WO2025085812A1

WO2025085812A1 - Devices for droplet deposition and methods of making thereof

Info

Publication number: WO2025085812A1
Application number: PCT/US2024/052065
Authority: WO
Inventors: Kshitiz GUPTA; Trent R. Northen
Original assignee: University of California Berkeley; University of California San Diego UCSD
Current assignee: University of California Berkeley; University of California San Diego UCSD
Priority date: 2023-10-20
Filing date: 2024-10-18
Publication date: 2025-04-24
Anticipated expiration: 2026-04-20

Abstract

This disclosure provides systems, methods, and apparatus related to depositing droplets. In one aspect, a device includes a base and an array of deposition tips attached to the base. The array of deposition tips is at least a 2x1 array of deposition tips. Each deposition tip of the array of deposition tips comprises a rod having a cylindrical cross section. The rod has a first diameter at a first end and a second diameter at a second end. The first diameter is greater than the second diameter. The first end of the rod is attached to the base. The rod includes a bend comprising a cantilever spring.

Description

DEVICES FOR DROPLET DEPOSITION AND METHODS OF MAKING THEREOF

Inventors: Kshitiz Gupta, Trent R. Northen

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63/591,847, filed October 20, 2023, which is herein incorporated by reference.

STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under Contract No. DE-AC02- 05CH11231 awarded by the U.S. Department of Energy. The government has certain rights in this invention.

TECHNICAL FIELD

[0003] This disclosure relates generally to devices for depositing droplets and methods of making thereof.

BACKGROUND

[0004] Mass spectrometry techniques such as nanostructure-initiator mass spectrometry (NIMS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI) use a laser to ionize target molecules. Molecules such as sugars, alcohols, lignin-derived substrates, and many others are deposited on an electrically conductive surface prior to desorption and ionization. The throughput of such characterization techniques is dependent on the number density of the sample molecule arrays deposited on the laser target plate.

[0005] Commercial droplet deposition tools are able to generate 1536 well format arrays. Such tools use complex pneumatic and acoustic techniques to eject droplets on to the target plate surface, making denser patterns unreliable and not repeatable.

SUMMARY

[0006] Described herein are devices including an array of deposition tips that can be used as a soft stamp for depositing nanoliter scale droplets (i.e., nanodroplets) onto a substrate (e.g., a laser target plate). In some embodiments, deposition tips a use surface tension driven contact- based droplet transfer mechanism. As the droplet transfer is contact based, the location of the samples on a substrate can be controlled with high precision. This helps to prevents crosscontamination, which is frequently observed in commercial droplet deposition tools due to droplet coalescence.

[0007] Details of one or more embodiments of the subject matter described in this specification are set forth in the accompanying drawings and the description below. Other features, aspects, and advantages will become apparent from the description, the drawings, and the claims. Note that the relative dimensions of the following figures may not be drawn to scale.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 shows an example of a cross-sectional schematic illustration of a device including a deposition tip.

[0009] Figure 2 shows an example of a schematic illustration of a device including an array of deposition tips.

[0010] Figure 3 shows an example of a schematic illustration of a device including an array of deposition tips.

[0011] Figure 4 shows an example of a flow diagram illustrating a manufacturing process for a device including an array of deposition tips.

DETAILED DESCRIPTION

[0012] Reference will now be made in detail to some specific examples of the invention including the best modes contemplated by the inventors for carrying out the invention. Examples of these specific embodiments are illustrated in the accompanying drawings. While the invention is described in conjunction with these specific embodiments, it will be understood that it is not intended to limit the invention to the described embodiments. On the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

[0013] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. Particular example embodiments of the present invention may be implemented without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present invention.

[0014] Various techniques and mechanisms of the present invention will sometimes be described in singular form for clarity. However, it should be noted that some embodiments include multiple iterations of a technique or multiple instantiations of a mechanism unless noted otherwise.

[0015] The terms “about” or “approximate” and the like are synonymous and are used to indicate that the value modified by the term has an understood range associated with it, where the range can be + 20%, ± 15%, ± 10%, ± 5%, or + 1%. The terms “substantially” and the like are used to indicate that a value is close to a targeted value, where close can mean, for example, the value is within 80% of the targeted value, within 85% of the targeted value, within 90% of the targeted value, within 95% of the targeted value, or within 99% of the targeted value.

