Methods and apparatus for manipulation and/or detection of biological samples and other objects

• US 20060020371A1
• Filed: 04/13/2005
• Published: 01/26/2006
• Est. Priority Date: 04/13/2004
• Status: Abandoned Application

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Hunt, Thomas, Liu, Yong, Ham, Donhee, Lee, Hakho, Westervelt, Robert
• Application Number:
  US11/105,322
• Publication Number:
  US 20060020371A1
• Time in Patent Office: Days
• US Class Current: 700/266
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• CPC Class Codes: B01L 2200/147 Employing temperature sensors
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2300/0877 Flow chambers
• CPC Class Codes: B01L 2300/1822 using Peltier elements
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 2400/043 magnetic forces
• CPC Class Codes: B01L 3/502761 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B03C 2201/26 for use in medical applications
• CPC Class Codes: B03C 5/005 Dielectrophoresis, i.e. dielectric particles migrating towards the region of highest field strength B03C5/02 takes precedence; electrophoresis B01D57/02
• CPC Class Codes: B03C 5/026 using open-gradient differential dielectric separation, i.e. using electrodes of special shapes for non-uniform field creation, e.g. Fluid Integrated Circuit [FIC]
• CPC Class Codes: G01N 15/1031 by measuring electrical or magnetic effects
• CPC Class Codes: G01N 24/08 by using nuclear magnetic resonance G01N24/12 takes precedence
• CPC Class Codes: G01N 24/10 by using electron paramagnetic resonance G01N24/12 takes precedence
• CPC Class Codes: G01R 33/302 Miniaturized sample handling arrangements for sampling small quantities, e.g. flow-through microfluidic NMR chips
• CPC Class Codes: G01R 33/307 specially adapted for moving the sample relative to the MR system, e.g. spinning mechanisms, flow cells or means for positioning the sample inside a spectrometer
• CPC Class Codes: G01R 33/34092 RF coils specially adapted for NMR spectrometers
• CPC Class Codes: G01R 33/3415 comprising arrays of sub-coils , i.e. phased-array coils with flexible receiver channels
• CPC Class Codes: G01R 33/465 applied to biological material, e.g. in vitro testing
• CPC Class Codes: G01R 33/4808 : Multimodal MR, e.g. MR combined with positron emission tomography [PET], MR combined with ultrasound or MR combined with computed tomography [CT]
• CPC Class Codes: G01R 33/5604 : Microscopy; Zooming

Abstract

Methods and apparatus for manipulation, detection, imaging, characterization, sorting and/or assembly of biological or other materials, involving an integration of CMOS or other semiconductor-based technology and microfluidics. In one implementation, various components relating to the generation of electric and/or magnetic fields are implemented on an IC chip that is fabricated using standard protocols. The generated electric and/or magnetic fields are used to manipulate and/or detect one or more dielectric and/or magnetic particles and distinguish different types of particles. A microfluidic system is fabricated either directly on top of the IC chip, or as a separate entity that is then appropriately bonded to the IC chip, to facilitate the introduction and removal of cells in a biocompatible environment, or other particles/objects of interest suspended in a fluid. The patterned electric and/or magnetic fields generated by the IC chip can trap and move biological cells or other objects inside the microfluidic system. Electric and/or magnetic field generating components also may be controlled using signals of various frequencies so as to detect one or more cells, particles or objects of interest, and even the type of particle or object of interest, by measuring resonance characteristics associated with interactions between samples and one or more of the field-generating devices. Such systems may be employed in a variety of biological and medical related applications, including cell sorting and tissue assembly.

Claims

1. An apparatus, comprising:

a plurality of CMOS fabricated field-generating components;

a microfluidic system configured to contain a fluid in proximity to the plurality of CMOS fabricated field-generating components; and

at least one controller configured to control the plurality of CMOS fabricated field-generating components to generate at least one electric or magnetic field having a sufficient strength to interact with at least one sample suspended in the fluid.

2. The apparatus of claim 1, wherein the at least one controller is configured to control the plurality of CMOS fabricated field-generating components to generate a plurality of programmable spatially or temporally variable electric or magnetic fields having a sufficient strength to interact with the at least one sample suspended in the fluid.

3. The apparatus of claim 2, further comprising at least one processor coupled to the at least one controller, the at least one processor configured to control the at least one controller so as to facilitate at least one of manipulation, detection, imaging and characterization of the at least one sample via the plurality of electric or magnetic fields.

4. The apparatus of claim 3, wherein the at least one processor is configured to facilitate programmable automated manipulation of the at least one sample based on detection of the at least one sample.

5. The apparatus of claim 1, wherein the at least one controller includes a plurality of CMOS fabricated field control components forming an integrated circuit chip together with the plurality of CMOS fabricated field-generating components.

