it is beneficial to increase or otherwise specify the brightness of the labels and / or resonator networks described herein to facilitate detection or identification of such resonator networks. For example, different analytes of interest in a sample can be present in different concentrations or amounts in the sample. In such examples, the number or concentration of proteins, receptors, small molecules, RNA segments, DNA segments, or other analytes of interest present in a sample (e.g., a sample containing cells that can be detected, identified, and / or classified by a flow cytometry device) can differ greatly (e.g., by multiple orders of magnitude). In such examples, adding an imaging agent containing two labels with approximately the same brightness to a sample can result in the brightness of a first of the labels configured to bind to a more prevalent analyte being much greater than the brightness of a second label configured to bind to an analyte that is less prevalent and therefore present in a lower concentration in the sample. The greater brightness of the first label in the sample can prevent or reduce detection of the second label in the sample. In such examples, it is beneficial to configure the second label to have a greater brightness than the first label. However, control over the brightness of such labels can be constrained by the limited library of resonators (eg, fluorophores) that are commercially or otherwise available.

[0118] Additionally, it would generally be beneficial to increase the brightness of the resonator networks described herein to facilitate detection of rare analytes, reduce the intensity of illumination required for such detection (e.g., to reduce photobleaching of labels and / or to prevent damage to samples due to such illumination), or to reduce the intensity of illumination required for some other use of the resonator network (e.g., performing optical logic functions, generating samples of random variables).

[0119] To increase or otherwise target the brightness of such a resonator network (e.g., relative to other labels present in the imaging agent), the resonator network can be configured to have multiple input resonators, output resonators, and / or resonator networks as described herein. The ability to control the brightness of such a resonator network or multiple different resonator networks (e.g., different resonator networks for each of two or more labels present in an imaging agent used for flow cytometry, molecular imaging, or some other application) can facilitate panel selection for flow cytometry (e.g., by allowing greater brightness to be targeted to labels corresponding to less abundant analytes in a sample compared to labels corresponding to more prevalent analytes) or other applications.

[0120] To control the brightness of the resonator network, DNA self-assembly or other techniques can be used to provide a resonator network with many instances of a single resonator or multiple resonators, so that the overall brightness of the resonator network is increased by an amount related to the number of resonator instances. This can include providing many copies of the resonator networks described herein (e.g., 100, 300a-f, 600a-b) to increase the effective brightness of such labels, reduce the number of photons detected from such labels and / or the time required to identify such labels (e.g., the number of irradiation pulses), or provide some other benefit. Such multiple resonators and / or multiple resonator networks can be located far enough apart within the label such that substantially no energy transfer (e.g., resonance energy transfer) occurs between the resonators and / or resonator networks. Additionally or alternatively, the resonators and / or resonator networks can participate in energy transfer (e.g., provide increased brightness of the resonator network via energy storage or some other mechanism, or provide some other benefit).

[0121] Additionally or alternatively, the absolute or relative number of input and / or output fluorophores of the label and / or the resonator network of the label can be specified to control the overall brightness of the resonator network. This can include specifying the resonator network so that one output resonator can receive energy (e.g., excitons) from multiple input resonators and / or a single input resonator can provide energy (e.g., excitons) to multiple output resonators. For example, FIG. 6C shows a schematic diagram of an exemplary resonator network 600c including six input resonators ("IN1"-"IN6") and an output resonator ("OUT"). As shown by the representative arrows, energy transfer can occur directly from each of the input resonators to the output resonator. Such a resonator network can provide increased brightness by increasing the absorption cross section of the resonator network, by providing additional sites that can be excited by irradiation, or through some other mechanism or process.

[0122] In another example, FIG. 6D shows a schematic diagram of an exemplary resonator network 600d including six output resonators ("OUT1"-"OUT6") and an input resonator ("IN"). As shown by the representative arrows, energy transfer can occur directly from the input resonators to each of the output resonators. Such a resonator network can provide increased brightness in instances where the probability of energy transfer from the input resonators to the output resonators is low, where the time to emission of light by the output resonators (e.g., fluorescence lifetime) is long, or through some other mechanism or process.

[0123] It should be noted that the resonator networks described herein can include both input resonators that can provide energy to multiple output resonators and output resonators that can receive energy from multiple input resonators. For example, FIG. 6E shows a schematic diagram of an exemplary resonator network 600e that includes ten input resonators ("IN1"-"IN10") and two output resonators ("OUT1" and "OUT2"). As shown by the representative arrows, energy transfer can occur directly from "IN1" and "IN2" to either of the output resonators. Energy transfer can also occur directly from "IN3"-"IN6" to "OUT1" and from "IN7"-"IN10" to "OUT2".

[0124] In some examples, the resonator network can include one or more intermediate resonators to transfer energy from the multiple input resonators to the output resonators and / or to transfer energy from the input resonators to the multiple output resonators (e.g., to increase the difference between the excitation wavelength of the input resonators and the emission wavelength of the output resonators to adjust the temporal decay profile of the resonator network). FIG. 6F shows a schematic diagram of an exemplary resonator network 600f described herein. The exemplary resonator network 600f includes five input resonators ("IN1"-"IN5"), two intermediate resonators ("M1" and "M2"), and an output resonator ("OUT"). The input resonators can be excited by receiving radiation from the environment of the resonator network 600f (e.g., radiation at the excitation wavelength of the input resonators).