[0016] Described herein are devices including an array of deposition tips that can be used to perform soft contact-based nanodroplet deposition on surfaces. Standard, commercially available, pipette tips are stiff and are designed to transfer liquids using, for example, pneumatic actuation. Standard pipette tips are designed to transfer a wide range of quantities, about 100 nanoliter (nl) to 1 milliliter (ml). The deposition tips described herein are designed to transfer small quantities (on the order of about 100 nl or less) of a liquid. The liquid may be any number of liquids, including target molecules dissolved in a solvent, a chemical, or a biochemical. The deposition tips, unlike standard pipette tips, are not hollow in some embodiments. The deposition tips are also designed to contact a substrate, again unlike standard pipette tips.

[0017] When a fluid handling robot loads a set of standard pipette tips (e.g., a 96 well format), the ends of all of the standard pipette tips may not lie in the same plane. Further, due to some variability in the flatness of the substrate, the pipette tip size, and the manner in which the pipette tips are attach to a fluid dispensing head, there may be a gap between the some ends of the tips and the substrate. Because of this, all the pipette tips may not transfer their contents on to the substrate.

[0018] The devices including deposition tips described herein include a spring mechanism as part of the deposition tip that helps to ensure all the deposition tips in an array of deposition tips contact a substrate by compressing deposition tips that are at a different height than other deposition tips. The deposition tips are also designed to interface with existing liquid handling/dispensing equipment.

[0019] Figure 1 shows an example of a cross-sectional schematic illustration of device including a deposition tip. Figure 2 shows an example of a schematic illustration of a device including an array of deposition tips. As shown in Figure 1, a device 100 includes a base 105 and a deposition tip 110 attached to the base 105. As shown in Figure 2, a device 200 includes a base 205 and an array of deposition tips 210 attached thereto. The array of deposition tips is at least a 2x1 array of deposition tips.

[0020] The deposition tips are described herein as being attached to the base. In some embodiments, the deposition tips being attached to the base also includes instances in which the deposition tips are part of the base. For example, the deposition tips being part of the base may occur in instances in which the device is injection molded. In some embodiments, the base and the deposition tips comprise the same material. In some embodiments, the base and the deposition tips are molded from the same material (e.g., a polymer).

[0021] Turning back to Figure 1 , a deposition tip 110 comprises a rod having a cylindrical cross section. The rod has a first diameter 115 at a first end 117 and a second diameter 125 at a second end 127, with the first diameter 115 being greater than the second diameter 125. In some embodiments, the first diameter is about 1 mm. In some embodiments, the second diameter is about 200 microns to 700 microns. The first end 117 of the rod is attached to the base 105.

[0022] The rod includes a bend 130 comprising a cantilever spring or forming the rod into a cantilever spring. A cantilever spring is a spring having a fixed end and a floating end that comprises a material with an elastic modulus such that the floating end of the spring can bend an amount and then return to its original position.

[0023] In some embodiments, the bend 130 forming the cantilever spring in the rod is proximate the first end 117 of the deposition tip 110. For example, in some embodiments, the bend 130 forming the cantilever spring in the rod starts at the first end 117 of the deposition tip. In some embodiments, the bend 130 has a radius or curvature of about 3 millimeters (mm) to 6 mm.

[0024] In some embodiments, the rod is straight (i.e., does not include a bend) proximate the second end 127 of the deposition tip 110. In some embodiments, the straight portion of the rod is substantially perpendicular to a plane defined by the base 205 shown in Figure 2. When the straight portion of the rod is substantially perpendicular to a plane defined by the base 205, when an array of deposition tips is brought into contact with a substrate (e.g., with a plane defined by the base 205 substantially parallel to the surface of the substrate), the deposition tips 210 will contact the substrate at about the same point (i.e., when the base 205 is a specified distance from the substrate).

[0025] All of the deposition tips, however, will likely not contact the substrate at the same point. For example, define a plane in which a majority of the second ends of the deposition tips reside. The deposition tips not in that plane may be slightly above or above the plane or slightly below or below the plane. These variations in deposition tip height may be due to the manufacturing tolerances of the array of deposition tips, for example, hi some embodiments, the substrate is substantially flat. However, there may be variations in the flatness of a substrate. When the deposition tips are contacted to a substrate, the deposition tips that are slightly below the plane will contact the substrate first. The springs of these deposition tips will compress and then the majority of the deposition tips will contact the substrate. Then, the springs of the majority of the deposition tips will compress as well and the tips that were above the plane will contact the substrate. The cantilever spring of each deposition tip allows for all or substantially all of the deposition tips to contact the substrate.

[0026] In some embodiments, the second end of the deposition tip comprises a rounded end. In some embodiments, a diameter of the rounded end is about the second diameter or a larger diameter. The size of the rounded end specifies, in part, the minimum size of a droplet that is deposited. The size of the rounded end can be specified for the specific application for which the droplet will be used.

