The present disclosure relates to a cartridge for analysis of biological sample and a method of distributing the biological sample in a fluid channel of the cartridge.
A cartridge made of different materials is designed for the analysis of biological samples in biomedical research and diagnostic applications. A biological or bio-chemical reaction is usually performed at an elevated temperature. Since coefficients of thermal expansion of the materials of the cartridge are different, a bonding strength therebetween becomes important. Bonding the materials of the cartridge has several ways including, for example, ultrasonic welding, thermal bonding or by screws, adhesive tape or glue.
In some embodiments, a cartridge includes a plate including a fluid inlet and a fluid outlet, a biochip disposed under the plate, and a first adhesive layer bonding the plate and the biochip. A fluid channel is formed between the plate and the biochip. The fluid inlet and the fluid outlet are in fluid communication with the fluid channel.
In some embodiments, the cartridge further includes a second adhesive layer having a composition different from a composition of the first adhesive layer. The second adhesive layer is in contact with the first adhesive layer.
In some embodiments, a hardness of the second adhesive layer is greater than a hardness of the first adhesive layer.
In some embodiments, the fluid channel includes a front portion, a middle portion and a rear portion arranged in sequence from the fluid inlet to the fluid outlet. A height of the rear portion is greater than or equal to a height of the front portion. The height of the front portion is greater than or equal to a height of the middle portion.
In some embodiments, the fluid channel includes a front portion, a middle portion and a rear portion arranged in sequence from the fluid inlet to the fluid outlet. A height of the front portion is greater than or equal to a height of the rear portion. The height of the rear portion is greater than or equal to a height of the middle portion.
In some embodiments, the fluid channel includes a front portion, a middle portion and a rear portion arranged in sequence from the fluid inlet to the fluid outlet. A height of the front portion is greater than or equal to a height of the middle portion. The height of the middle portion is greater than or equal to a height of the rear portion.
In some embodiments, the fluid channel includes a front portion, a middle portion and a rear portion arranged in sequence from the fluid inlet to the fluid outlet. A height of the rear portion is less than a height of the front portion. The height of the front portion is less than a height of the middle portion.
In some embodiments, the fluid channel includes a front portion, a middle portion and a rear portion arranged in sequence from the fluid inlet to the fluid outlet. A height of the front portion is less than a height of the rear portion. The height of the rear portion is less than a height of the middle portion.
In some embodiments, the fluid channel includes a front portion, a middle portion and a rear portion arranged in sequence from the fluid inlet to the fluid outlet. A height of the front portion is less than a height of the middle portion. The height of the middle portion is less than a height of the rear portion.
In some embodiments, a method of distributing a biological sample in a fluid channel of a cartridge includes bonding a plate including a fluid inlet and a fluid outlet to a biochip to form a cartridge using a first adhesive layer; injecting a biological sample through the fluid inlet to flow into the fluid channel in a direction; and injecting a liquid having a material immiscible with a material of the biological sample through the fluid inlet to push the biological sample along the direction. A fluid channel is formed between the biochip and the plate. The fluid channel includes a front portion, a middle portion and a rear portion arranged in sequence from the fluid inlet to the fluid outlet.
In some embodiments, the method further includes bonding the plate and the biochip using a second adhesive layer after the bonding the plate to the biochip using the first adhesive layer. A hardness of the first adhesive layer is less than a hardness of the second adhesive layer.
In some embodiments, the method further includes heating the biochip before injecting the biological sample.
In some embodiments, the method further includes heating the biochip after injecting the biological sample such that air bubbles in a well of the biochip has sufficient buoyant force to escape from the well.
In some embodiments, the method further includes tilting the cartridge with an angle with respect to a vertical direction defined by gravity prior to injecting the biological sample. The angle is in a range from about 0° to about 90°.
In some embodiments, a flow velocity of the biological sample in the rear portion is less than or equal to a flow velocity of the biological sample in the front portion, and the flow velocity of the biological sample in the front portion is less than or equal to a flow velocity of the biological sample in the middle portion.
In some embodiments, a flow velocity of the biological sample in the front portion is less than or equal to a flow velocity of the biological sample in the rear portion, and the flow velocity of the biological sample in the rear portion is less than or equal to a flow velocity of the biological sample in the middle portion.
In some embodiments, a flow velocity of the biological sample in the front portion is less than or equal to a flow velocity of the biological sample in the middle portion, and the flow velocity of the biological sample in the middle portion is less than or equal to a flow velocity of the biological sample in the rear portion.
