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«Novel Biophotonic Imaging Techniques for Assessing Women’s Reproductive Health by Tyler Kaine Drake Department of Biomedical Engineering Duke ...»

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Kent Weinhold Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biomedical Engineering in the Graduate School of Duke University 2013


Novel Biophotonic Imaging Techniques for Assessing Women’s Reproductive Health by Tyler Kaine Drake Department of Biomedical Engineering Duke University Date:_______________________



Adam Wax, Supervisor ___________________________

David Katz __________________________

–  –  –

Abstract Women make up over half the population in the United States, but medical advancements in areas of women’s health have typically lagged behind the rest of the medical field.

Specifically, two major threats to women’s reproductive health include human immunodeficiency virus (HIV), and cervical cancer with accompanying human papillomavirus (HPV) infection.

This dissertation presents the development and application of two novel optical imaging technologies aimed at improving aspects of women’s reproductive health.

The presented work details the instrumentation development of a probe- based, dual- modality optical imaging instrument, which features simultaneous imaging of fluorimetry and multiplexed low coherence interferometry (mLCI) to measure in vivo microbicide gel thickness distributions.

The study explores the optical performance of the device and provides proof of concept measurements on a calibration socket, tissue phantom, and preliminary in vivo human data.

Once the instrument is fully characterized, it is applied in a clinical trial in which in vivo human vaginal gel thickness distributions are measured.

Gel distribution data obtained by the instrument’s modalities are compared in order to assess the ability of mLCI making accurate in vivo measurements.

The results of the study show that mLCI is capable of measuring microbicide gel thicknesses with high axial resolution (10 µ;m) without the need of

–  –  –

exogenous contrast agents.

Differences between the fluorimetry and mLCI modalities are then exploited to show a methodology for calculating the extent of microbicide gel dilution with the dual- modality instrument.

Limitations in cervical cancer screening are then addressed as angle- resolved low coherence interferometry (a/LCI) is used in an ex vivo pilot study to assess the feasibility of a/LCI in identifying dysplasia in cervical tissues.

The study found that the average nuclear diameter found by a/LCI in the basal layer of ectocervical epithelium showed a statistically significant increase in size in dysplastic tissue.

These results indicate that a/LCI is capable of identifying cervical dysplasia in ectocervical epithelium.

The results of the work presented in this dissertation show that dual- modality optical imaging with fluorimetry and mLCI, and the a/LCI technique show promise in advancing technologies used in the field of women’s reproductive health.

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x List of Tables

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1 Introduction

1 1.1 Motivation

1 1.2 Project overview

7 1.3 Document organization

9 2 Background

12 2.1 Introduction

12 2.2 Microbicides

13 2.2.1 Microbicide gel effectiveness

13 2.2.2 Microbicide gel dilution

14 2.2.3 Microbicide imaging


–  –  –

2.2.5 Measuring microbicide distribution with LCI

20 2.3 Cervical Cancer

23 2.3.1 Cervical Intraepithelial Neoplasia and risk factors

23 2.3.2 Cervical cancer screening

24 2.3.3 Optical detection techniques


–  –  –

2.4 Summary

30 3 Instrumentation

32 3.1 Introduction

32 3.2 Dual- modality optical imaging instrument

33 3.2.1 Benchtop multiplexed low coherence interferometry (mLCI) instrument....

33 3.2.2 Clinical dual- modality optical imaging instrument

46 3.2.3 Clinical application

56 3.2.4 Dual- modality instrument updates

61 3.3 Summary

67 4 In vivo dual- modality optical imaging instrument clinical study

68 4.1 Introduction

68 4.2 Study design


–  –  –

4.4 Results

72 4.5 Discussion

78 4.6 Summary

79 5 Measuring dilution of microbicide gels

81 5.1 Introduction

81 5.2 Study design

82 5.3 Results


–  –  –

5.5 Summary

93 6 Ex vivo a/LCI cervical dysplasia study

95 6.1 Introduction

95 6.2 a/LCI clinical instrument

96 6.3 a/LCI data acquisition and processing

99 6.4 Study design

101 6.5 Data analysis

102 6.6 Nuclear morphology results

103 6.7 Discussion

107 6.8 Summary

112 7 Conclusions and future directions



118 Biography


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List of Tables Table 2.1:

a/LCI results to date

29 Table 3.1:

OSNR, Axial Resolution, and Falloff

40 Table 3.2:

Measured OSNR and axial resolution values for the clinical mLCI device.....

53 Table 4.1:

Summary results for clinical dual- modality study

73 Table 4.2:

Fraction of coating thickness distribution with less than 100 µ;m thickness and axial extent of azimuthally averaged coating with thickness greater than 100 µ;m...........


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Table 5.2:

Calculated line of best fit from weighted least- squares regression for each of the serial dilutions

86 Table 5.3:

Error analysis


Table 6.1:

Average nuclear morphology measurements at each of the 50 µ;m depth segments for optical biopsies as measured by a/LCI.


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Figure 2.2:

Michelson interferometer diagram.

17 Figure 2.3:

Diagram of the LCI Fourier transform relationship

19 Figure 2.4:

Common path LCI system

21 Figure 2.5:

Second generation LCI systeme.


