1) A new wearable diffuse optical spectroscopy (DOSI) device is being developed to non-invasively monitor breast cancer patients undergoing neoadjuvant chemotherapy. 2) Current imaging methods can only assess response after 1.5-2 months of treatment, but DOSI may be able to predict long-term response as early as the first week of therapy. 3) The project aims to create a portable frequency domain digital DOSI system and a flexible wearable probe to allow continuous monitoring during chemotherapy infusion.

1. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
A New Wearable Diffuse
Optical Spectroscopic Imaging
(DOSI) Device:
Darren Roblyer, Ph.D.
Biomedical Optical Technologies Lab (BOTLab)
Boston University
1

2. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Between 74-87% of breast cancer patients
treated with presurgical (neoadjuvant)
chemotherapy have a suboptimal/incomplete
response*
Clinical Problem: Chemotherapy does
not work for all patients
Zakhireh, Gomez, and
Esserman 2008, EJC
*National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol
B-18 Rastogi et al. 2008, JCO
Reasons for poor response rates:
• Redundant molecular escape
pathways/resistance
• Poor drug delivery
• Biopsy sampling errors/tumor
heterogeneity
• Tumors evolve

3. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Current “Early” imaging markers are after
1.5-2 months of treatment
pre-surgical, neoadjuvant chemotherapy
Zakhireh, Gomez, and Esserman 2008, EJC
Non-response (NR):
<50% reduction
Partial Response (PR):
at least 50% reduction
Pathologic Complete Response (pCR):
no residual invasive disease
BeforeChemoAfterChemo

4. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Potential Benefits of Early Monitoring
• Spare patients the side-effects of ineffective
treatment
• Reduce wasted resources
• Potential for adaptive treatment regimens
• Chemotherapy becomes promising to more
patients
• Optical technologies are suited to the task
– Non-invasive
– Non-ionizing, no contrast agents
– Can monitor patients frequently over time
4

5. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Diffuse Optical Spectroscopy (DOS) is emerging
as a new tool for therapy monitoring )
Tromberg et al. 2005 Breast Cancer Research
Handheld probe scanned over the breast
Measurements take 20 min – 1 hour
handheld probe
clinical measurement procedure

6. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
DOS Measurement Procedure
Breast Cancer Training Model Image from: http://www.eworldpoint.com
Map
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Tromberg et al. 2005 Breast Cancer Research
Measurement Locations
Post Processed “Functional” Map
Tumor

7. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
DOS Functional Contrast
● Increased tumor perfusion, and metabolism detected
by elevated Total Hb, Oxy Hb, and Deoxy Hb
Elevated water
Elevated blood
Decreased lipid
● Tumor edema and tumor cell proliferation lead to
increased water content
● Tumors displace bulk lipid when growing leading to
decreased lipid content
TUMOR
TOI =
ctHHb´Water
Lipid

8. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
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Baseline
Week 3
of Therapy
Week 12
End Therapy
H2O (%) Tissue Optical IndexLipid (%)
0 1 2 365 70 75 80 8510 15 20 25
Oxyhemoglobin (µM) Deoxyhemoglobin (µM)
5 10 15 20 2 4 6 8
DOSI Measurements Predict Response
4cm Lipid
WaterctHHb
TOI


45 y.o.
pCR
Cerussi et al. 2007 PNAS; Cerussi et al. 2001 Academic Radiology

9. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Roblyer et al. PNAS, 2011
17 subjects measured at least 3 times during the first
7 days of therapy
Long-term response can be predicted in the
first week of therapy with DOS

10. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Hemodynamic Changes Occur During Infusion
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ctHbO2 ctHHb StO2
Baseline
0:00
Post-paclitaxel
2:19
Post carboplatin
3:14
1/3 bevacizumab
3:50
2/3 bevacizumab
4:47
Post bevacizumab
5:33
Post-premedications
1:23
µM
µM
%
mm
39 y.o.
2.4cm tumor (US)
0.2cm at surgery
Non-pCR
-30%
Less than 10% change in lipids and water
-10% -7%

11. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Safe: DOS uses non-ionizing light
Content Rich: Provides tumor
metabolic/functional information
Minimal Infrastructure: Relatively
inexpensive, increasingly portable
Diffuse Optical Spectroscopy (DOS)
A. Cerussi et al., Trans. Royl. Soc. (2011)
These features allow us to measure patients
at exciting new timepoints

12. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Current DOS technology is not optimized for the
doctors office, infusion suite, or home use.)
Tromberg et al. 2005 Breast Cancer Research
Past generation DOS
New generation DOS
Deliverable 2: wearable probe
Deliverable 1: portable
digital DOS system

13. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Frequency-Domain DOSContinuous Wave (CW) DOS
O’Sullivan, JBO 2012
)Frequency-Domain DOS provides quantitative information )
• Least complex
• measures relative changes in
tissue oxygenation of short times
• more complex
• measures absolute
concentrations of:
• Oxyhemoglobin
• Deoxyhemoglobin
• Water
• Fat
• Measurements comparable days-
months
We use both of these
methods for monitoring
different parts of treatment

14. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Deliverable 1: portable
frequency domain digital
DOS system
Deliverable 2: wearable
CW infusion probe
Different therapy timepoint require
different technologies

15. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
$15,000
Entry level Network Analyzer
$1,000
ADC12D1800 Analog-to-Digital
Converter
$200
ADS62P49 Analog-to-Digital
Converter
Deliverable 1:
Frequency Domain
digital DOS (dDOS)
Digital DOS can replace analog DOS
Error of Digital DOS
compared to analog DOS

16. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Innovative Signal Processing is Necessary to
Reduce Costs and Power Consumption
• Input frequency swept 50-400MHz
• ADC Specifications (ADS62P49):
– Maximum sample rate of 250 MHz
• Shannon-Nyquist Criteria: sample rate must be greater
than 800MHz to reconstruct the original signal
• Undersampling technique is necessary to utilize low-
speed ADC for a high speed application.
16
undersampled or aliased signal
Undersampling
• reduces PCB design complexity
• reduces power consumption by 7x
• reduces ADC cost by 20x

17. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Deliverable 1: dDOS prototype
17
Direct Digital Synthesizer (DDS) Motherboard and ADC
Price Reduction: ~15x
Size Reduction: ~45x
System on a Chip (SoC)
ECE Senior Design Group:
2014 Design Excellence Award

18. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
End User Software
Raw data
Patient informationInstrument parameters

19. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Deliverable 1: Current Status
19
Novel Design Features:
• 6 signal generators
• Wavelength multiplexing
• Measurement speed: .34 seconds
• PCB dimensions: 9.5” x 6.4”
Ongoing/Future Work:
• Laboratory testing
• Integration of lasers
• Clinical testing

20. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Deliverable 2: Wearable Probe/Infusion Monitor
Current Single Channel Probe:
Operator Moves probe point by point
~30 min to 1 hour measurement time
per breast
Proposed Imaging Probe:
Flexible probe conforms to breast
Continuous Measurements during infusion
5cm
side view
bottom view
Detector: Photodiode
Source: LED array
5cm

21. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Deliverable 2: Wearable probe
21
Single-optode prototype
photodiodeDual wavelength LED
Bottom View
Transimpedance amplifier
Optical phantom
Data logger
Current controller
Prototype Test Parameters:
• LEDs
• Photodiodes
• Measurement electronics

22. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Deliverable 2: Wearable probe
22
Multi-optode prototype
photodiode
Dual wavelength LEDs
Prototype Test Parameters:
• Optode geometry
Future Work:
• Flexible PCB
• Skin friendly interface
• Device packaging

23. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Project Summary
• Working prototypes of the new portable dDOS system
(deliverable 1) and the wearable probe (deliverable 2)
have been fabricated.
• We have received follow-up funding from the CFTCC and
the ACS that will allow us to complete fabrication/testing
and conduct a clinical study with the DOS prototypes.
23
CFTCC team

24. CFTCC 2nd Annual Science Symposium – May 2014 NIH U54-EB-015403-02
Acknowledgements
Funding:
• CFTCC Summer Fellowship
• CFTCC Research Grant
• BU ACS Pilot Research Grant
• ACS Research Scholar Grant
Biomedical Optical
Technologies Lab (BOTLab):
BU Biostatstics:
Janice Weinberg, Ph.D.
BU ECE Senior Design Group:
Chris Woodall
Thomas Nadovich
Benjamin Harvery
Caroline Ekchian
Andy Mo
UC Irvine/Beckman Laser
Institute:
Bruce Tromberg, Ph.D.
Graduate Students:
Fei Teng
Syeda Tabassum
Yanyu Zhao
Staff:
Raeef Istfan
BU Biology:
David Waxman, Ph.D
BMC:
Rita Blanchard, M.D.
BU BME:
Irving Bigio, Ph.D.
BU Electronics Design Facility:
Eric Hazen
Contact Information:
Darren Roblyer
roblyer@bu.edu
Collaborators:
Undergraduates:
Justin Jung
Sanjana Pannem
Shaheer Piracha
Jason Porter
Justin Hong