[0125] The two intermediary resonators are arranged as a resonator wire between the input resonator and the output resonator. That is, the two intermediary resonators are arranged so that the first intermediary resonator can receive energy from each of the input resonators, the second intermediary resonator can receive energy from the first intermediary resonator, and the output resonator can receive energy from the second intermediary resonator. The number of resonators in such a resonator wire can be specified to adjust the temporal decay profile of the resonator network 600f (e.g., to adjust the delay or width of a peak in the decay profile, to increase the average decay of the decay profile, or to adjust some other characteristic of the temporal decay profile), to increase the difference between the excitation wavelength of the input resonator and the emission wavelength of the output resonator, or to provide some other benefit.

[0126] The resonator networks of the resonator networks described herein can exhibit different topologies, for example branched topologies. Such branched topologies can include multiple different resonator wires, the ends of which are connected to input resonators, output resonators, intermediate resonators (e.g., terminal resonators of one or more other resonator wires), or connected in some other manner to provide a resonator network exhibiting a desired temporal decay profile.

[0127] In some examples, the label and / or resonator network may include multiple input resonators, intermediate resonators, and / or output resonators interconnected in some manner to provide some or all of the benefits described herein. For example, FIG. 6G shows a schematic diagram of an exemplary resonator network 600g including regions of output resonators ("OUT") and input resonators ("IN"). As shown by the representative arrows, energy transfer can occur from multiple input resonators directly to each of the output resonators, and from each input resonator to one or more output resonators.

[0128] The brightness of such a resonator network or other resonator networks described herein (e.g., 600c, 600d, 600e, 600f) can be adjusted by controlling the ratio of the number of input resonators in the network to the number of output resonators in the network. For example, for a particular input resonator, output resonator, and environmental condition, the brightness of the resonator network can be increased by increasing the ratio of the number of input resonators to the number of output resonators (i.e., increasing the number of input resonators relative to the number of output resonators). Thus, the relative brightness of two labels, including an imaging agent (e.g., an imaging agent used to stain a sample of cells for flow cytometry), can be adjusted by adjusting the ratio of input resonators to output resonators of the two labels (e.g., such that a first ratio of input resonators to output resonators of a first label differs from a second ratio of input resonators to output resonators of a second label by a specified amount).

[0129] The brightness of the label and / or resonator network can also be increased by providing a network of input resonators in which energy received by the input resonators of the network (e.g., from environmental illumination) is transferred to the output resonators of the network via one or more additional input resonators. Such an input resonator region can act to increase the absorption cross section of the resonator network by substantially absorbing a majority of the photons that cross the planar shape and / or three-dimensional volume defined by the input resonator region. Furthermore, the input resonators can exhibit bidirectional energy transfer (e.g., adjacent pairs of input resonators can transfer energy in either direction between them), allowing the resonator region to exhibit a buildup of absorbed energy. Such a buildup can increase the probability that photons that cross the region are absorbed and / or that the energy absorbed by the region is successfully transferred through the overall resonator network to the output resonators. Such a resonator network can include many input resonators per output resonator, for example more than four input resonators per output resonator, or more than 30 input resonators per output resonator. The input resonators in such an input resonator region can all be the same type of input resonator (e.g., the same type of fluorophore with overlapping excitation and emission spectra so that different instances of the fluorophore can transfer energy between each other), or can be different types of resonators (e.g., allowing absorption of photons at multiple different excitation wavelengths or providing some other benefit).

[0130] For example, FIG. 6H shows a schematic diagram of an exemplary resonator network 600h that includes regions of output resonators ("OUT") and input resonators ("IN"). As shown by the representative arrows, energy transfer can occur bidirectionally between adjacent input resonators. In addition, energy transfer can occur directly from multiple adjacent input resonators to an output resonator. Thus, an output resonator can receive energy indirectly from a non-adjacent input resonator via energy transmission through an intermediate input resonator. VI. Exemplary Logical Resonator Networks

[0131] The resonator networks described herein (e.g., part of a sign and used to generate a random number generator) can be configured to exhibit optically modulatable or otherwise controllable behavior. In some examples, the network behavior can be optically controllable, allowing the network to perform logic operations or provide some other benefit. Such optical control can be provided by one or more resonators of the network having an optically inducible "dark state" in which the resonator is incapable or less capable of transmitting and / or receiving energy (e.g., excitons) when in the dark state. Additionally or alternatively, the behavior of the resonator network can relate to properties of the network's environment (e.g., pH level, binding of an analyte of interest to the network), allowing the resonator network to be used to optically detect properties of the network's environment. In some examples, a single resonator network can include both sensor behavior and optically controllable behavior, allowing a single resonator network to be optically controlled to detect multiple different analytes or other environmental variables (e.g., by operating optical logic elements of the network to "address" specific sensed variables of interest).