–  –  –

Figure 3.2:

Diagram of the silicon v- groove chip

36 Figure 3.3:

Reference arm OPL adjustment.

37 Figure 3.4:

B- scan of a mirror from the mLCI system before pathlength correction........


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Figure 3.6:

Calibration socket used to verify the linearity of the mLCI system................

43 Figure 3.7:

Scan pattern and tissue phantom geometry for benchtop mLCI imaging.....

44 Figure 3.8:

(a) A- scan data from channel 1 of the phantom study and (b) mLCI scan of gel distribution on the tissue phantom

45 Figure 3.9:

Diagram of the dual- modality optical imaging instrument

47 Figure 3.10:

Schematic of the clinical mLCI instrument

49 Figure 3.11:

mLCI imaging module and endoscopic probe

50 Figure 3.12:

Zemax simulations of the imaging module geometry.

51 Figure 3.13:

Clinical mLCI instrument

52 Figure 3.14:

Spot size at mLCI focus

54 Figure 3.15:

Calibration socket study


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Figure 3.16:

Scanning Pattern of dual- modality instrument

57 Figure 3.17:

Human in vivo gel thickness distributions

59 Figure 3.18:

(a) Contour lines from the fluorimetric data overlaid onto a topological map of the mLCI data for comparison.

(b) B- scan of example human data

60 Figure 3.19:

Example data from the optical imaging instrument

62 Figure 3.20:

Photograph of the optical imaging instrument distal probe tip

63 Figure 3.21:

Example topological map showing failed mLCI depth scans

64 Figure 3.22:

Overlaid A- scans revealing the reflection from the outer epoxy tube surface.

65 Figure 3.23:

Photographs of the clinical optical imaging instrument


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Figure 4.2:

Example human in vivo gel coating measurements

75 Figure 4.3:

Azimuthally averaged coating thickness distribution from mLCI and fluorimetry


Figure 4.4:

Axial extent at which azimuthally averaged coating falls below 100 µ;m thickness


Figure 5.1:

Probe geometry as used with the test socket


Figure 5.2:

Example dual- modality data for 33% VFS dilution of fluorescein- labeled FACTS- 001 gel

85 Figure 5.3:

Slope values resulting from weighted linear least- squares regression plotted against gel dilution values.


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Figure 6.1:

Diagram of the clinical a/LCI instrument

97 Figure 6.2:

Photographs of the clinical a/LCI system


–  –  –

Figure 6.3:

Typical a/LCI data

100 Figure 6.4:

Average nuclear diameter at the basal layer

105 Figure 6.5:

ROC curves

106 Figure 6.6:

Scatter plot showing nuclear size versus nuclear density

107 Figure 6.7:

a/LCI A- scans of cervical tissue types.

109 Figure 6.8:

Histology of the cervix

109 Figure 6.9:

Possible roles of a/LCI in the CIN screening and treatment process.



–  –  –

Acknowledgements I owe a big thank you to those who helped me along the way at Duke University.

Thank you to my advisor, Adam Wax, who first gave me a position in the lab when I was a master’s student desperately looking for work.

His kind offer eventually led me to pursue a Ph.D.

in BME, something I never considered when I first made the journey to North Carolina.

Adam’s incredible knowledge and guidance helped me grow as a leader, and I’ve really enjoyed my time in the BIOS lab.

I also owe a great deal of gratitude to Dr.

David Katz, who mentored me many times in his office, on everything from rock and roll to statistics.


Katz taught me to think on a much larger scale than I was used to as an engineer, and that has helped me in many aspects of life.

I also must thank my labmates, both past and present.

Nick Graf and Neil Terry took me under their wings when I entered Duke and helped me with everything – brainstorming optics, parking, and where to get lunch in Durham.

I thank both of them because I wouldn’t have made it otherwise.

Most importantly, I want to thank my parents, Dave and Andree.

I know you both worked incredibly hard to raise me the way you did, and I will forever admire you.

I’m extremely proud of where I came from and what I have done, and I owe it all to you.

Thank you.

I love you.

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1 Introduction

1.1 Motivation Traditionally, medical research has overlooked the distinctive health needs of women, even though over half the population of the U.S.

is female.1, 2 In 2008, the U.S.

Department of Health and Human Services asked the Institute of Medicine to examine what has been learned in women’s research over the past two decades and how well it has been put into practice.

The committee concluded that while women’s health research has improved over the past 20 years, much work remains in all aspects of women’s health research.1 The female reproductive system is among the most sensitive to infection in the human body.1 Sexually transmitted diseases, including human immunodeficiency virus (HIV) and cervical cancer with co- infection of human papillomavirus (HPV), are among the biggest threats to women’s reproductive health.

Technologies which are specific to the unique anatomical and physiological characteristics of female reproductive system, are necessary to advance research in these fields and improve women’s healthcare.

In recent years, large amounts of research has been focused on developing optical, or light- based, technologies.

However, many of the optical technologies used in assessing women’s reproductive health, such as colposcopy, have been in use since the early 1900s.3 In order to advance research in women’s reproductive health, applications 1 of these new optical technologies must be examined, specifically in women’s reproductive system imaging.

One major danger to women’s health, especially in third world or developing countries, remains HIV and acquired immunodeficiency syndrome (AIDS).

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