Real-Time Intraoperative Fluorescence Imager for Microscopic Residual Tumor in Breast Cancer

Transcription

1 Real-Time Intraoperative Fluorescence Imager for Microscopic Residual Tumor in Breast Cancer Efthymios Papageorgiou, Dr. Mekhail Anwar (UCSF), Prof. Bernhard Boser (UC Berkeley)

2 Outline Microscopic cancer: background and motivation Angle-selective fluorescence contact imaging ASIC Amorphous silicon absorption filter Integration & Conclusion

3 Microscopic Cancer: Background & Motivation

4 Microscopic residual cancer Large Tumor: Typically 1-3cm diameter 5cm Mammogram Human Tissue

5 Microscopic residual cancer Tumor Left Behind: 10s-1000s of cells >200 cells known to be harmful (AJCC Handbook) 1cm Resection cavity: 3-30cm 2 surface area Human Tissue

6 Residual cancer is a widespread problem Chance of Cancer Returning (%) No Residual Tumor Cancer Left Behind

7 Impact of residual tumor in breast cancer 230,000 women diagnosed each year in U.S.

8 Impact of residual tumor in breast cancer 230,000 women diagnosed each year in U.S. 65%, 150,000 undergo lumpectomies

9 Impact of residual tumor in breast cancer 230,000 women diagnosed each year in U.S. 65%, 150,000 undergo lumpectomies 16.5%, 40,000 have residual tumor Further treatment: Additional surgery ($40,000)

10 Detection: sensor requirements Human Tissue

11 Detection: sensor requirements Fit in 1-3cm diameter resection cavity Human Tissue

12 Detection: sensor requirements Fit in 1-3cm diameter resection cavity Image entire 3-30cm 2 rapidly Human Tissue

13 Detection: sensor requirements Fit in 1-3cm diameter resection cavity Image entire 3-30cm 2 rapidly Clusters of >200 cells (AJCC) If >200 cells, should be removed Human Tissue

14 Detection: sensor requirements Fit in 1-3cm diameter resection cavity Image entire 3-30cm 2 rapidly Clusters of >200 cells (AJCC) Should not disrupt surgeon s typical workflow If >200 cells, should be removed Human Tissue

15 Medical Imaging Techniques MRI: CT: philips.com usa.healthcare.siemens.com No cancer-specific markers

16 Medical Imaging Techniques MRI: CT: philips.com usa.healthcare.siemens.com No cancer-specific markers Rely on non-specific factors (i.e., asymmetry)

17 Medical Imaging Techniques MRI: CT: philips.com usa.healthcare.siemens.com No cancer-specific markers Rely on non-specific factors (i.e., asymmetry) Can only detect ~1cm 3 tumor = 1 billion cells

18 Fluorescence imaging Targeted molecular labels: Antibody + Fluorophore

19 Fluorescence imaging Targeted molecular labels: Antibody + Fluorophore Labeled cancer cells

20 Fluorescence imaging Targeted molecular labels: Antibody + Fluorophore Excitation source Excitation Light Labeled cancer cells Emission Light

21 Fluorescence imaging Targeted molecular labels: Antibody + Fluorophore Excitation source Wavelength filter Excitation Light Labeled cancer cells Emission Light

22 Fluorescence imaging Targeted molecular labels: Excitation source Antibody + Fluorophore Sensor Wavelength filter Excitation Light Labeled cancer cells Emission Light

23 Normalized Emission Targeted fluorescence labels Clinically tested fluorophores in vivo IR700DX IR800CW ICG Normalized Emission, 633nm Excitation For testing purposes Quantum dots (Qdot 705) Bind with targeted antibody Breast: Trastuzumab (Herceptin) Wavelength (nm)

24 Fluorescence microscope High resolution Bulky Cannot enter tumor bed Restricted to LOS Fluorescence microscope 1 Microscope >2m Miss sidewalls! Rigid optics Breast tumor bed Operating Table 1 Van Dam et al., Nature Medicine, 2011.

25 Fiber optic-based imagers Inside tumor bed Fiber bending radius limited to >2cm for fiber bundle diameter >3mm 1 Fiber optic bundle Cannot image all points of complex tumor cavity! Breast tumor bed 1 D. Shin et al., PLoS One, June, 2010.

26 Contact imaging using CMOS IC Can mount on a flexible probe, place directly against tissue No physically constraining optics Scalable CMOS Image Sensor Breast tumor bed Cancer Cell Fluorescent tag

27 Blur and background light Sensor Two objects

28 Blur and background light Two images Sensor Two objects

29 Blur and background light Two images Sensor Two objects Gap

30 Blur and background light Two images Sensor Two objects Images blur Gap

31 Blur and background light Two images Sensor Object can be lost Two objects Images blur Gap Cancer cell cluster

32 Angle-Selective Contact Imaging ASIC

33 Blur Angle-selective gratings (ASG) No optics

34 Blur Angle-selective gratings (ASG) No optics Blinders

35 Blur Angle-selective gratings (ASG) No optics Top View Cross-Section Metal Oxide Single Photodiode Side View Blinders

36 Block off-axis light Blocked Passes through

37 Depth (μm) Depth (μm) Depth (μm) ASG 2D Simulations incidence incidence incidence Distance (μm)

38 ASG perspective side view M5 M μm

39 ASG orthographic top view 45μm 2.4μm

40 10μm 500μm System overview Background Signal Cancer Signal Tissue Biomarker Cancer Fluorophore Quartz Wavelength Filter 6.8μm Excitation Light CMOS Chip ASG over PD 55μm

41 2.25mm Chip block diagram Chip Boundary 4.7mm 80x36 Pixel Array Shared Column Current Sources 80 Reset Lines 80 Signal Lines 10:1 MUX and Output Buffers Digital Drive Digital Control 8 Reset Lines 8 Signal Lines 8 12-bit ADCs FPGA