6. The apparatus of claim 5, wherein the microfluidic system is coupled integrally with the integrated circuit chip to form a CMOS/microfluidic hybrid system.

7. The apparatus of claim 6, wherein the microfluidic system includes at least one polyimide layer, disposed above the CMOS fabricated field-generating components, in which at least one microfluidic channel or reservoir is formed.

8. The apparatus of claim 6, wherein the microfluidic system includes at least one epoxy layer, disposed above the CMOS fabricated field-generating components, in which at least one microfluidic channel or reservoir is formed.

9. The apparatus of claim 6, wherein the microfluidic system includes at least one polydimethylsiloxane (PDMS) mold, disposed above the CMOS fabricated field-generating components, in which at least one microfluidic channel or reservoir is formed.

10. The apparatus of claim 5, wherein the plurality of field control components includes:

a plurality of programmable switching or multiplexing components; and

a plurality of current or voltage sources.

11. The apparatus of claim 10, wherein the plurality of field control components further includes a plurality of high frequency detection components configured to facilitate at least one of detection, imaging and characterization of the at least one sample suspended in the fluid via the generated at least one electric or magnetic field.

12. The apparatus of claim 11, further comprising at least one CMOS fabricated temperature regulation component forming the integrated circuit chip together with the plurality of CMOS fabricated field control components and the plurality of CMOS fabricated field-generating components.

13. The apparatus of claim 12, further comprising at least one processor coupled to the at least one controller, the at least one processor configured to control the at least one controller so as to facilitate at least one of manipulation, detection, imaging and characterization of the at least one sample via the generated at least one electric or magnetic field.

14. The apparatus of claim 13, wherein the at least one processor is configured to facilitate programmable automated manipulation of the at least one sample based on detection of the at least one sample.

15. The apparatus of claim 1, wherein the plurality of CMOS fabricated field-generating components includes a plurality of microcoils.

16. The apparatus of claim 15, wherein the plurality of microcoils are arranged as a two-dimensional array.

17. The apparatus of claim 15, wherein each microcoil includes at least two axially concentric spatially separated portions of conductor turns.

18. The apparatus of claim 15, wherein the at least one controller includes a plurality of switching or multiplexing components and a plurality of current or voltage sources coupled to the plurality of microcoils.

19. The apparatus of claim 18, wherein the at least one controller further includes a plurality of radio frequency (RF) detection components coupled to the plurality of microcoils.

20. The apparatus of claim 19, wherein the plurality of RF detection components includes a frequency locked loop configured to facilitate at least one of detection, imaging and characterization of the at least one sample suspended in the fluid.

21. The apparatus of claim 20, wherein the frequency locked loop includes at least one bridge circuit, the at least one bridge circuit including at least one microcoil of the plurality of microcoils, the at least one bridge circuit configured to generate at least one signal representing a change in an inductance of the at least one microcoil due to a presence of the at least one sample in proximity to the at least one microcoil.

22. A method, comprising an act of:

A) generating at least one electric of magnetic field from a plurality of CMOS fabricated field-generating components, the at least one electric or magnetic field having a sufficient strength to interact with at least one sample suspended in a fluid contained in a microfluidic system in proximity to the plurality of CMOS fabricated field-generating components.

23. The method of claim 22, wherein the act A) includes an act of:

A1) generating a plurality of programmable spatially or temporally variable electric or magnetic fields having a sufficient strength to interact with the at least one sample suspended in the fluid.

24. The method of claim 23, further comprising an act of:

B) controlling the plurality of electric or magnetic fields so as to facilitate at least one of manipulation, detection, imaging and characterization of the at least one sample.

25. The method of claim 24, wherein the act B) comprises an act of:

controlling the plurality of electric or magnetic fields so as to facilitate automated manipulation of the at least one sample based on detection of the at least one sample.

26. The method of claim 24, wherein the act Al) comprises an act of:

applying a voltage or current to the plurality of CMOS fabricated field-generation components via a plurality of programmable switching or multiplexing components.

27. The method of claim 24, wherein the act A1) comprises an act of:

A2) applying at least one high frequency signal to at least one field-generation component of the plurality of CMOS fabricated field-generation components to facilitate at least one of detection, imaging and characterization of the at least one sample.

28. The method of claim 27, wherein the act A2) comprises an act of:

monitoring a frequency of the at least one high frequency signal, wherein the frequency indicates the presence or absence of the at least one sample in proximity to the at least one field-generation component.

29. The method of claim 27, further comprising an act of:

C) regulating a temperature of the at least one sample.

30. The method of claim 22, wherein the plurality of CMOS fabricated field-generating components includes a plurality of microcoils, each microcoil including at least two axially concentric spatially separated portions of conductor turns.