Nanoscale Calorimeter on Chip for High-Sensitivity Biochemical Analysis
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Solution Overview
Problem
Current isothermal titration calorimetry (ITC) technologies are costly, lack sensitivity, and have limitations in miniaturization due to challenges in heat retention and environmental disturbance isolation, restricting their use in biological and pharmaceutical applications, particularly in differential scanning calorimetry (DSC) and thermal shift assays (TSA).
Innovation Solution
The development of a microfluidic chip-based array of calorimeter devices with gas-impermeable fluidic enclosures, suspended chambers, and thermopile thermal sensors, capable of measuring temperature differentials and fluorescence signals, allowing for high-resolution temperature control and miniaturization to nanoliter scales, enabling simultaneous DSC and TSA measurements.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional ITC technologies are used, then measurement capability is provided, but cost is prohibitively costly and sensitivity is limited
Solution Approach 1:
The invention divides a single conventional calorimeter into multiple independent micro-calorimetric chambers (first chamber and second chamber) on a common substrate. Each chamber can perform measurements independently, enabling parallel processing and reducing the cost per measurement while maintaining or improving sensitivity through miniaturization and reduced thermal mass.
Solution Approach 2:
The invention employs microfluidic channels to deliver samples and reagents to the micro-calorimetric chambers. This fluidic integration enables automated sample handling, precise delivery control, and integration with standard microplate formats, reducing operational complexity and cost while improving measurement throughput and sensitivity.
2Quantity of substance
If miniaturization is pursued to reduce sample volume, then sample consumption decreases, but heat retention and isolation from environmental disturbances become challenging
Solution Approach 1:
The invention uses thin-film thermal isolation layers deposited on the substrate beneath each micro-calorimetric chamber. These thin films provide effective thermal blocking from the substrate while maintaining the miniaturized chamber geometry, enabling heat retention in small sample volumes without requiring vacuum encapsulation or bulky insulation.
Solution Approach 2:
The invention nests multiple functional elements within the micro-calorimetric chamber structure: the sample chamber is formed within the substrate, thermal isolation layers are deposited on the substrate beneath the chamber, and microfluidic channels are integrated into the substrate. This nested arrangement maximizes space utilization and maintains thermal isolation in the miniaturized format.
3Adaptability or versatility
If conventional DSC instruments are used, then DSC measurements are performed, but the ability to perform TSA measurements is not available
Solution Approach 1:
The invention designs a universal micro-calorimetric platform that can perform both DSC and TSA measurements using the same physical apparatus. The system uses a temperature sensor to detect heat changes for DSC and can detect fluorescence signals for TSA, eliminating the need for separate specialized instruments and enabling versatile measurement capability from a single device.
Solution Approach 2:
The invention merges DSC and TSA measurement capabilities into a single integrated instrument. The micro-calorimetric chambers serve both thermal measurement (DSC) and fluorescence detection (TSA) functions, combining what were previously separate measurement modalities into one versatile platform that reduces instrument complexity and enables simultaneous or sequential performance of both assay types.
4Quantity of substance
If reaction volume is decreased for miniaturization, then sample amount reduces, but heat production and signal reduce proportionally
Solution Approach 1:
The invention employs thin thermal isolation films that minimize heat loss from the miniaturized chambers to the substrate. This effective thermal blocking maintains signal strength in small reaction volumes by preventing heat dissipation, allowing the system to detect small thermal changes from minimal sample amounts that would otherwise be lost to the substrate.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This solution provides high-speed, high-throughput, and sensitive measurements with minimal sample usage, overcoming the limitations of existing technologies by achieving precise thermal control and isolation, enabling efficient characterization of biochemical interactions and stability.
Implementation Method 1
at least one thermal sensor disposed between the chip and the first and second chambers, wherein the thermal sensor is adapted to measure a temperature differential between the first and second chambers
Implementation Method 2
at least one heater in thermal communication with at least one chamber
Data Source
AI summary
An article comprising: an array of calorimeter devices, wherein the device comprises: at least one fluidic enclosure disposed on a microfluidic chip, wherein the fluidic enclosure is substantially gas impermeable; at least one first chamber and at least one second chamber, wherein the first chamber and the second chamber are disposed within and enclosed by the fluidic enclosure, wherein the first chamber and the second chamber are not vacuum encapsulated; at least two microfluidic channels connected to the first chamber and at least two microfluidic channels connected to the second chamber; and at least one thermal sensor disposed between the chip and the first and second chambers, wherein the thermal sensor is adapted to measure a temperature differential between the first and second chambers. Examples include DSC and TSA devices. Biological binding and melting experiments can be done with high sensitivity.