A microcalorimeter chip based on flexible printed circuit technology and its fabrication method

Abstract

This invention discloses a microcalorimeter chip based on flexible printed circuit technology and its fabrication method. The microcalorimeter chip includes: a substrate, a virtual reaction chamber, and a temperature-sensitive unit; the virtual reaction chamber, located in the central detection area of ​​the substrate, is used to encapsulate the sample; the virtual reaction chamber is formed by adding mineral oil to the surface of the substrate, which has undergone oleophobic treatment; the temperature-sensitive unit, located at the bottom of the substrate, is used to detect the temperature of the sample during the reaction process. This invention uses mineral oil added to the surface of the oleophobic-treated substrate to form the virtual reaction chamber, and uses vacuum oil with a low saturated vapor pressure to encapsulate the sample, preventing its evaporation in a vacuum environment. The open reaction chamber simplifies the fabrication process of microfluidic channels.

Description

Technical Field

[0001] This invention relates to the field of microcalorimeter chip technology, and in particular to a microcalorimeter chip based on flexible printed circuit technology and its fabrication method. Background Technology

[0002] Many physical changes, chemical reactions, and biological processes are related to the generation or absorption of heat. Therefore, calorimetry is a powerful tool for studying these processes, directly detecting heat changes during the process. Microcalorimetry, which was subsequently developed, has become a powerful means of studying biothermodynamics and biokinetics. It is a label-free, non-invasive detection method that can directly and in real-time monitor heat changes during the metabolism of living cells and the interactions between biological macromolecules. Currently, microcalorimetry techniques applicable to the thermal analysis of fluid samples are mainly divided into two categories: traditional microcalorimeter instruments and microcalorimeter chip systems based on microelectromechanical systems (MEMS) technology. Traditional microcalorimeter instruments generally use large-volume aluminum crucibles or specially designed containers of hundreds of microliters to encapsulate samples, resulting in large sample volumes, slow thermal response times, and low temperature resolution. Microcalorimeter chips based on MEMS technology, on the other hand, can perform rapid, high-resolution thermal analysis of trace liquid samples; however, their complex and expensive chip manufacturing process keeps this technology in the laboratory research stage.

[0003] To meet the need for real-time monitoring of the thermal balance of biochemical reactions, especially for high-precision measurement of single-cell metabolic heat and enthalpy changes in trace chemical reactions, microcalorimeters need to achieve power resolution of nW or below. However, current microcalorimeter chips require complex microfabrication processes; furthermore, microcalorimeter chips operating in a vacuum environment require encapsulation of water-based samples, further complicating the chip fabrication process. Temperature sensors fabricated using thin-film technology, due to microfabrication and material inhomogeneities, often exhibit resistance values ​​that are difficult to perfectly match their nominal values, meaning the resistance values ​​show a certain degree of dispersion. These resistance differences must be compensated for by external electronic devices, introducing noise into the system and resulting in a higher limit of detection (LOD). Summary of the Invention

[0004] To address the above problems, this invention provides a microcalorimeter chip based on flexible printed circuit technology and its fabrication method.

[0005] To achieve the above objectives, the present invention provides the following solution:

[0006] A microcalorimeter chip based on flexible printed circuit technology includes: a substrate, a virtual reaction chamber, and multiple temperature-sensitive units; the virtual reaction chamber is disposed in the central detection area of ​​the substrate and is used to encapsulate the sample; the virtual reaction chamber is formed by adding mineral oil to the central detection area of ​​the substrate that has undergone oleophobic treatment; the multiple temperature-sensitive units are disposed at the bottom of the central detection area of ​​the substrate and are used to detect the temperature of the sample during the reaction process.

[0007] Optionally, the substrate is made of a polyimide film.

[0008] Optionally, the temperature-sensitive unit may be a standardized Pt1000 resistance temperature detector (RTD) or a semiconductor thermistor.

[0009] Optionally, the substrate has a hollow structure.

[0010] This invention also provides a method for fabricating a microcalorimeter chip based on flexible printed circuit technology, comprising:

[0011] Preparation of flexible polyimide substrates;

[0012] Multiple temperature-sensitive units with the same nominal resistance value are soldered to the corresponding positions on the substrate using surface mount technology.

[0013] Mineral oil is added to the central detection area of ​​the substrate to form a virtual reaction chamber.