[0132] Optical control of resonator network behavior can be provided through a variety of methods. In some examples, the state of individual resonators can be optically tuned. This can be done irreversibly, for example, by photobleaching one or more resonators by irradiating the resonator with radiation at the excitation wavelength of the resonator(s) with an intensity above a threshold level. Alternatively, the state of individual resonators can be reversibly tuned, for example, by optically inducing the resonator(s) to a "dark state."

[0133] A "dark state" is a state in which a resonator (e.g., a fluorophore, a quantum dot, or any other optically active molecule or atom described herein) is incapable or reduced of transmitting and / or receiving energy (e.g., photons, excitons) to and / or from the resonator's environment (e.g., other resonators in a resonator network). A resonator can be put into an optically dark state by irradiation with light of a particular wavelength. Such irradiation can put a resonator into a dark state, for example, by transitioning electrons to another energy state that prevents the resonator from absorbing additional energy, by causing the resonator to gain / lose charge (e.g., by receiving electrons from the environment and / or donating electrons to the environment), or by subjecting the resonator to some other process. Thus, a resonator network including one or more such resonators (i.e., resonators that can be optically controlled to be in a dark state) can have a temporal decay profile, a probability of photon re-emission after irradiation, or some other property that is optically controllable by providing sufficient irradiation to put the resonator(s) into a dark state.

[0134] Such dark state resonators can be provided as part of a resonator network to enable optical control of the flow of energy (e.g., excitons) through the network. Such a resonator network can be configured such that the dark state resonators act to facilitate the flow of energy through the resonator network (e.g., from one part of the network to another part and / or from the input of the network to the output of the network) when in the dark state. Additionally or alternatively, the resonator network can be configured such that the dark state resonators act to inhibit the flow of energy through the resonator network (e.g., from one part of the network to another part and / or from the input of the network to the output of the network) when in the dark state. Such optically controllable inhibition and / or excitation can be used to provide logic gates, energy flow control in the resonator network, or various other behaviors and / or applications.

[0135] Such optically inducible dark state resonators can be applied in various ways within a resonator network to inhibit the flow of energy through the resonator network when in the dark state. For example, such an inhibiting resonator can be provided as part of a path for energy flow within the resonator network. Thus, when the inhibiting resonator is in the dark state (e.g., by illuminating the resonator network with light of an appropriate wavelength), it completely or partially prevents the flow of energy along that path, thus completely or partially inhibiting the flow of energy along that path.

[0136] This is illustrated by way of example in FIGS. 7A and 7B, which show an exemplary resonator network 700a at different times. The resonator network 700a includes a readout resonator ("CLK"), an input resonator ("IN"), and an output resonator ("OUT"). When the input resonator is not in a dark state (as shown in FIG. 7A), energy (e.g., excitons) can be transferred from the readout resonator (e.g., in response to the readout resonator being illuminated by light 710a at the excitation wavelength of the readout resonator) to the input resonator and from the input resonator to the output resonator. Thus, when the input resonator is not in a dark state, the illumination 710a absorbed by the resonator network (readout resonator) can be transferred through the resonator network 700a to the output resonator and then emitted from the output resonator as photons 720a.

[0137] Conversely, when the input resonators are in the dark state (indicated by the "IN" resonators depicted in dashed lines in FIG. 7B), no energy (e.g., excitons) can be transferred from the readout resonators to the input resonators, and from the input resonators to the output resonators. Thus, when the input resonators are in the dark state, the illumination 710a absorbed by the resonator network (the readout resonators) is not transferred through the resonator network 700a to the output resonators, and thus the output resonators do not responsively emit photons.

[0138] Additionally or alternatively, such resonators exhibiting an optically inducible dark state can be applied in various ways within a resonator network to promote the flow of energy through the resonator network when in the dark state. For example, such promotion resonators can be provided as part of an alternative dissipative and / or non-radiative path of energy flow within the resonator network. Such promotion resonators that are not in the dark state can act as a sink or otherwise preferentially receive energy (e.g., excitons) and prevent the energy from proceeding to the output resonators or other parts of the resonator network. Thus, when the promotion resonators are in the dark state (e.g., by illuminating the resonator network with light of an appropriate wavelength), energy does not flow to the promotion resonators and can therefore flow along a different path through the network (e.g., to the output resonators).

[0139] This is illustrated by way of example in FIGS. 7C and 7D, which show an exemplary resonator network 700b at different times. The resonator network 700b includes a readout resonator ("CLK"), an input resonator ("IN"), a mediator resonator ("M"), and an output resonator ("OUT"). When the input resonator is not in a dark state (as shown in FIG. 7C), energy (e.g., excitons) can be transferred from the readout resonator (e.g., in response to the readout resonator being illuminated by light 710b at the excitation wavelength of the readout resonator) to the mediator resonator, and from the mediator resonator to either the input resonator or the output resonator. If transferred to the input resonator, the energy is likely to be dissipated (e.g., lost from the network as heat or released as photons at the emission wavelength of the input resonator), and if transferred to the output resonator, the energy is likely to be released from the output resonator as photons at the emission wavelength of the output resonator.