[0027] In some embodiments, a length of the rod is about 30 mm to 40 mm. In some embodiments, a length of the rod measured from the base is about 15 mm to 25 mm, or about 20 mm. The length of the rod may be specified to vary the stiffness of the cantilever spring; a greater length makes for a less stiff spring.

[0028] In some embodiments, the rod is a tapering rod. In some embodiments, the rod is a cylindrical rod. In some embodiments, the rod is a tapering cylindrical rod.

[0029] In some embodiments, the base is configured to interface with an array of pipettes. In some embodiments, each deposition tip in the array of deposition tips corresponds to a pipette in the array of pipettes. Such an interface would allow the device to be used with existing liquid handling/dispensing equipment. For example, the base 205 shown in Figure 2 can be used to mount the device on liquid handling/dispensing equipment that uses standard pipette tips.

[0030] In some embodiments, the device comprises a polymer. In some embodiments, the polymer is a polymer from a group polypropylene, a cyclo-olefin (COC), polycarbonate (PC), polyether ether ketone (PEEK), and polytetrafluoroethylene (PTFE). Other polymers that have moderate chemical resistance and that are able to be sterilized and/or cleaned in an autoclave can also be used.

[0031] In some embodiments, the second end of each deposition tip of the array of deposition tips is about 9 millimeters from the second end of any other deposition tip in the array. In some embodiments, the array of deposition tips is an 8x1 array of deposition tips or an 8x12 array of deposition tips. In some embodiments, an 8x12 array of deposition tips is arranged such that the deposition tips are arranged in a square pattern. Such an 8x12 array of deposition tips would allow the deposition tips to be immersed in liquids contained in a 96-well plate. Different wells in the well plate could contain the same liquid or different liquids. 96-well plates have a 9 mm well-to-well spacing. An 8x1 array of deposition tips could be used with a row of wells of a 96-well plate. Other standard well plates could be also be used with different arrays of deposition tips. For example, a 24-well plate (4x6 array of deposition tips), a 48-well plate (6x8 array of deposition tips), 384-well plate (16x24 array of deposition tips), a 1536-well plate (32x48 array of deposition tips), and a 6144-well plate (64x96 array of deposition tips) can be used.

[0032] To obtain a high density of liquid droplets on a substrate, the deposition tips of an array of deposition tips are contacted with the substrate after dipping the tips in specified liquids. The specified liquids may be contained in a well plate, for example. Then, the array of deposition tips may be shifted by a small distance (e.g., about 1 mm), depending on the size of the array. Then, the deposition tips may be contacted again with the substrate. This process could be repeated until the array of deposition tips is shifted to an extent that the liquid droplets will be deposited on top of one another. The deposition tips may be dipped in the specified liquids (e.g., contained in a well plate), as needed, during the droplet deposition process. Such an offsetting technique can be used to create 6144 (and even denser) liquid droplet patterns using an array of deposition tips (e.g., an array of 96 deposition tips).

[0033] In some embodiments, the second end of the rod comprises a polymer ball. Such a polymer ball 135 is shown in Figure 1. In some embodiments, a polymer of the polymer ball is a hydrophobic polymer. For example, the liquid to be deposited may be hydrophobic or hydrophilic. If the liquid is hydrophobic, the polymer ball may be hydrophobic. In such cases, when a liquid is adsorbed to a deposition tip, the liquid will be transferred to the substrate when contacted with the deposition tip.

[0034] In some embodiments, the polymer ball comprises a polymer or is a polymer from a group polydimethylsiloxane (PDMS), a silicone, and a hydrogel. PDMS may be used as hydrophobic compounds are adsorbed on it after the deposition tip is dipped in a well containing the compound. The compound is then transferred to the substrate when the deposition tip is contacted to the substrate. Hydrogels can be used as they absorb liquids (e.g., similar to a sponge). For example, a hydrogel that can be used is polyethylene glycol diacrylate (PEGDA). Other inert and stable elastomeric polymers may also be used. Different polymers for the polymer ball may be specified based on the liquid deposition requirements. In some embodiments, the polymer ball is about 500 microns to 700 microns in diameter, or about 500 microns in diameter.

[0035] In some embodiments, instead of the rod having a cylindrical cross section (i.e., the rod being a cylindrical rod), the rod may have a different cross section, such as a square cross section or a triangular cross section.

[0036] Figure 3 shows an example of a schematic illustration of a device including an array of deposition tips. As shown in Figure 3, a device 300 includes a base 305 with an array of deposition tips 310 attached thereto.

