Methods and system for image guided cell ablation with microscopic resolution

• US 10,285,759 B2
• Filed: 09/29/2017
• Issued: 05/14/2019
• Est. Priority Date: 12/08/2010
• Status: Active Grant

• Current Assignee: Lumicell, Inc.
• Original Assignee: Lumicell, Inc.
• Inventors: Lee, W. David, Ferrer, Jorge
• Primary Examiner(s): Farah, Ahmed M
• Application Number:
  US15/721,247
• Publication Number:
  US 20180021090A1
• Time in Patent Office: 592 Days
• Field of Search: 606 3, 606 9- 12, 606 16, 607 88- 92, 600310, 600317, 600323, 600329, 382128-131, 382133, 128898, 128922
• CPC Class Codes: A61B 18/02 by cooling, e.g. cryogenic techniques devices for cooling specific reflex points of the body within cell-life limits A61H39/06
• CPC Class Codes: A61B 18/12 by passing a current through the tissue to be heated, e.g. high-frequency current
• CPC Class Codes: A61B 18/14 Probes or electrodes therefor
• CPC Class Codes: A61B 18/20 using laser
• CPC Class Codes: A61B 18/22 the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
• CPC Class Codes: A61B 18/24 with a catheter A61B18/26, A61B18/28 take precedence
• CPC Class Codes: A61B 2017/00057 Light
• CPC Class Codes: A61B 2017/0011 piezoelectric
• CPC Class Codes: A61B 2018/00029 open
• CPC Class Codes: A61B 2018/00351 Heart
• CPC Class Codes: A61B 2018/00434 Neural system
• CPC Class Codes: A61B 2018/00565 Bone
• CPC Class Codes: A61B 2018/00577 Ablation
• CPC Class Codes: A61B 2018/00642 with feedback, i.e. closed loop control
• CPC Class Codes: A61B 2018/00886 Duration
• CPC Class Codes: A61B 2018/00904 Automatic detection of target tissue
• CPC Class Codes: A61B 2018/00982 combined with or comprising means for visual or photographic inspections inside the body, e.g. endoscopes
• CPC Class Codes: A61B 2018/20351 Scanning mechanisms
• CPC Class Codes: A61B 2018/20359 by movable mirrors, e.g. galvanometric
• CPC Class Codes: A61B 2018/20361 with redirecting based on sensed condition, e.g. tissue analysis or tissue movement
• CPC Class Codes: A61B 2018/2283 : with pivotable mirrors
• CPC Class Codes: A61B 2503/40 : Animals
• CPC Class Codes: A61B 2562/028 : Microscale sensors, e.g. electromechanical sensors [MEMS]
• CPC Class Codes: A61B 2576/00 : Medical imaging apparatus involving image processing or analysis A61B1/00009, A61B6/52 and A61B8/52 take precedence; image processing per se G06T; details of algorithms for analysing medical images G06T7/0012
• CPC Class Codes: A61B 34/20 : Surgical navigation systems; Devices for tracking or guiding surgical instruments, e.g. for frameless stereotaxis
• CPC Class Codes: A61B 90/30 : Devices for illuminating a surgical field, the devices having an interrelation with other surgical devices or with a surgical procedure
• CPC Class Codes: A61B 90/361 : Image-producing devices, e.g. surgical cameras
• CPC Class Codes: A61B 90/39 : Markers, e.g. radio-opaque or breast lesions markers

Abstract

The invention provides systems and method for the removal of diseased cells during surgery.

Claims

1. An in vivo method of treating a subject with a tumor comprising:

(a) administering a composition comprising a molecular imaging probe to the subject, wherein the imaging probe labels tumor cells and/or tumor associated cells;

(b) permitting the molecular imaging probe to clear preferentially from healthy tissue leaving the tumor cells and/or tumor associated cells labeled;

(c) performing initial resection surgery to remove tumor cells from the subject thereby creating a resection bed;

(d) directing light towards the resection bed to excite the molecular imaging probe;

(e) obtaining an in situ fluorescence image of the resection bed using an imaging system;

(f) detecting the labeled tumor cells and/or the labeled tumor associated cells, if present in the resection bed, using the fluorescence image; and

(g) if labeled tumor cells and/or labeled tumor associated cells are detected in (f), performing further resection surgery to remove the labeled tumor cells and/or labeled tumor associated cells.

2. The method of claim 1, wherein detecting the labeled tumor cells and/or the labeled tumor associated cells, if present in the resection bed, comprises detecting the labeled tumor associated cells, if present in the resection bed.