[0140] The relative probabilities of different energy transfers between resonators are illustrated by the relative line thickness of the representative arrows in Figures 7C and 7D. Thus, for the exemplary network 700b, when the input resonators are not in the dark state, it is more likely that the mediator resonators transfer energy to the input resonators than to the output resonators. Thus, when the input resonators are not in the dark state, the radiation 710b absorbed by the resonator network (readout resonators) is more likely to be absorbed and then dissipated by the input resonators than to be received by the output resonators and transmitted as photons from the network 700b.

[0141] Conversely, when the input resonator is in a dark state (indicated by the "IN" resonator being drawn with dashed lines in FIG. 7D), energy (e.g., excitons) cannot be transferred from the mediator resonator to the input resonator and therefore to the output resonator. Thus, when the input resonator is in a dark state, radiation 710b absorbed by the resonator network (readout resonator) can be transferred through the resonator network 700b to the output resonator and then emitted from the output resonator as photons 720a.

[0142] Such behavior can be used to implement logic gates or other computational or gating functions within the resonator networks described herein. For example, the resonator network 700a shown in Figures 7A and 7B can be used as a NOT gate, with the "evaluation" of the gate being triggered by the excitation of the readout resonator. Detection of the gate output can be achieved by detecting whether the output resonator has emitted a photon in response to the "evaluation". The gate input is applied by providing (or not providing) illumination at the input wavelength such that the input resonator is in a dark state. Thus, a "high" input (sufficient illumination to cause the input to be in a dark state) results in a "low" output (the network does not emit photons from the output resonator in response to the excitation of the readout resonator). Conversely, a "low" input results in a "high" output, providing the behavior of a NOT gate.

[0143] The structure of the resonators can be designed to provide any logic gate function or other computational or gating function. This can include providing multiple "input" resonators, which can be put into a dark state by providing radiation of an appropriate wavelength to the input resonators. These additional input resonators can differ with respect to the wavelength of light required to induce the dark state. These additional resonators can also differ with respect to whether they facilitate or inhibit the flow of energy through the network. Thus, light provided (or not) at these different wavelengths can represent different logic inputs to the resonator network. These wavelengths can differ by more than a specified amount (e.g., more than 10 nanometers or more than 50 nanometers) to allow for reliable and independent signal transmission along each of the different logic inputs.

[0144] An example of such a resonator network configured as a logical AND gate is shown in FIG. 8A. The resonator network 800a includes a readout resonator ("CLK"), two intermediate resonators ("M1" and "M2"), two input resonators ("IN1" and "IN2"), and an output resonator ("OUT"). The relative probabilities of different energy transfers between these resonators are indicated by the relative line thicknesses of the representative arrows in FIG. 8A. Thus, in order to transfer energy from the readout resonator to the output resonator with high probability, both input resonators must be in a dark state (e.g., in response to the provision of illumination at the respective input wavelengths).

[0145] Another example of such a resonator network configured as a logical OR gate is shown in FIG. 8B. Resonator network 800b includes a readout resonator ("CLK"), two intermediate resonators ("M1" and "M2"), two input resonators ("IN1" and "IN2"), and an output resonator ("OUT"). The relative probability of different energy transfers between these resonators is indicated by the relative line thickness of the representative arrows in FIG. 8B. Thus, in order to transfer energy from the readout resonator to the output resonator with high probability, at least one of the input resonators must be in a dark state (e.g., in response to the provision of illumination of one or both of the respective input wavelengths).

[0146] Another example of such a resonator network configured as a logical NAND gate is shown in FIG. 8C. The resonator network 800c includes a readout resonator ("CLK"), two input resonators ("IN1" and "IN2"), and an output resonator ("OUT"). The relative probability of different energy transfers between these resonators is shown by the relative line thickness of the representative arrows in FIG. 8C. Thus, to transfer energy with high probability from the readout resonator to the output resonator, only one of the input resonators can be in a dark state (e.g., in response to the provision of illumination of one or the other of the respective input wavelengths, or to the provision of neither illumination).

[0147] Another example of such a resonator network configured as a logical NOR gate is shown in FIG. 8D. The resonator network 800d includes a readout resonator ("CLK"), two input resonators ("IN1" and "IN2"), and an output resonator ("OUT"). The relative probabilities of different energy transfers between these resonators are indicated by the relative line thicknesses of the representative arrows in FIG. 8D. Thus, in order to transfer energy from the readout resonator to the output resonator with high probability, neither of the input resonators can be in a dark state (e.g., in response to no illumination of any of the respective input wavelengths being provided).

[0148] To achieve a specified logical function or behavior, multiple input resonators that go dark in response to receiving illumination of the same wavelength can be provided in a single resonator network. An example of such a resonator network configured as a logical XOR gate is shown in FIG. 8E. The resonator network 800e includes a readout resonator ("CLK"), two intermediate resonators ("M1" and "M2"), four input resonators ("IN1a", "IN1b", "IN2a", and "IN2b"), and an output resonator ("OUT"). The relative probability of different energy transfers between these resonators is indicated by the relative line thickness of the representative arrows in FIG. 8E. Thus, to transfer energy from the readout resonator to the output resonator with high probability, only one of the input resonators must go dark (e.g., in response to being provided with illumination of one or the other of the respective input wavelengths exclusively).