[0014] Optionally, the preparation of the flexible polyimide substrate specifically includes:

[0015] The desired circuit pattern is formed on a copper foil board using an etching process, resulting in a patterned copper foil board;

[0016] The patterned copper foil plate and polyimide film are placed in a press and hot-pressed together to obtain a flexible circuit board.

[0017] Using CNC machine tools, flexible circuit boards are processed according to the designed pattern;

[0018] A nickel layer is electroplated on the surface of the copper foil, and then dry film lithography is used as a barrier layer to electroplat a gold layer as a solder pad at the required locations.

[0019] Optionally, an etching process is used to form the desired circuit pattern on the copper foil board to obtain a patterned copper foil board, specifically including:

[0020] A dry film is applied to a copper foil using a hot-pressing method. The pattern on the photomask is transferred to the dry film by exposure under ultraviolet light. Subsequently, development is performed to remove unwanted non-structural parts. Then, the dry film is used as a barrier layer to etch away unwanted copper in a copper etching solution to form the desired circuit pattern. After removing the residual dry film, a patterned copper foil is obtained.

[0021] Optionally, before adding mineral oil to the substrate surface to form a virtual reaction chamber, the method further includes:

[0022] The substrate surface is treated with hydrophobic and oleophobic agents, and an additional perfluorodecyltriethoxysilane monolayer is formed on the substrate surface using chemical vapor deposition, so that the contact angles of water and oil on the substrate surface reach 99.4° and 55.2°, respectively.

[0023] According to specific embodiments provided by the present invention, the present invention discloses the following technical effects:

[0024] The microcalorimeter chip provided by this invention uses a flexible polyimide substrate and selects surface-mount Pt1000 or semiconductor thermistors as the temperature sensing unit, avoiding complex microfabrication processes. Simultaneously, the standardized temperature detection device increases the stability and consistency of the microcalorimeter. This invention adds mineral oil to the oleophobic substrate surface to form a virtual reaction chamber. The open reaction chamber reduces the fabrication process of the microfluidic channels. Furthermore, when testing in a vacuum environment is required, vacuum oil with a low saturated vapor pressure can be used to encapsulate the sample, preventing evaporation in a vacuum environment. The open reaction chamber simplifies the fabrication process of the microfluidic channels. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 A schematic diagram of the microcalorimeter chip based on flexible printed circuit technology provided by the present invention;

[0027] Figure 2 A schematic diagram of a detection circuit board for a microcalorimeter chip based on flexible printed circuit technology provided by the present invention. Detailed Implementation

[0028] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0030] like Figure 1 As shown, the microcalorimeter chip based on flexible printed circuit technology provided by this invention includes: a substrate, a virtual reaction chamber, and multiple temperature-sensitive units. The virtual reaction chamber, located in the central detection area of ​​the substrate, is used to encapsulate the sample; the virtual reaction chamber is formed by adding mineral oil to the central detection area of ​​the substrate, which has already undergone oleophobic treatment. The temperature-sensitive units, located at the bottom of the central detection area of ​​the substrate, are used to detect the temperature of the sample during the reaction process. The temperature-sensitive units employ standardized Pt1000 resistance thermometers or semiconductor thermistors.

[0031] In a specific embodiment, the flexible microcalorimeter chip uses a 100μm thick perforated polyimide film as a substrate. Four cantilever beams, 1mm wide and 15mm long, support the central detection area to reduce heat conduction from the sample to the surrounding area. The central detection area is a 2mm diameter circular polyimide disk for holding the sample, with pre-reserved Pt1000 resistance temperature detector (RTD) pads underneath. Subsequently, two Pt1000 (SMD 0603) RTDs with the same nominal resistance value are soldered to corresponding positions on the polyimide substrate. Finally, the two microcalorimeter chips are soldered onto the detection circuit board using a surface mount technology (SMT) process. Figure 2 As shown, the detection circuit board mainly consists of a Wheatstone bridge circuit and a differential amplifier circuit. Two identical microcalorimeter chips are connected in the Wheatstone bridge, one as the test chip and the other as the reference chip. Temperature changes caused by the sample during the reaction are detected by Pt1000 transistors located on the polyimide film and amplified by an AD8221 differential amplifier. The output signal is further processed by a lock-in amplifier to increase the signal-to-noise ratio and improve detection sensitivity. Finally, the signal changes are recorded using an oscilloscope. The four Pt1000 transistors in the bridge circuit can be balanced with each other, eliminating the need for additional resistors to compensate for differences in the temperature sensor resistance.

