Device and method for in vivo noninvasive magnetic manipulation of circulating objects in bioflows

• US 10,342,430 B2
• Filed: 06/29/2015
• Issued: 07/09/2019
• Est. Priority Date: 12/13/2007
• Status: Active Grant

• Current Assignee: Bioventures, LLC
• Original Assignee: Bioventures, LLC
• Inventors: Zharov, Vladimir Pavlovich
• Primary Examiner(s): Luong, Peter
• Application Number:
  US14/754,034
• Publication Number:
  US 20150351640A1
• Time in Patent Office: 1,471 Days
• CPC Class Codes: A61B 18/1815 using microwaves
• CPC Class Codes: A61B 18/20 using laser
• CPC Class Codes: A61B 5/0059 using light, e.g. diagnosis by transillumination, diascopy, fluorescence A61B5/0093, A61B5/1455, A61B5/02416 and A61B5/0261 take precedence
• CPC Class Codes: A61B 5/0095 by applying light and detecting acoustic waves, i.e. photoacoustic measurements
• CPC Class Codes: A61B 5/412 Detecting or monitoring sepsis
• CPC Class Codes: A61B 5/415 the glands, e.g. tonsils, adenoids or thymus
• CPC Class Codes: A61B 5/416 the spleen
• CPC Class Codes: A61B 5/418 lymph vessels, ducts or nodes
• CPC Class Codes: A61B 8/08 Detecting organic movements or changes, e.g. tumours, cysts, swellings A61B8/02 - A61B8/06 take precedence
• CPC Class Codes: A61B 8/481 involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream analysis of echo signal exploiting properties of a contrast enhancer in devices for short-range imaging with acoustic waves G01S7/52039
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• CPC Class Codes: B03C 1/288 disposed at the outer circumference of a recipient
• CPC Class Codes: B03C 1/30 Combinations with other devices, not otherwise provided for
• CPC Class Codes: B03C 2201/06 Ionising electrode being a needle
• CPC Class Codes: B03C 2201/26 for use in medical or biological applications
• CPC Class Codes: G01N 15/1425 using an analyser being characterised by its control arrangement
• CPC Class Codes: G01N 15/1434 Optical arrangements
• CPC Class Codes: G01N 15/147 the analysis being performed on a sample stream
• CPC Class Codes: G01N 2015/1477 Multiparameters

Abstract

A device and methods for the non-invasive manipulation and detection of target objects such as cells, pathogens, microparticles, and nanoparticles in vivo using an external magnetic field are described. In one aspect, a device and method for capturing and detecting intrinsically magnetic target objects or target objects labeled with at least one magnetic particle within the area of interest using an in vivo flow cytometer are described.

Claims

1. A device for the manipulation and detection of a magnetic target object within a moving biofluid of a living organism, comprising:

an in vivo flow cytometer for detecting the magnetic target object within an area of interest, wherein the in vivo flow cytometer is an in vivo photoacoustic flow cytometer comprising;

at least one laser;

at least one optical module; and

at least one ultrasound transducer; and

at least one magnet for producing a magnetic field that manipulates the magnetic target object within the area of interest.

2. The device of claim 1, wherein the manipulation of the magnetic target object is chosen from enrichment, capture, sorting, separation, concentration within a selected region of the biofluid, or any combination thereof of the target object within the area of interest.

3. The device of claim 1, wherein the manipulation of the magnetic target object is clustering of the magnetic target object within the area of interest.

4. The device of claim 3, wherein the clustering of the magnetic target object within the area of interest forms laser-induced microbubbles or nanobubbles around the clustered magnetic target objects.

5. The device of claim 3, wherein the clustering of the magnetic target object within the area of interest creates a photoacoustic signal amplification.

6. The device of claim 1, wherein the at least one magnet is situated at a distance between about 0.1 mm and about 20 cm from the area of interest.

7. The device of claim 1, wherein the device detects the magnetic target object at a detection sensitivity ranging from about 1 to about 10000 target objects per L of the moving biofluid.

8. The device of claim 1, wherein the at least one magnet produces a field that captures the magnetic target object within the area of interest.

9. The device of claim 1, wherein the moving biofluid is chosen from blood, lymph, cerebrospinal fluid, urine, chyme, cytosol, tears, or interstitial fluid.

10. The device of claim 1, wherein the magnetic target object is chosen from an intrinsically magnetic target object or a target object labeled with a magnetic particle.

11. The device of claim 10, wherein the magnetic particle is chosen from a magnetic nanoparticle or a magnetic microparticle having a size ranging from about 5 nm to about 10 μ

m.

12. The device of claim 1, wherein the magnetic target object is labeled with a contrast agent selected from an ultrasound contrast agent, a photoacoustic contrast agent, a hybrid contrast agent, a fluorescent contrast agent, a Raman contrast agent, an MRI contrast agent, a superconductivity quantum interference device contrast agent, a PET contrast agent, and a CT contrast agent.

13. The device of claim 12, wherein the hybrid contrast agent is a nanoparticle complex or a microparticle complex chosen from a gold-magnetic complex, a quantum dot-magnetic complex, a carbon nanotube-magnetic complex, a radionucleotide-magnetic complex, a surface enhanced resonance scattering-magnetic complex, or any combination thereof.

14. The device of claim 1, wherein the magnetic field has a strength ranging from about 0.1 T to about 20 T.

15. The device of claim 13, wherein the magnetic field is chosen from a permanent field, a pulsed field, and a series of magnetic field pulses.

16. The device of claim 1, wherein the in vivo photoacoustic flow cytometer comprises a laser fiber for delivering at least one laser pulse to the area of interest, wherein the laser fiber comprises a focusing tip to transmit the at least one laser pulse to the area of interest.