[0149] Another example of such a resonator network configured as a logical XNOR gate is shown in FIG. 8F. The resonator network 800f includes a readout resonator ("CLK"), two intermediate resonators ("M1" and "M2"), four input resonators ("IN1a", "IN1b", "IN2a", and "IN2b"), and an output resonator ("OUT"). The relative probability of different energy transfers between these resonators is indicated by the relative line thickness of the representative arrows in FIG. 8F. Thus, in order to transfer energy with high probability from the readout resonator to the output resonator, either both input resonators should be in a dark state or none of the input resonators should be in a dark state (e.g., in response to both illuminations of the respective input wavelengths being provided or none of the illuminations of the respective input wavelengths being provided).

[0150] The resonator network can include input resonators (e.g., resonators exhibiting a dark state, where the dark state can be optically induced and / or otherwise optically controlled) as described herein to control the flow of energy through the resonator network (e.g., between different parts of the resonator network). Such inputs can be controlled to selectively activate or deactivate parts of the resonator network. This is illustrated by way of example in FIG. 9A, which shows a resonator network 900a including a readout resonator ("CLK"), three input resonators ("IN1", "IN2", and "IN3"), and three output resonators ("OUT1", "OUT2", and "OUT3"). The relative probability of different energy transfers between these resonators is illustrated by the relative line thickness of the representative arrows in FIG. 9A. Thus, in order to transmit energy from the readout resonator to a particular one of the output resonators, the corresponding input resonator must not be in a dark state. Thus, by providing (or not providing) illumination at the input wavelengths of each of the input resonators, one can select the output resonator(s) that can emit photons in response to excitation of the readout resonator. For example, to select the "OUT1" output resonator, one can provide light at a dark state inducing wavelength for the second input resonator ("IN2") and the third input resonator ("IN3").

[0151] Resonator networks that are optically controllable (e.g., by optically inducing a dark state in one or more resonators of the network) can be applied to provide various benefits. For example, a label comprising a resonator network as described herein can include such a dark state resonator to provide further multiplexing for label detection and identification. This can include a label that exhibits a first temporal decay profile or other time-dependent probability density function for the relative timing of emission of photons in response to illumination when the input resonator of the label is in a dark state. The label can then exhibit a second temporal decay profile or other time-dependent probability density function when the input resonator is not in a dark state. Thus, the label can be optically interrogated during a first and a second time period, and the input resonator is not in a dark state during the first time period, but is in a dark state during the second time period (e.g., by illumination with an excitation wavelength of the input resonator). The detected relative timing of emission of light from the label in response to illumination during the first and second time periods can be used together to identify the label.

[0152] In another example, the resonator network described herein can include such resonators in a dark state to provide a controllable time-dependent probability density function for the timing of photon emission from the resonator network(s) in response to irradiation. The detected relative timing can be used to generate a sample of a random variable, the probability distribution of which is related to the time-dependent probability density function exhibited by the resonator network(s). The dark state of one or more input resonators of such a resonator network can modify the time-dependent probability density function exhibited by the resonator network(s). Thus, by controlling whether such input resonator(s) are in a dark state, the probability distribution of the random variable sample generated therefrom can be controlled.

[0153] In some examples, this can include applying a dark state of an input resonator in the resonator network to control whether a section of the resonator network is available to transfer energy from the readout resonators of the network to the output resonators of the network. Each such configuration of the network that includes only the portion of the network that is "enabled" by the dark state of the input resonator(s) can correspond to a different time-dependent probability density function and can therefore be used to generate different samples of the random variable.

[0154] This is illustrated by way of example in FIG. 9B, which shows a resonator network 900b including a readout resonator ("CLK"), three input resonators ("IN1", "IN2", and "IN3"), twelve mediator resonators ("M1"-"M12"), and an output resonator ("OUT"). The relative probabilities of different energy transfers between these resonators are illustrated by the relative line thicknesses of the representative arrows in FIG. 9B. Thus, in order to transfer energy from the readout resonator to the output resonator, at least one of the input resonators must not be in a dark state. The overall time-dependent probability density function exhibited by the resonator network 900b for the timing of emission of photons from the output resonators in response to excitation of the readout resonator is related to whether each of the input resonators is in a dark state or not. Thus, for example, when the input resonators of "IN2" and "IN3" are in the dark state and "IN1" is not in the dark state, the resonator network 900b exhibits a time-dependent probability density function associated with the resonator wires composed of "IN1", "M1", "M2", "M3", and "M4". In another example, when the input resonator of "IN3" is in the dark state and the resonators of "IN1" and "IN2" are not in the dark state, the resonator network 900b exhibits a time-dependent probability density function associated with a combination of the time-dependent probability density function of the resonator wires composed of "IN1", "M1", "M2", "M3", and "M4" and an additional time-dependent probability density function associated with the resonator wires composed of "IN2", "M5", and "M6".