[0032] This invention combines flexible printed circuit (FPC) technology to design and fabricate a microcalorimeter chip, and uses a standard Pt1000 resistance temperature detector (RTD) as the temperature sensing element. Compared to traditional microcalorimeter chips, it eliminates the need for complex and expensive micro / nano manufacturing processes. Furthermore, the standardized temperature sensing element avoids device inhomogeneity, providing a new technical means for the simple and mass production of microcalorimeter chips. The open-type microcalorimeter chip employs a virtual reaction chamber of "water-in-oil" droplets, simplifying operation and preventing the evaporation of liquid samples during testing.

[0033] The microcalorimeter chip provided by this invention is fabricated using standard flexible printed circuit technology. The specific fabrication process steps are as follows:

[0034] 1. Preparation of flexible polyimide substrate:

[0035] The desired circuit pattern is formed on a copper foil using an etching process: a dry film (photoresist) is applied to a copper foil of approximately 13.4 μm thickness using a hot-pressing method. The pattern on the photomask is transferred to the dry film by exposure under ultraviolet light. Subsequently, development is performed to remove the unwanted non-structural parts. Then, the dry film is used as a barrier layer to etch away the unwanted copper in a copper etching solution, forming the designed circuit loop. After removing the residual dry film, the patterned copper foil is obtained.

[0036] The processed copper foil and a 100μm thick flexible polyimide (PI) are placed into a pressing machine for hot pressing bonding.

[0037] Using CNC machine tools, the pressed flexible circuit board is processed according to the design pattern.

[0038] Nickel-gold plating involves electroplating a 2μm thick nickel layer onto the surface of the copper foil, then using dry film lithography as a barrier layer, and finally electroplating a gold layer at the desired locations as solder pads.

[0039] 2. Multiple temperature-sensitive units with the same nominal resistance value are soldered to the corresponding positions on the substrate using surface mount technology.

[0040] In a specific embodiment, a surface-mount thermistor in a 0603 package is used, with dimensions of (1.6 × 0.8 × 0.45) mm. 3 Surface mount technology for temperature-sensitive components is achieved using a solder paste profile with a melting temperature around 183 degrees Celsius via reflow soldering.

[0041] 3. Add mineral oil to the central detection area of ​​the substrate to form a virtual reaction chamber.

[0042] In a specific embodiment, the test sample is loaded using a nano-injector. Approximately 200 nmL of mineral oil is first added to the oleophobic treated polyimide surface to encapsulate the sample droplet and prevent evaporation. Then, approximately 50 nmL of sample is injected into the oil droplet using the nano-injector, forming a stable "water-in-oil" virtual reaction chamber. The maximum volume of the oil droplet and the sample can reach 2 μL and 500 nmL, respectively. Two reacting samples can also be added to the oil droplet to detect heat changes during the reaction. Before sample loading, the polyimide surface needs to be hydrophobic and oleophobic treated. An additional perfluorodecyltriethoxysilane monolayer is formed on the polyimide surface using chemical vapor deposition, achieving contact angles of 99.4° for water and 55.2° for oil. This is because the polyimide surface is hydrophobic (73.1° contact angle) but oleophilic (6.5° contact angle for mineral oil), which cannot form well-encapsulated oil droplets. Furthermore, to reduce baseline temperature drift and improve the resolution of the microcalorimeter system, the test chip is mounted in a constant-temperature vacuum chamber, consisting of three nested brass chambers with a large thermal mass, and a separate temperature control system ensures temperature stability. The PCB board connecting the microcalorimeter chip is directly fixed inside the constant-temperature vacuum chamber and connected to the outside via an electrical interface on the chamber. An observation window on the chamber allows for recording sample changes under a microscope while monitoring thermal equilibrium.

