System and method for preparation and delivery of biological samples for charged particle analysis

Patent metadata

Field	Value
Publication number	US-11217425-B2
Application number	US-202016914924-A
Country	US
Kind code	B2
Filing date	Jun 29, 2020
Priority date	Jun 28, 2019
Publication date	Jan 4, 2022
Grant date	Jan 4, 2022

Abstract

Systems and method for the preparation and delivery of biological samples for charged particle analysis are disclosed herein. An example system at least includes an ion filter coupled to select a sample ion from an ionized sample supply, the ion filter including a quadrupole filter to select the sample ion from the sample supply, an energy reduction cell coupled to receive the selected sample ion and reduce a kinetic energy of the sample ion, a validation unit coupled to receive the sample ion and determine whether the sample ion is a target sample ion, a substrate coupled to receive the sample, wherein the substrate is electron transparent, an ion transport module coupled to receive the sample ion from the ion filter and transport the sample ion to the substrate, and an imaging system arranged to image, with a low energy charged particle beam, the sample located on the substrate, wherein the substrate is arranged in an analysis location. The imaging system including a charge particle emitter coupled to direct coherent charged particles toward the sample; and a detector arranged to detect interference patterns formed from interaction of the coherent charged particles and the sample.

First claim

What is claimed is:

1. A system for holographic imaging, the system comprising:
an ion filter coupled to select a sample ion from an ionized sample supply, the ion filter including a quadrupole filter to select the sample ion from the sample supply;
an energy reduction cell coupled to receive the selected sample ion and reduce a kinetic energy of the sample ion;
a substrate coupled to receive the sample, wherein the substrate is electron transparent;
an ion transport module coupled to receive the sample ion from the energy reduction cell and transport the sample ion downstream to the substrate; and
an imaging system arranged to image, with a low energy coherent electron beam, the sample located on the substrate, wherein the substrate is arranged in an analysis location, the imaging system including:
an emitter coupled to direct the low energy coherent electron beam toward the sample; and
a detector arranged to detect interference patterns formed from interaction of electrons of the low energy coherent electron beam and the sample.

2. The system of claim 1 , further including;
a substrate holder arranged to hold the substrate, the substrate holder including motors for moving the substrate holder from a deposition position to the analysis position.

3. The system of claim 2 , further comprising:
track extended from the deposition location to the analysis location, wherein the substrate holder is mounted on the track for translation between the deposition location and the analysis location.

4. The system of claim 2 , wherein the substrate holder includes heaters to heat the substrate.

5. The system of claim 1 , further including an optical energy source coupled to provide optical energy to the substrate.

6. The system of claim 1 , wherein the ion transport module includes a plurality of differential pumping stages, and wherein the ion transport module receives the sample ion at a first vacuum level and provides the sample ion at a second vacuum level, the second vacuum level higher than the first vacuum level, wherein each differential pumping stage of the plurality of differential pumping stages respectively increases the vacuum level from the first to second vacuum level.

7. The system of claim 6 , wherein a final differential pumping stage of the plurality of differential pumping stages includes a retarding lens disposed on an output, the retarding lens coupled to reduce the kinetic energy of the sample ion before providing the sample ion to the substrate.

8. The system of claim 7 , wherein the retarding lens includes first and second lens elements, the first lens element biased in relation to the second lens element to focus the sample ions.

9. The system of claim 1 , wherein the substrate is formed from one of graphene, hexagonal boron nitride, molybdenum diselenide, and hafnium disulfide, or other two-dimensional material.

10. The system of claim 9 , wherein the graphene is a single- or double-layer graphene sheet.

11. The system of claim 1 , further including an ionizer coupled to receive a sample supply, ionize the sample supply, and provide the ionized sample supply to the ion filter.

12. The system of claim 1 , wherein at least the ion filter, energy reduction cell and validation unit are included in a mass spectrometer.

13. The system of claim 1 , further including a gate valve to couple and decouple the imaging system from at least part of the ion transport module.

14. The system of claim 1 , further comprising dampening supports, wherein at least the imaging system is mounted on the dampening supports.

15. A method comprising:
ionizing a sample supply;
filtering, with a quadrupole mass filter, a target sample ion from the ionized sample supply;
depositing the target sample ion onto a substrate; and
imaging, with charged particles, a target sample on the substrate, the substrate located in an analysis location, wherein the target sample is a neutralized target sample ion.

16. The method of claim 15 , further comprising;
translating the substrate from a deposition location to the analysis location after the target sample is deposited onto the substrate.

17. The method of claim 15 , wherein depositing the target sample ion onto a substrate includes transporting the target sample via a plurality of differentially-pumped stages from at least the quadrupole mass filter to the substrate.

18. The method of claim 15 , wherein depositing the target sample onto a substrate incudes soft-landing the target sample ion on the substrate with a retarding lens biased to reduce a kinetic energy of the target sample ion before landing on the substrate.

19. The method of claim 15 , further including:
collisionally cooling the target sample ion prior to depositing the target sample ion onto the substrate.

20. The method of claim 15 , further including:
validating the target sample ion with mass measurement or partial sequencing.

21. The method of claim 15 , further including;
reconstructing an image of the target sample based on the imaging of the target sample, wherein the imaging forms interference patterns and the reconstruction provides a profile image.

22. The method of claim 15 , further comprising:
while imaging the target sample, ionizing and filtering a subsequent sample supply.

23. The method of claim 22 , further comprising collisionally cooling the subsequent sample supply.

24. The method of claim 22 , further comprising validating the subsequent sample supply.

25. The method of claim 15 , further including cleaning the substrate.

26. The method of claim 25 , wherein cleaning the substrate includes one of direct heating, radiative heating, and inductive heating.

Assignees

• Fei Co

Inventors

• Straw Marcus
• Makarov Alexander
• Gilbert Josh
• Torok Aaron
• Christian Joseph
• Bahm Alan
• Liu Kun
• Nichols Tom
• Kosmoski Jeff
• Grinfeld Dmitry

Classifications

• H01J37/20

  Means for supporting or positioning the object or the material; Means for adjusting diaphragms or lenses associated with the support · CPC title

• H01J37/295 Primary

  Electron or ion diffraction tubes · CPC title

• H01J49/4215

  Quadrupole mass filters (H01J49/4225 takes precedence) · CPC title

• G01N27/62

  by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode · CPC title

• H01J2237/05

  Arrangements for energy or mass analysis · CPC title