[0155] In yet another example, the resonator networks described herein can include sensors that detect properties of the environment of the resonator network, such as the pH of a solution to which the resonator network is exposed, or the presence or amount of an analyte bound to a receptor of the resonator network. Such resonator networks can include various sensor elements or other components (e.g., resonators of the network itself) that can convert properties of the environment of the network into optically detectable changes in the resonator network (e.g., a change in the overall intensity or probability of light emission in response to illumination, a change in the time decay function and / or time-dependent probability density function of light emission from the network in response to illumination). For example, one or more resonators of a resonator network can have optical properties (e.g., a property that is quenched or dark) that relate to the pH or other properties of the solution to which the resonator is exposed, whether the resonator is bound to an analyte of interest, or some other property of interest in the environment of the resonator network.

[0156] In another example, such a sensor can include a receptor (e.g., an antibody, an aptamer, one or more proteins, DNA or RNA strands) that preferentially binds to an analyte of interest (e.g., a protein, a hormone, a cell, a cell surface receptor or other cell surface element, a complementary DNA or RNA strand, a small molecule, a metal ion). The binding state of such a receptor to the analyte of interest can then be related in various ways to one or more detectable optical properties of the resonator network. For example, binding of the analyte to the receptor can result in a change in the relative position of one or more resonators in the resonator network, thus changing an optically detectable property of the resonator network (e.g., a change in the overall intensity or probability of light emission in response to irradiation, a change in the time decay function and / or the time-dependent probability density function of light emission from the network in response to irradiation). Such a change can be caused by a change in the morphology of the receptor, a change in the morphology of one or more elements of the framework of the resonator network, or a change in the position of the resonator or framework element linked to the receptor. Additionally or alternatively, the receptor can be coupled to and / or be part of a resonator in the network (e.g., a portion of a protein that includes a fluorescent moiety), such that the absence of the receptor binding to an instance of the analyte causes the resonator to be quenched or otherwise optically disabled. Alternatively, the binding of the receptor to an instance of the analyte can cause the resonator to be quenched or otherwise optically disabled.

[0157] This is illustrated by way of example in Figures 10A and 10B, which show an exemplary resonator network 1000. The resonator network 1000 includes a readout resonator ("CLK"), a receptor 730 that preferentially binds to an analyte 735 of interest, an intermediary resonator ("IN") that is quenched when an instance of the analyte 735 is bound to the receptor 730, and an output resonator ("OUT"). Thus, when the receptor 730 is not bound to an instance of the analyte, the resonator network 1000 can emit light 720a in response to receiving light 710a at the excitation wavelength of the readout resonator (as shown in Figure 10A). Conversely, when the receptor 730 is bound to an instance of the analyte 735, the resonator network 1000 cannot emit light in response to receiving light 710a at the excitation wavelength of the readout resonator (as shown in Figure 10B), because the intermediary resonator is quenched and therefore unavailable to transfer the received energy from the readout resonator to the output resonator.

[0158] A resonator network configured to optically sense one or more properties of the environment of the resonator network as described above can include input resonators that exhibit one or more dark states. Such input resonators can enable multiplexing of the resonator network to detect multiple different environmental properties using the network. For example, the resonators can include multiple different receptors that selectively interact with respective different analytes, which, when bound to respective instances of the analyte, quench respective resonators of the network or otherwise induce changes in the optical properties of respective portions of the resonator network. One or more input resonators can be provided within such a resonator network, which can be used to enable optically controlled multiplexing of analyte detection. This can include using the input resonators to implement logic gates or other means of addressing the sensing bodies, such that the resonator network response to the excitation of the readout resonators (e.g., intensity or timing of light emission from the output resonators of the resonator network) is related to whether an optically selected one of the receptors is bound to a corresponding instance of the analyte. Such optically controlled multiplexing can also enable sub-wavelength imaging and / or analyte assays by allowing optical control and / or selection of different portions of the resonator network separated from each other by distances smaller than the imaging wavelength. VII. Exemplary Methods

[0159] 11 is a flow diagram of a method 1100 for interrogating a sample to detect and identify one or more labels described herein that may be contained in the sample. For illustrative purposes, the label identified in method 1100 includes (i) an input resonator, (ii) an output resonator characterized by an emission wavelength, and (iii) a network of one or more intermediary resonators. The relative positions of the input resonator, output resonator, and one or more intermediary resonators within the label are such that in response to the input resonator being excited by irradiation (e.g., a pulse of laser light at the excitation wavelength of the input resonator), energy can be transferred from the input resonator to the output resonator via the network of one or more intermediary resonators.

[0160] The method 1100 includes illuminating the sample including the label (1110). This can include illuminating the sample with one or more illumination pulses. Such illumination pulses can be ultrashort pulses having pulse widths from attoseconds to nanoseconds. The illumination pulses can have different spectra and / or can include different wavelengths of light. For example, a first illumination pulse can include light at an excitation wavelength of an input resonator of the label, and a second illumination pulse can include light at an excitation wavelength of an input resonator of a different label. In another example, a first illumination pulse can include light at an excitation wavelength of an input resonator of the label, and a second illumination pulse can include light at an excitation wavelength of an additional input resonator of the label.