In some embodiments, a flow velocity of the biological sample in the rear portion is greater than a flow velocity of the biological sample in the front portion, and the flow velocity of the biological sample in the front portion is greater than a flow velocity of the biological sample in the middle portion.
In some embodiments, a flow velocity of the biological sample in the front portion is greater than a flow velocity of the biological sample in the rear portion, and the flow velocity of the biological sample in the rear portion is greater than a flow velocity of the biological sample in the middle portion.
In some embodiments, a flow velocity of the biological sample in the front portion is greater than a flow velocity of the biological sample in the middle portion, and the flow velocity of the biological sample in the middle portion is greater than a flow velocity of the biological sample in the rear portion.
It is to be understood that both the foregoing general description and the following detailed description are by examples, and are intended to provide further explanation of the disclosure as claimed.
The disclosure can be more fully understood by reading the following detailed description of the embodiments, with reference made to the accompanying drawings as follows:
Reference will now be made in detail to the present embodiments of the disclosure, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings and the description to refer to the same or like parts.
In some embodiments, the flow velocity of the biological sample can be controlled by the height of the fluid channel C when the cross-sectional area of the fluid channel C is fixed. The fluid channel C includes a front portion 100, a middle portion 200 and a rear portion 300 arranged in sequence from the fluid inlet 14 to the fluid outlet 16. For example, the front portion 100 of the fluid channel C has a height H1, the middle portion 200 of the fluid channel C has a height H2, and the rear portion 300 of the fluid channel C has a height H3. The front portion 100 is closer to the fluid inlet 14 than the middle portion 200 is. The rear portion 300 is closer to the fluid outlet 16 than the middle portion 200 is. The middle portion 200 is between the front portion 100 and the rear portion 300. The heights of H1, H2 and H3 can be controlled by a bonding process of the plate 10 and the biochip 12, for example, by the pressure applied to the plate 10 and the biochip 12 during the ultrasonic welding process.
In some embodiments, the height H3 of the rear portion 300 is greater than or equal to the height H1 of the front portion 100, so that a flow velocity of the fluid in the rear portion 300 is less than or equal to a flow velocity of the fluid in the front portion 100. The height H1 of the front portion 100 is greater than or equal to the height H2 of the middle portion 200, so that the flow velocity of the fluid in the front portion 100 is less than or equal to a flow velocity of the fluid in the middle portion 200.
In some embodiments, the height H1 of the front portion 100 is greater than or equal to the height H3 of the rear portion 300, so that a flow velocity of the fluid in the front portion 100 is less than or equal to a flow velocity of the fluid in the rear portion 300. The height H3 of the rear portion 300 is greater than or equal to the height H2 of the middle portion 200, so that the flow velocity of the fluid in the rear portion 300 is less than or equal to a flow velocity of the fluid in the middle portion 200.
In some embodiments, the height H1 of the front portion 100 is greater than or equal to the height H2 of the middle portion 200, so that a flow velocity of the fluid in the front portion 100 is less than or equal to a flow velocity of the fluid in the middle portion 200. The height H2 of the middle portion 200 is greater than or equal to the height H3 of the rear portion 300, so that the flow velocity of the fluid in the middle portion 200 is less than or equal to a flow velocity of the fluid in the rear portion 300.
In some embodiments, the height H3 of the rear portion 300 is less than the height H1 of the front portion 100, so that a flow velocity of the fluid in the rear portion 300 is greater than a flow velocity of the fluid in the front portion 100. The height H1 of the front portion 100 is less than the height H2 of the middle portion 200, so that the flow velocity of the fluid in the front portion 100 is greater than a flow velocity of the fluid in the middle portion 200.
In some embodiments, the height H1 of the front portion 100 is less than the height H3 of the rear portion 300, so that a flow velocity of the fluid in the front portion 100 is greater than a flow velocity of the fluid in the rear portion 300. The height H3 of the rear portion 300 is less than the height H2 of the middle portion 200, so that the flow velocity of the fluid in the rear portion 300 is greater than a flow velocity of the fluid in the middle portion 200.
In some embodiments, the height H1 of the front portion 100 is less than the height H2 of the middle portion 200, so that a flow velocity of the fluid in the front portion 100 is greater than a flow velocity of the fluid in the middle portion 200. The height H2 of the middle portion 200 is less than the height H3 of the rear portion 300, so that the flow velocity of the fluid in the middle portion 200 is greater than a flow velocity of the fluid in the rear portion 300.