[0043] The microcalorimeter chip provided by this invention can be manufactured by any printed circuit board (PCB) manufacturer using a provided design layout, eliminating the need for a microfabrication laboratory and simplifying the chip fabrication process to a low cost. A resistance temperature detector, such as Pt1000 or other types of temperature sensors, fabricated using surface mount technology (SMT) is employed as the high-precision temperature measurement element of the microcalorimeter chip. This precise temperature sensor forms a differential detection system based on a Wheatstone bridge. Since all four resistors forming the bridge are almost identical, the bridge itself does not require additional adjustable resistors for balancing, avoiding the introduction of additional electrical noise and reducing the system's detection limit. Furthermore, by adding a thermistor to the microcalorimeter chip substrate film, differential scanning calorimetry studies can be performed. During experiments, the microcalorimeter chip with a flexible circuit board is directly fixed to the internal isolation chamber of a constant-temperature vacuum chamber. As long as the vacuum level is higher than the saturated vapor pressure of the vacuum oil used to cover the sample, the open-type microcalorimeter can operate in a vacuum without the problem of sample evaporation. The resulting microcalorimeter chip system can achieve a thermal power resolution at the picometer level, which is of great significance for basic research in revealing the mechanisms of thermal reaction processes, biological cell metabolism, and drug metabolism. It also has important applications in disease diagnosis and treatment as well as drug screening.

[0044] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0045] This document uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, those skilled in the art will recognize that, based on the ideas of the present invention, there will be changes in the specific implementation methods and application scope. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A microcalorimeter chip based on flexible printed circuit technology, characterized in that, include: Substrate, virtual reaction chamber, multiple temperature-sensitive units; The substrate is made of flexible polyimide film and is prepared using flexible printed circuit technology. The virtual reaction chamber is located in the central detection area of ​​the substrate and is used to encapsulate the sample; The virtual reaction chamber is formed by adding mineral oil to the central detection area of ​​a substrate that has undergone oleophobic treatment; multiple temperature-sensitive units are disposed at the bottom of the central detection area of ​​the substrate to detect the temperature of the sample during the reaction process; the temperature-sensitive units are standardized Pt1000 resistance thermometers or semiconductor thermistors; multiple temperature-sensitive units with the same nominal resistance value are soldered to the corresponding positions on the substrate using surface mount technology. First, mineral oil is added to the surface of the substrate that has been treated with oleophobic coating to encapsulate the sample droplets. Then, a nano-injector is used to inject the sample into the oil droplets to form a stable "water-in-oil" virtual reaction chamber. When testing in a vacuum environment, vacuum oil with low saturated vapor pressure is used to encapsulate the sample; The substrate has a hollow structure.

2. The microcalorimeter chip based on flexible printed circuit technology according to claim 1, characterized in that, The method for fabricating the microcalorimeter chip based on flexible printed circuit technology includes: Preparation of flexible polyimide substrates; Multiple temperature-sensitive units with the same nominal resistance value are soldered to the corresponding positions on the substrate using surface mount technology. Mineral oil is added to the central detection area of ​​the substrate to form a virtual reaction chamber.

3. The microcalorimeter chip based on flexible printed circuit technology according to claim 2, characterized in that, The preparation of the flexible polyimide substrate specifically includes: The desired circuit pattern is formed on a copper foil board using an etching process, resulting in a patterned copper foil board; The patterned copper foil plate and polyimide film are placed in a press and hot-pressed together to obtain a flexible circuit board. Using CNC machine tools, flexible circuit boards are processed according to the designed pattern; A nickel layer is electroplated on the surface of the copper foil, and then dry film lithography is used as a barrier layer to electroplat a gold layer as a solder pad at the required locations.

4. The microcalorimeter chip based on flexible printed circuit technology according to claim 3, characterized in that, The desired circuit pattern is formed on a copper foil board using an etching process, resulting in a patterned copper foil board, specifically including: A dry film is applied to a copper foil using a hot-pressing method. The pattern on the photomask is transferred to the dry film by exposure under ultraviolet light. Subsequently, development is performed to remove unwanted non-structural parts. Then, the dry film is used as a barrier layer to etch away unwanted copper in a copper etching solution to form the desired circuit pattern. After removing the residual dry film, a patterned copper foil is obtained.

5. The microcalorimeter chip based on flexible printed circuit technology according to claim 2, characterized in that, Before adding mineral oil to the substrate surface to form a virtual reaction chamber, the method further includes: The substrate surface is treated with hydrophobic and oleophobic agents, and an additional perfluorodecyltriethoxysilane monolayer is formed on the substrate surface using chemical vapor deposition, so that the contact angles of water and oil on the substrate surface reach 99.4° and 55.2°, respectively.

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