17. The device of claim 1, wherein the at least one magnet comprises two or more magnets situated along a direction of movement of the moving biofluid.

18. The device of claim 17, further comprising a securing cuff including the two or more magnets.

19. The device of claim 1, wherein at least one magnet is configured to be in contact with the external integument of the living organism.

20. The device of claim 18, further comprising a magnetic cuff including the at least one magnet.

21. The device of claim 1, wherein the at least one magnet is configured to be invasively situated in the vicinity of the moving biofluid.

22. The device of claim 21, further comprising an invasive insertion device chosen from a needle or a catheter, wherein the invasive insertion device includes the at least one magnet.

23. The device of claim 1, further comprising an extracorporeal shunt including a circulatory bypass tube for continuously withdrawing the moving biofluid out of the living organism, directing the moving biofluid through the circulatory bypass tube, and returning the moving biofluid back into the organism, wherein the area of interest includes a cross-section of the circulatory bypass tube.

24. A method of manipulating and detecting magnetic target objects within a moving biofluid of a living organism, comprising:

situating at least one magnet to manipulate the magnetic target objects within a magnetic field produced by the at least one magnet in an area of interest; and

detecting the magnetic target objects using an in vivo flow cytometer, wherein the in vivo flow cytometer is an in vivo photoacoustic flow cytometer comprising;

at least one laser;

at least one optical module; and

at least one ultrasound transducer.

25. The method of claim 24, wherein the manipulation of the magnetic target objects is chosen from enrichment, capture, sorting, separation, concentration within a selected region of the biofluid, or any combination thereof of the target objects within the area of interest.

26. The method of claim 24, wherein the manipulation of the magnetic target objects is clustering of the magnetic target object within the area of interest.

27. The device of claim 26, wherein the clustering of the magnetic target object within the area of interest forms laser-induced microbubbles or nanobubbles around the clustered magnetic target objects.

28. The device of claim 26, wherein the clustering of the magnetic target object within the area of interest creates a photoacoustic signal amplification.

29. The method of claim 24, wherein the at least one magnet is situated at a distance between about 0.1 mm and about 20 cm from the area of interest.

30. The method of claim 24, wherein the device detects the magnetic target objects at a detection sensitivity ranging from about 1 to about 10000 target objects per L of the moving biofluid.

31. The method of claim 24, wherein the at least one magnet produces a field that captures the magnetic target objects within the area of interest.

32. The method of claim 24, wherein the moving biofluid is chosen from blood, lymph, cerebrospinal fluid, urine, chyme, cytosol, tears, or interstitial fluid.

33. The method of claim 24, wherein the magnetic target objects are chosen from intrinsically magnetic target objects or target objects labeled with magnetic particles.

34. The method of claim 33, further comprising labeling target objects with magnetic particles to obtain the target objects labeled with magnetic particles.

35. The method of claim 33, wherein the magnetic particles are chosen from magnetic nanoparticles or magnetic microparticles having a size ranging from about 5 nm to about 10 μ

m.

36. The method of claim 33, wherein the magnetic particles used to label the target objects comprise magnetic nanoparticles conjugated with first targeting moieties chosen from antibodies, ligands, antigens, or cell marker proteins.

37. The method of claim 33, wherein the target objects are labeled with magnetic particles and the target objects are chosen from biomarkers, drugs, toxins, microparticles, nanoparticles, viruses, or cells.

38. The method of claim 37, wherein the biomarkers are chosen from proteins, antibodies, hormones, single-stranded DNA fragments, double-stranded DNA fragments, or RNA fragments.

39. The method of claim 37, wherein the cells are chosen from pathogenic bacteria, pathogenic fungi, pathogenic protists, or cancer cells.

40. The method of claim 39, wherein the cancer cells are metastatic cancer stem cells resulting from a cancer chosen from melanoma, leukemia, brain cancer, breast cancer, colon cancer, prostate cancer, ovarian cancer, pancreatic cancer, or testicular cancer.

41. The method of claim 36, further comprising injecting the magnetic particles conjugated with targeting moieties into the moving biofluid prior to situating the at least one magnet.

42. The method of claim 34, wherein the target objects are additionally labeled with contrast agents chosen from ultrasound contrast agents, photoacoustic contrast agents, hybrid contrast agents, fluorescent contrast agents, Raman contrast agents, MRI contrast agents, superconductivity quantum interference device contrast agents, PET contrast agents, or CT contrast agents.

43. The method of claim 42, wherein the hybrid contrast agents are nanoparticle complexes or a microparticle complexes chosen from gold-magnetic complexes, quantum dot-magnetic complexes, carbon nanotube-magnetic complexes, radionucleotide-magnetic complexes, surface enhanced resonance scattering-magnetic complexes, or any combination thereof.

44. The method of claim 42, wherein the contrast agents used to additionally label the target objects are conjugated with second targeting moieties chosen from antibodies, ligands, antigens, or cell marker proteins, wherein the second targeting moieties are different from the first targeting moieties.

45. The method of claim 44, further comprising injecting the conjugated contrast agent into the moving biofluid prior to situating the at least one magnet.

46. The method of claim 45, wherein the at least one magnet is incorporated into an invasive insertion device chosen from a needle device or a catheter device.

47. The method of claim 24, wherein the moving biofluid flows through a circulatory vessel chosen from a blood vessel, a lymphatic vessel, an extracorporeal shunt, or any combination thereof.

48. The method of claim 47, wherein the at least one magnet is invasively situated in the vicinity of the circulatory vessel.

49. The method of claim 24, further comprising subjecting the detected magnetic target objects to an additional process chosen from removal for biochemical or genetic analysis;

non-invasive eradication using high-energy pulses chosen from laser pulses, microwave pulses, or ultrasound pulses;

magnetic purging;

mechanical removal;

needle extraction;

or any combination thereof.