[0037] Figure 4 shows an example of a flow diagram illustrating a manufacturing process for a device including an array of deposition tips. The manufacturing process described in Figure 4 may be used to manufacture any of the devices described herein.

[0038] Starting at block 405 of the process 400 shown in Figure 4, a device is injection molded. In some embodiments, the device is injection molded with a polymer. I.e., in some embodiments, the device comprises a polymer. The device comprises a base and an array of deposition tips attached to base. The array of deposition tips is at least a 2x1 array of deposition tips. Each deposition tip of the array of deposition tips comprises a rod having a cylindrical cross section. The rod has a first diameter at a first end and a second diameter at a second end, with the first diameter being greater than the second diameter. The first end of the rod is attached to the base. The rod includes a bend comprising a cantilever spring.

[0039] In some embodiments, instead of injection molding the device, the device is fabricated using a 3D printer.

[0040] In some embodiments, the process 400 further includes dipping each deposition tip of the array of deposition tips in a second polymer at block 410. In some embodiments, the second polymer is a hydrophobic polymer. At block 410, each deposition tip of the array of deposition tips is removed from the second polymer. After block 410, the mass of the second polymer forms the polymer ball; for example, when holding a plane defining the base parallel to the ground after removing the deposition tips from the second polymer. In some embodiments, the second polymer is a polymer from a group polydimethylsiloxane (PDMS), a silicone, and a hydrogel. In some embodiments, the process 400 further includes curing the second polymer. For example, when the second polymer is PDMS, the curing operation may include curing the PDMS in an oven at about 80 °C.

CONCLUSION

[0041] In the foregoing specification, the invention has been described with reference to specific embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

Claims

CLAIMS What is claimed is:

1. A device comprising: a base; and an array of deposition tips attached to the base, the array of deposition tips being at least a 2x1 array of deposition tips, each deposition tip of the array of deposition tips comprising a rod having a cylindrical cross section, the rod having a first diameter at a first end and a second diameter at a second end, the first diameter being greater than the second diameter, the first end of the rod being attached to the base, and the rod including a bend comprising a cantilever spring.

2. The device of claim 1, wherein the first diameter is about 1 millimeter, and wherein the second diameter is about 200 microns to 700 microns.

3. The device of claim 1, wherein the second end comprises a rounded end.

4. The device of claim 1, wherein the second end comprises a rounded end, and wherein a diameter of the rounded end is about the second diameter or a larger diameter.

5. The device of claim 1, wherein a length of the rod is about 30 millimeters to 40 millimeters.

6. The device of claim 1, wherein a length of the rod measured from the base is about 15 millimeters to 25 millimeters.

7. The device of claim 1, wherein the rod is a tapering rod.

8. The device of claim 1, wherein the rod is a cylindrical rod.

9. The device of claim 1, wherein the base is configured to interface with an array of pipettes, and wherein each deposition tip in the array of deposition tips corresponds to a pipette in the array of pipettes.

10. The device of claim 1, wherein the device is a polymer from a group polypropylene, a cycloolefin (COC), polycarbonate (PC), polyether ether ketone (PEEK), and polytetrafluoroethylene (PTFE) .

11. The device of claim 1, wherein the second end of the rod comprises a polymer ball

12. The device of claim 11, wherein a polymer of the polymer ball is a hydrophobic polymer.

13. The device of claim 11, wherein the polymer ball is about 500 microns to 700 microns in diameter.

14. The device of claim 11, wherein the polymer ball is a polymer from a group polydimethylsiloxane (PDMS), a silicone, and a hydrogel.

15. The device of claim 1, wherein the second end of each deposition tip of the array of deposition tips is about 9 millimeters from the second end of any other deposition tips in the array.

16. The device of claim 1, wherein the array of deposition tips is an 8x1 array of tips or an 8x12 array of deposition tips.

17. The device of claim 16, wherein the 8x12 array of deposition tips is arranged such that the deposition tips are arranged in a square pattern.

18. A method comprising: injection molding a device, the device comprising a polymer, the device comprising: a base, and an array of deposition tips attached to the base, the array of deposition tips being at least a 2x1 array of deposition tips, each deposition tip of the array of deposition tips comprising a rod having a cylindrical cross section, the rod having a first diameter at a first end and a second diameter at a second end, the first diameter being greater than the second diameter, the first end of the rod being attached to the base, and the rod including a bend comprising a cantilever spring.

19. The method of claim 1, further comprising: dipping each deposition tip of the array of deposition tips in a second polymer; and removing each deposition tip of the array of deposition tips from the second polymer.

20. The method of claim 19, wherein the second polymer is a polymer from a group polydimethylsiloxane (PDMS), a silicone, and a hydrogel.