[0161] The method 1100 also includes detecting 1120 a timing of emission of a plurality of photons from the sample within a detection wavelength range relative to illumination of the sample. The detection wavelength range includes the emission wavelength of the output resonator of the label. Detecting the timing of emission of a plurality of photons from the sample can include detecting the timing of receipt of individual photons, for example, using a single photon avalanche diode, a photomultiplier tube, or some other detector element(s). Additionally or alternatively, detecting the timing of emission of a plurality of photons from the sample can include detecting the timing of a peak or other feature of the variation over time of the intensity, velocity, or other property of the photons emitted from the sample.

[0162] The method 1100 further includes determining an identity of the label based on the detected timing of the emission of the plurality of photons (1130). Determining the identity of the label includes selecting the identity of the label from a set of known labels. Determining the identity of the label can include comparing the detected timing of the emission of the plurality of photons to a set of temporal decay profiles corresponding to the known labels. For example, the detected timing of the emission of the plurality of photons can be used to determine a probability density function for the timing of the emission of photons from the sample in response to illumination of the sample. The probability density function so determined can then be compared to each of the known temporal decay profiles. Such a comparison can include determining a statistical divergence between the probability density function and the known temporal decay profiles, such as the Kullback-Leibler divergence, the Jensen-Shannon divergence, the Bregman divergence, or a measure of Fisher information.

[0163] Method 1100 may include additional or alternative steps as described elsewhere herein. For example, method 1100 may include identifying cells or other components of the sample based on the determined identity of one or more labels in the sample. Method 1100 may include classifying cells or other particles in the sample based on the determined identity of the labels (e.g., the sample may be included in a flow channel of a flow cytometry device, and cells in the flow chamber may be classified according to the determined identity of one or more labels in the flow channel). Method 1100 may include emitting light at an excitation wavelength of the resonator that exhibits a dark state of the resonator wavelength such that a temporal decay profile or other optically detectable property of the label is adjusted, and identifying the label may include determining that the detected timing corresponds to an adjusted state of the optically detectable property. The exemplary method 1100 shown in FIG. 11 is meant as an illustrative and non-limiting example. Additional or alternative elements of the method are anticipated as would be apparent to one of skill in the art.

[0164] FIG. 12 is a flow diagram of a method 1200 of querying a resonator network to detect an analyte as described herein. For illustrative purposes, the resonator network of method 1200 includes: (i) a first input resonator having a dark state and capable of entering the dark state in response to receiving irradiation at a first input excitation wavelength; (ii) a readout resonator capable of receiving energy from irradiation at a readout wavelength; (iii) an intermediary resonator; (iv) an output resonator; (v) a sensor comprising a receptor that preferentially binds to the analyte; and (vi) a scaffold. The first input resonator, the readout resonator, the sensor, and the output resonator are coupled to the scaffold. The scaffold maintains the relative positions of the first input resonator, the readout resonator, the intermediary resonator, the sensor, and the output resonator so that energy can be transmitted from the readout resonator to the output resonator via the intermediary resonator, and so that the probability of energy being transmitted from the readout resonator to the output resonator when the first input resonator is in the dark state is related to whether the receptor is bound to an instance of the analyte.

[0165] The method 1200 includes illuminating the resonator network with light at a first input wavelength for a first period of time (1210). This may include illuminating the sample with one or more pulses of illumination. The duration and / or number of such pulses of illumination may be specified to ensure that the first input resonators have likely entered a dark state, e.g., the provided light at the first input wavelength may be provided for more than a threshold duration.

[0166] The method 1200 includes illuminating the resonator network with light at a readout wavelength during a first time period (1220). This can include illuminating the sample with one or more illumination pulses. Such illumination pulses can be ultrashort pulses having pulse widths from attoseconds to nanoseconds. The illumination pulses can have different spectra and / or can include different light wavelengths. For example, a first illumination pulse can include light at an excitation wavelength of an input resonator of a label, and a second illumination pulse can include light at an excitation wavelength of an input resonator of a different label. In another example, a first illumination pulse can include light at an excitation wavelength of an input resonator of a label, and a second illumination pulse can include light at an excitation wavelength of an additional input resonator of a label. The light at the readout wavelength can be provided after providing the light at the first input wavelength.

[0167] The method 1200 also includes detecting an intensity of light emitted from the output resonators of the resonator network during the first time period (1230). This can include detecting the timing of such light emission relative to the timing of one or more light pulses provided at the readout wavelength. Detecting the intensity of light emitted from the resonator network can include detecting the timing of emission of a plurality of photons from a population of the resonator network, for example, detecting the timing of receipt of individual photons using a single photon avalanche diode, a photomultiplier tube, or some other detector element(s). Additionally or alternatively, detecting the timing of emission of a plurality of photons from the sample can include detecting the timing of a peak or other feature of the variation over time of the intensity, rate, or other property of the photons emitted from the sample. Detecting the intensity of light emitted from the resonator network can include detecting the total amount of light emitted from the output resonators, for example, by integrating a signal related to the intensity of the detected light.