42 Reset Col Signal Col Pixel architecture: CTIA Reset Switch Φ R SF C int C LR PD w/asg Φ S SF C LS

43 Complete pixel In Pixel 1.8V 1.8V M 11 V b1 V b1 M 4 Φ R M 13 M 12 SF Reset M 10 V b2 V b2 M 3 Φ R C LR M 9 M 8 V rep V b3 Φ RST M 7 Φ RST V M x 6 Φ RST M 5 PD w/asg C int V b3 M 2 M 1 Φ S Φ S M 15 M 14 C LS SF Signal

44 Lateral flux MOM integration capacitor Metal 5 Metal 3-4 and Vias C int = 11fF, Responsivity = 8.2V/s per pw Metal 2

45 2.25mm Chip micrograph 4.7mm 80x36 Angle-Selective Pixel Array Column current sources and output buffers Digital decoders and row select circuits

46 2.25mm Chip micrograph Pixel Pitch = 55μm PD Area = (44μm) 2 Fill Factor = 28% 4.7mm 80x36 Angle-Selective Pixel Array Pixel Close-up 55μm Readout Column current sources and output buffers Digital decoders and row select circuits Angle-selective grating over photodiode

47 Normalized Pixel Response Angle-selectivity Input light 14dB boost in SBR 0 Sensor θ ±18 Angle of Incident Light ( )

48 Cell-imaging experimental setup Angle-Selective ASIC & optical wavelength filter Sensor Quartz, 0.5mm Coverslip, 0.15mm Labeled cancer cells in Matrigel, ~40μm thick Glass slide, 1.5mm

49 3D breast cancer cell cultures ASIC Image, T int = 50ms 500µm Microscope Image, T int = 1s 500µm

50 3D breast cancer cell cultures ASIC Image, T int = 50ms A: 180 cells, 15.1dB SNR A 500µm B B: 270 cells, 15.7dB SNR Microscope Image, T int = 1s A B 500µm

51 SNR (db) SNR vs. Cell Cluster Size SNR 15dB 160 Cells Number of Cells in Cluster

52 Human HER2+ breast cancer tissue #1 Microscope Image Custom ASIC Image 75ms 75ms, filtered 5s Cancer Healthy 4.4mm

53 Human HER2+ breast cancer tissue #2 Microscope Image Custom ASIC Image 75ms 75ms, filtered 4.4mm 5s

54 Amorphous Silicon Absorption Filter

55 Oblique illumination Necessary for in vivo contact imaging Tissue Cancer Steep! (70 ) Quartz Wavelength Filter Excitation Light CMOS Chip

56 Oblique illumination Necessary for in vivo contact imaging Tissue Cancer Scattering off tissue Quartz Wavelength Filter Excitation Light CMOS Chip

57 Thin-film interference filters Alternating layers with different indices of refraction Incident light Reflected light Transmitted light chroma.com

58 Interference filter angle dependence

59 Absorption filters

60 Absorption filters Colored glass 2-3mm thickness!

61 Transmittance Amorphous silicon absorption a-si bandgap ~1.65eV, 750nm wavelength λ edge = hc E g No Transmission Transmission Wavelength

62 Transmittance Transmittance Amorphous silicon absorption a-si bandgap ~1.65eV, 750nm wavelength λ edge = hc E g Urbach tail No Transmission Transmission Wavelength Cody et al., Physical Review Letters, Wavelength

63 Fabricated amorphous silicon filters 5μm, 10μm, 15μm thickness layers a-si:h on a 500μm thickness fused silica wafer 5μm thickness

64 Fabricated amorphous silicon filters 5μm, 10μm, 15μm thickness layers a-si:h on a 500μm thickness fused silica wafer 5μm thickness 700nm thickness

65 Measured transmittance spectra 1.4μm 633nm 54% in passband

66 Transmittance spectra and IR700DX

67 Relative angular response, λ ex = 633nm

68 15 μm a-si 10 μm a-si Hillocks form during fabrication 200 μm 100 μm 200 μm 200 μm

69 ASIC with a-si optical filter 4.7mm

70 Human HER2+ Tissue and a-si filter T int = 75ms T int = 5s

71 Alternative semiconductor materials Material Bandgap (ev) Wavelength (nm) Gallium Phosphide (GaP) Cadmium Selenide (CdSe) Amorphous Silicon (a-si) Gallium Arsenide (GaAs) Indium Phosphide (InP) Crystalline Silicon (c-si)

72 Integration

73 Integrate laser diodes surrounding ASIC Necessary for in vivo contact imaging Tissue Cancer Excitation Light Excitation Light Quartz Wavelength Filter Laser Diode Chip Laser Diode Chip CMOS Chip

74 Integrated system on Flex PCB

75 Conclusion Large optics can t be used in a tumor cavity A contact image sensor with ASG and amorphous silicon optical filter images the entire cavity Breast cancer detection <200 cells, 3D cultures Human HER2+ tissue Combines in vivo use, resolution, and speed Currently performing animal testing to validate the sensor in vivo

76 Acknowledgements The Department of Defense (DoD), the Mary Kay Foundation, the American Society of Clinical Oncology (ASCO) Hui Zhang and Dr. Catherine Park, UCSF TSMC University Shuttle Program for chip fabrication Mark Brunson and Darick Baker, University of Washington Nanofabrication Facility My colleagues: Simeon Giverts, Hossein Najafi, Burak Eminoglu, Behnam Behroozpour, Pramod Murali, Hao-Yen Tang, Andy Michaels

77 Commercialization through industry/university partnerships since 1986 Booth 1339 Contact Dr. Mike Cable bsac.berkeley.edu 2016 University of California Berkeley Sensor & Actuator Center