Orthogonal polybiosensing and imaging systems

Abstract

Toward forming a single hybrid biosensing-imaging system that can operate inside an incubator, structures and methods are directed to placing modular and removable biosensors and biocompatible interfaces in 3D transparent test wells that contain biological samples. The technology enables continuous monitoring of multiple simultaneous parameters and functions of a living cell or cell clusters such as alterations of cellular ligands, physicochemical biomarkers, phenotypes, and/or extracellular compositions upon interactions with analytes or during progressions. Methods of capturing and analyzing direct orthogonal information from biological samples in 2D and 3D, which are conducive to generating new insights are presented.

1 - 43 . (canceled) 
     
     
         44 . A device comprising:
 a. a test plate comprising at least one well, each well configured to contain a substance to be analyzed, where each well comprises a side wall structure and a bottom wall;   b. an insert comprising a substrate having conductive interconnects, wherein the substrate includes one or more flaps, bent at an angle relative to an adjoining portion of the substrate, and including at least one conductive interconnect, further wherein the insert is coupled to the test plate with one or more flaps extending into each well; and   c. one or more sensors attached to the one or more flaps, each sensor coupled to a corresponding conductive interconnect of the flap, wherein each sensor is configured to sense a characteristic of the substance and to generate a corresponding sensed signal.   
     
     
         45 . The device of  claim 44  wherein the substrate comprises a flexible substrate. 
     
     
         46 . The device of  claim 45  wherein the flexible substrate comprises a flexible circuit board. 
     
     
         47 - 51 . (canceled) 
     
     
         52 . The device of  claim 44  wherein the one or more sensors comprises a plurality of sensors sensing a plurality of different modalities, wherein each sensor is configured to sense a characteristic of the substance according to one of the modalities. 
     
     
         53 . The device of  claim 52  wherein the test plate comprises a plurality of wells, and the substrate is configured as a plurality of partitions, at least one partition per well, wherein each partition comprises one or more flaps. 
     
     
         54 - 57 . (canceled) 
     
     
         58 . The device of  claim 44  wherein the device further comprises electronic circuitry coupled to the plurality of sensors via the conductive interconnects of the substrate, wherein the electronic circuitry is configured to selectively access one or more sensors and output the sensed signals from the selectively accessed one or more sensors. 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . The device of  claim 52  wherein each of the modalities comprises one of optical measuring, impedance measuring, chemical measuring, or acoustic measuring. 
     
     
         62 . The device of  claim 44  wherein the substance to be analyzed comprises a biological sample comprising live cells. 
     
     
         63 - 65 . (canceled) 
     
     
         66 . A device comprising:
 a. a test plate comprising at least one well, each well configured to contain a substance to be analyzed, where each well comprises a side wall structure and a bottom wall;   b. a lid coupled to the side wall structure;   c. an insert coupled to the lid, wherein the insert includes one or more support structures extending from a surface of the insert facing the well into the well, each support structure having at least one conductive interconnect; and   d. one or more sensors attached to each support structure, each sensor coupled to a corresponding conductive interconnect of the support structure, wherein each sensor is configured to sense a characteristic of the substance and to generate a corresponding sensed signal.   
     
     
         67 . A device comprising:
 a. a test plate comprising at least one well, each well configured to contain a substance to be analyzed, where each well comprises a side wall structure and a bottom wall;   b. a lid coupled to the side wall structure;   c. an insert comprising a transparent substrate having conductive interconnects, wherein the substrate includes a portion that extends into the well and along at least a portion of the bottom wall, further wherein insert also includes one or more support structures coupled to the portion that extends along the bottom wall, each support structure extending into the well and each support structure having at least one conductive interconnect; and   d. one or more sensors attached to each support structure, each sensor coupled to a corresponding conductive interconnect of the support structure, wherein each sensor is configured to sense a characteristic of the substance and to generate a corresponding sensed signal.   
     
     
         68 - 159 . (canceled) 
     
     
         160 . The device of  claim 66  wherein the one or more sensors comprises a plurality of sensors sensing a plurality of different modalities, wherein each sensor is configured to sense a characteristic of the substance according to one of the modalities. 
     
     
         161 . The device of  claim 160  wherein the test plate comprises a plurality of wells, and a substrate is configured as a plurality of partitions, at least one partition per well, wherein each partition comprises one or more flaps. 
     
     
         162 . The device of  claim 160  wherein each of the modalities comprises one of optical measuring, impedance measuring, chemical measuring, or acoustic measuring. 
     
     
         163 . The device of  claim 66  wherein the substance to be analyzed comprises a biological sample comprising live cells. 
     
     
         164 . The device of  claim 67  wherein the substrate comprises a flexible substrate. 
     
     
         165 . The device of  claim 164  wherein the flexible substrate comprises a flexible circuit board. 
     
     
         166 . The device of  claim 67  wherein the one or more sensors comprises a plurality of sensors sensing a plurality of different modalities, wherein each sensor is configured to sense a characteristic of the substance according to one of the modalities. 
     
     
         167 . The device of  claim 166  wherein the test plate comprises a plurality of wells, and the substrate is configured as a plurality of partitions, at least one partition per well, wherein each partition comprises one or more flaps. 
     
     
         168 . The device of  claim 67  wherein the device further comprises electronic circuitry coupled to the plurality of sensors via the conductive interconnects of the substrate, wherein the electronic circuitry is configured to selectively access one or more sensors and output the sensed signals from the selectively accessed one or more sensors. 
     
     
         169 . The device of  claim 166  wherein each of the modalities comprises one of optical measuring, impedance measuring, chemical measuring, or acoustic measuring.