[0168] Method 1200 may include additional or alternative steps as described elsewhere herein. Method 1200 may include determining the presence, amount, count, or other characteristic of the analyte based on the detected intensity of the emitted light. In some examples, the resonator network may be configured to allow detection of multiple analytes, for example, by a process of optically multiplexing and / or addressing multiple different sensors of the resonator network. For example, the resonator network may include a second sensor sensitive to a second analyte and a second input resonator coupled with the remainder of the resonator network, such that the probability of energy transmission from the readout resonator to the output resonator when the second input resonator is in a dark state and the first input resonator is not in a dark state is related to whether the second receptor is bound to an instance of the second analyte. In such examples, method 1200 may include illuminating the resonator network with light at an excitation wavelength of the second input resonator during a second time period, illuminating the resonator network with light at a readout wavelength, and detecting the intensity of light emitted from the resonator network during the second time period. The intensity detected during the second time period can then be used to determine the concentration, presence, count, or some other information regarding the second analyte. The exemplary method 1200 shown in Figure 12 is meant as an illustrative and non-limiting example. Additional or alternative elements of the method are contemplated, as will be apparent to one of ordinary skill in the art.

[0169] 13 is a flow diagram of a method 1300 for generating samples of random variables using a multiple resonator network as described herein. For illustrative purposes, the resonator network identified in method 1300 includes (i) a first input resonator having a dark state and capable of entering a dark state in response to receiving illumination at a first input wavelength, (ii) a readout resonator capable of receiving energy from illumination at a readout wavelength, (iii) two or more mediator resonators, (iv) an output resonator, and (v) a scaffold. The first input resonator, the readout resonator, the two or more mediator resonators, and the output resonator are coupled to the scaffold. The scaffold maintains relative positions of the first input resonator, the readout resonator, the two or more mediator resonators, and the output resonator so that energy can be transferred from the readout resonator to the output resonator via the mediator resonator, and such that the resonator network emits photons from the output resonator in response to the readout resonator receiving irradiation at the readout wavelength according to a time-dependent probability density function, a detectable characteristic of which is related to whether the first input resonator is in a dark state.

[0170] The method 1300 includes illuminating the plurality of resonator networks with light at a first input wavelength for a first period of time (1310). This may include illuminating the sample with one or more pulses of illumination. The duration and / or number of such pulses of illumination may be specified to ensure that the first input resonators of each of the resonator networks and / or the specified portion of the resonator networks have likely entered a dark state, e.g., the provided light at the first input wavelength may be provided for more than a threshold duration.

[0171] The method 1300 includes illuminating 1320 the plurality of resonator networks with light at a readout wavelength during a first period of time. This may include illuminating the sample with one or more illumination pulses. Such illumination pulses may be ultrashort pulses having pulse widths on the order of attoseconds to nanoseconds.

[0172] The method 1300 also includes detecting 1330 a timing of emission of the plurality of photons from output resonators of the plurality of resonator network relative to illumination of the resonator network. Detecting the timing of emission of the plurality of photons from the resonator network can include detecting the timing of receipt of individual photons, for example, using a single photon avalanche diode, a photomultiplier tube, or some other detector element(s). Additionally or alternatively, detecting the timing of emission of the plurality of photons from the sample can include detecting the timing of a peak or other feature of a variation over time of an intensity, velocity, or other property of photons emitted from the sample.

[0173] Method 1300 may include additional or alternative steps as described elsewhere herein. For example, method 1300 may include generating a sample of the random variable based on the detected timing, e.g., by applying a function to the detected timing. Method 1300 may include generating an additional sample of the random variable by illuminating the resonator network and detecting the timing of emission of the photon(s) emitted in response from the resonator network. The resonator network may include one or more additional input resonators, and method 1300 may include generating an additional sample of the random variable by optically controlling the input resonators of the resonator network during additional time periods, such that the resonator network exhibits a time-dependent probability density function corresponding to the additional random variable. The sample of the random variable may be generated by detecting the timing of emission of light from the resonator network in response to the illumination. The exemplary method 1300 shown in FIG. 13 is meant as an illustrative and non-limiting example. Additional or alternative elements of the method are anticipated, as will be apparent to those skilled in the art. VIII. Conclusion

[0174] "Fluorescent taggants with temporally coded signatures" (Wang, S., Vyas, R., Dwyer, C, "Fluorescent taggants with temporally coded signatures," Optics Express, Vol. 24, No. 14, 11 July 2016) is incorporated herein by reference. All references cited herein are incorporated by reference. In addition, the present invention is not intended to be limited to the disclosed embodiments of the present invention. The above disclosure highlights certain specific embodiments of the present invention, and it is to be understood that all modifications or alternatives equivalent to those embodiments fall within the spirit and scope of the present invention as defined by the appended claims.

[0175] The particular arrangements shown in the figures should not be considered limiting. It should be understood that other embodiments may include more or less of each element shown in a given figure. Further, some of the illustrated elements may be combined or omitted. Additionally, example embodiments may include elements not shown in the figures.

[0176] In addition, while various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for illustrative purposes only and are not intended to be limiting, with the true scope being indicated by the following claims. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure generally described and illustrated in the figures herein can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are contemplated herein.

Claims

[Claim 1] An object, method or system as described in this specification and drawings.

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