PCR has proven a phenomenally successful technology for genetic analysis, because it is so simple and requires relatively low cost instrumentation. PCR involves the concept of thermal cycling: alternating steps of melting DNA, annealing short primers to the resulting single strands, and extending those primers to make new copies of double stranded DNA. In thermal cycling, the PCR reaction mixture is repeatedly cycled from high temperatures (>90° C.) for melting the DNA, to lower temperatures (40° C. to 70° C.) for primer annealing and extension.
In some embodiments, the plate 10 and the biochip 12 may include different materials, for example, the plate 10 includes polymeric material and the biochip 12 includes silicon. The interface between the plate 10 and the biochip 12 are thus subject to thermal stresses that occur during PCR periods in which the cartridge 1 is heated or cooled. The thermal stresses, and consequent thermally induced strains, at the interface between the plate 10 and the biochip 12 arise from a mismatch in coefficient of thermal expansion (CTE) between the plate 10 and the biochip 12.
In particular, a second adhesive layer 26 is positioned between the plate 10 and the biochip 12 and bonds the biochip 12 to the plate 10. In particular, the second adhesive layer 26 is in contact with the second inner sidewall 22 of the fence portion 10b and a bottom surface 33 of the biochip 12. The second adhesive layer 26 is in contact with the first adhesive layer 24. The second adhesive layer 26 is configured to protect the first adhesive layer 24 and enhance the bonding strength between the plate 10 and the biochip 12. The second adhesive layer 26 has a second chemical property, such as flow velocity, wetability, strength, gap filling, material compatibility, temperature versus viscosity, ease of application, or another suitable adhesive or chemical property. The second chemical property is different from the first chemical property. For example, the hardness of the second adhesive layer 26 is greater than the hardness of the first adhesive layer 24. In some embodiments, the hardness of the first adhesive layer 24 is less than 60 Shore D. In some embodiments, the hardness of the second adhesive layer 26 is greater than 60 Shore D. In some embodiments, the first and second adhesive layers 24 and 26 include silicone glue, thermal-plastic glue, thermal-set glue, photo-chemical glue, epoxy resin, or a combination thereof. The hardnesses of the first and second adhesive layers 24 and 26 can be adjusted by different compositions of the glues.
In some embodiments, the formations of the first and second adhesive layers 24 and 26 are performed in a range from about 4° C. to about 110° C. The first and second adhesive layers 24 and 26 have a glass transition temperature (Tg) of greater than about 90° C., and a visible light transmittance of at least 80% in the wavelength range from about 400 nm to 700 nm. Furthermore, the first and second adhesive layers 24 and 26 have a self-fluorescence intensity lower than 3000 a.u.
The cartridge 1 may have various types of fluid control mechanism for the purpose of controlling a continuous and uniform flow of a fluid, for example, the biological sample. Still referring to
Referring to
A filling process can be adapted in biological sample distribution before PCR.
The biochip 12 is configured to execute bio-chemistry reaction, for example, PCR. In particular, the biochip 12 functions as a carrier and includes a plurality of wells 44 to be filled by the biological sample (e.g., the first liquid 46). Reference is made to
In some embodiments, the first liquid 46 has high surface tension and low specific weight such that it is difficult for the first liquid 46 to fill the wells 44 in the biochip 12 uniformly since surface tension is the dominate force to control microscale fluid flow. Reference is made to
Reference is made to
In some embodiments, the biochip 12 is heated via the thermal conducting plate 18 that is attached to an electric thermal heating and cooling device 20 (see
Although the present disclosure has been described in considerable detail with reference to certain embodiments thereof, other embodiments are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the embodiments contained herein.
It will be apparent to those skilled in the art that various modifications and variations can be made to the structure of the present disclosure without departing from the scope or spirit of the disclosure. In view of the foregoing, it is intended that the present disclosure cover modifications and variations of this disclosure provided they fall within the scope of the following claims.
This application claims priority to U.S. Provisional Patent Application Ser. No. 62/584,935, filed Nov. 13, 2017 and U.S. Provisional Patent Application Ser. No. 62/634,936, filed Feb. 26, 2018, which are herein incorporated by reference in its entirety.
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Number | Date | Country | |
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20190143322 A1 | May 2019 | US |
Number | Date | Country | |
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62584935 | Nov 2017 | US | |
62634936 | Feb 2018 | US |