3. The method of claim 1, wherein detecting the labeled tumor cells and/or the labeled tumor associated cells, if present in the resection bed, comprises detecting both the labeled tumor cells and the labeled tumor associated cells, if present in the resection bed.

4. The method of claim 1, wherein the tumor associated cells include tumor associated inflammation cells and/or tumor associated macrophages.

5. The method of claim 1, wherein the light has a wavelength between 100 nm and 2500 nm.

6. The method of claim 1, wherein the molecular imaging probe is a clearance differential probe including a fluorescent label attached to a pharmacokinetic modifier that results in the molecular imaging probe clearing preferentially from the healthy tissue leaving the tumor cells and/or tumor associated cells labeled.

7. The method of claim 6, wherein the fluorescent label has optical properties in the visible spectrum of 350 nm to 670 nm.

8. The method of claim 6, wherein the pharmacokinetic modifier has a molecular weight of between 20,000 g/mol and 40,000 g/mol.

9. The method of claim 6, wherein the pharmacokinetic modifier is selected from the group consisting of polyethylene glycol (PEG), dextran, polyethylene oxide (PEO), polyoxyethylene (POE), methoxypolyethylene glycol (MPEG), methoxypolypropylene glycol, polyethylene glycol-diacid, polyethylene glycol monoamine, MPEG monoamine, MPEG hydrazide, MPEG imidazole, copolymers of polyethylene glycol and monoxypolypropylene glycol, branched polypropylene glycol, polypropylene glycol, and polylacic-polyglycolic acid.

10. The method of claim 6, wherein the molecular imaging probe comprises a polyethylene glycol (PEG) having a molecular weight of between 20,000 g/mol and 40,000 g/mol.

11. The method of claim 6, wherein the fluorescent label is selected from the group consisting of Cy3, Cy3.5, Cy5, Alexa 568, Alexa 546, Alexa 610, Alexa 647, ROX, TAMRA, Bodipy 576, Bodipy 581, Bodipy TR, Bodipy 630, VivoTag 645, and Texas Red.

12. The method of claim 1, wherein the imaging system images the tumor bed with single-cell resolution.

13. The method of claim 1, wherein the composition is administered systemically to the subject.

14. The method of claim 1, wherein the composition is applied to a tissue surface of the subject.

15. The method of claim 1, wherein the molecular imaging probe is imaged at between 12 and 36 hours after administration.

16. The method of claim 1, wherein the image allows for selective detection of the labeled tumor cells and/or labeled tumor associated cells within about 1 cm from the surface of the tissue resection bed and excludes deep tissue emission.

17. The method of claim 1, wherein the subject is a mammal.

18. The method of claim 17, wherein the subject is a human.

19. The method of claim 1, wherein the molecular imaging probe clears preferentially from healthy tissue leaving both tumor cells and tumor associated cells labeled.

20. The method of claim 1, wherein the imaging system comprises:

(a) a light source that directs the light towards the resection bed;

(b) an optical receptor configured to receive light from the resection bed and obtain the in situ fluorescence image; and

(c) an image processor that receives the fluorescence image from the optical receptor and detects the labeled tumor cells and/or the labeled tumor associated cells if present in the resection bed.

21. The method of claim 20, wherein the image processor comprises a field of view (FOV) greater than a diameter of a cell of the resection bed and an analysis resolution matched to the diameter of a cell of the resection bed and configured to receive and analyze light corresponding to each cell in the FOV.

22. The method of claim 20, wherein the light directed by the light source towards the resection bed excites the molecular imaging probe such that the probe emits light.

23. The method of claim 20, wherein the optical receptor comprises at least one selected from a charge-coupled device (CCD), an avalanche photodiode (APD), and a complementary metal-oxide semiconductor (CMOS).

24. The method of claim 20, wherein the optical receptor comprises an array of pixels with an analysis resolution substantially equal to a diameter of the tumor cells and/or tumor associated cells.

25. The method of claim 20, wherein the imaging system locates the labeled tumor cells and/or the labeled tumor associated cells.

26. The method of claim 25, wherein the image processor outputs camera pixel locations of the labeled tumor cells and/or the labeled tumor associated cells.

27. The method of claim 20, wherein the image processor detects the labeled tumor cells and/or the labeled tumor associated cells, if present in the resection bed, by comparing a fluorescence at each location in the image with a fluorescence threshold.