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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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Ectocervical and endocervical tissues were successfully identified with a/LCI, and these differences are also outlined in this section.

Finally, possible clinical roles of a/LCI in screening of CIN are identified.

Chapter

7 concludes the dissertation document with a summary of the presented work.

Potential future studies for the dual- modality optical imaging instrument and a/LCI instrument are discussed.

11 2 Background

2.1 Introduction In order to understand the novel instrumentation and clinical applications that are presented in this document, background information on microbicide gels are first introduced in Section 2.2.

Information on the importance of gel coating and in vivo measurement of the coating is discussed.

Remote sensing of microbicide gel distributions is briefly discussed in Section 2.2.

3.

Changes in gel behavior due to dilution are discussed next, as well as the importance of measuring in vivo dilution.

Section 2.2.

4 continues with basic descriptions of LCI and Fourier- domain LCI before summarizing the preliminary common- path system as described by Braun et al.26 The further development of a second generation LCI system, with full Michelson geometry, and speed limitations of the system are detailed.

Section 2.3 discusses the background of cervical intraepithelial neoplasia, or cervical dysplasia.

Current cervical screening techniques and their limitations are discussed in Section 2.3.2.

A review of optical methods developed for the detection of cervical dysplasia technologies then follows.

Chapter 2 concludes with the background of the a/LCI technique and a review of studies in which a/LCI was used to detect dysplasia in epithelial tissue.

12

2.2 Microbicides 2.2.1 Microbicide gel effectiveness Microbicides are a class of drugs that protect against sexually transmitted infections, such as HIV/AIDS.

The drugs contain active pharmaceutical ingredients (APIs) which neutralize pathogens by inhibiting viral transmission within the mucosa proper, or neutralizing viruses before they contact mucosal surfaces.5- 9, 44 They can be packaged in a variety of dosage forms such as gels, water- soluble films, or tablets, and dosage form has a high impact on efficacy.

Effective microbicide development requires evaluation of pharmacokinetics to determine if the API drug molecules are delivered to target tissue or fluids, and if the API is delivered at the proper rate and dosage.

This research focuses on the development of novel optical imaging devices for measuring the thickness distributions of microbicide gels in vivo.

These measurements can then be used with mechanistic models to predict API delivery efficacy of potential microbicide gel formulations.

The distribution of microbicide gel upon deployment in the vaginal is key to the gel’s biological effectiveness.

Microbicide gels act as delivery vehicles for APIs, as well as serve a physical barrier role, preventing HIV virus from reaching target immune cells for infection.

The extent of gel coverage, gel thickness, and its overall structure are crucial factors in studying microbicidal gel products.11, 15, 16 Figure 2.1 shows the 13 importance of microbicide gel distribution in the vagina, and the necessity of developing an accurate measurement modality for in vivo human studies.

Figure 2.1:

Illustration of an in vivo microbicide gel distribution.

As shown in Figure 2.1, even small areas of incomplete gel coating, or bare spots, leaves the exposed tissue vulnerable to HIV infection.

Also, studies have shown that a coating layer with a thickness in excess of 100 µ;m may be sufficient to neutralize semen- borne HIV before it can contact epithelium tissue and result in an infection.11 Therefore, the ability to measure in vivo gel coating thickness accurately is paramount in the evaluation of candidate microbicide products.

2.2.2 Microbicide gel dilution The coating distribution of microbicide gels is altered by dilution in vivo.

The products come into contact with other ambient fluids in the vagina, such as mucus or semen.

The diluted gels have altered rheological properties and thus coating flow and coverage.

Measuring this dilution is paramount in studying the behavior of microbicide products.

14 The actual amount of dilution that occurs to a gel in the vaginal canal is unknown, and most likely varies during the menstrual cycle and with age.

Lai et al.

estimated that the average net dilution in the vagina ranges from about 10% to 30% by ambient fluids, while semen dilutions are 50% and vary with time after ejaculation.45 The study also found that even a small amount of dilution influenced coating rates of three placebo microbicide gel formulations.

Therefore, it is necessary to include dilution affects when studying the in vivo behavior of microbicide gels.45 2.2.3 Microbicide imaging Although microbicide gel thickness distribution drug delivery properties can be predicted with computational modeling, there is a need for methodologies and devices that can directly measure in vivo distributions.

The quantitative gel distribution data from such devices provides pharmacokinetic and pharmacodynamics information on potential microbicide products.





Magnetic resonance imaging (MRI), single- photon emission computed tomography (SPECT), and gamma scintigraphy, have all been used as remote sensing techniques for measuring in vivo microbicide distributions.17- 21, 46 These imaging modalities provide useful information on general pelvic anatomy and global gel distribution, but they have several drawbacks.

MRI typically uses a gadolinium chelate contrast agent to enhance contrast of between gels and soft tissues18, and this contrast agent may diffuse from the gels into tissues and fluids, giving a false signal.

SPECT and gamma scintigraphy use ionizing radiation from radioisotopes to 15 create contrast, delivering unnecessary radiation doses to radiosensitive organs in the pelvic region.

MRI, SPECT, and gamma scintigraphy also all lack the necessary resolution to detect thin coating layers, on the order of 100 µ;m.

Studies on HIV neutralization dynamics and diffusion through gels by Geonnotti et al.

and Lai et al.

have found that this threshold of coating is necessary to prevent HIV infection through a gel layer.

To address the need for high resolution imaging of microbicide gel distribution in the vagina a fluorimetric imaging system was designed and built by Henderson et al., which included an endoscopic probe- based imaging technique.28 The device was successfully used in a clinical trial to compare human intravaginal coating distributions of two placebo gels, Conceptrol (Advanced Care Products;

Brunswick, NJ) and Advantage (Columbia Laboratories;

Aventura, FL).27 The coating measurements obtained with the device were consistent with mechanistic models, and gel layers 50 µ;m were successfully measured.

However, this instrument requires an exogenous contrast agent, fluorescein, to be added to the gels for measurement.

Like MRI, the contrast agents may diffuse from the gels to tissue over extended time studies, limiting the time interval after insertion for imaging.

2.2.4 Low coherence interferometry Low coherence interferometry, or LCI, is capable of high resolution imaging of layers in a sample.

It uses broadband light in an interferometry scheme to perform 16 depth- ranging measurements of light scattered or reflected by a sample, typically with micron resolution.

LCI exploits the property of low coherence light in that interference will only occur if the optical path length (OPL) difference of the sample field and reference field are matched to within the limited coherence length of light the source.

The basis of LCI is the Michelson interferometer, shown below in Figure 2.2.

–  –  –

Light from a low coherence source, typically a superluminescent diode (SLD) is split into two paths, or arms, by a 50/50 beamsplitter.

The light in the reference arm is reflected by a mirror, while the light in the sample arm is incident onto a sample.

The light returned from the sample is recombined with the light from the reference arm by the beamsplitter and directed to a detector.

The interference pattern between the two arms is analyzed to determine the OPL difference between the sample reflectors and reference reflector.

17 In time- domain LCI, the reference mirror is scanned in path length to provide depth information about the sample.

However, in Fourier- domain LCI, the mirror is held static and depth information is obtained by measuring the spectrum of the interference signal.

Fourier transforming the spectral interferogram then produces a depth- scan.

Reflected light from points within the sample and the reference reflector combine to produce spectral oscillations, which when Fourier transformed, reveal the relative OPL between the scattering points.

The signal, I, captured by the detector is given

by:

–  –  –

where ES and ER are the sample and reference fields, Δz is the OPL difference between the sample and reference arms, k is the wavenumber of the light source, and φ is the phase difference between the two fields.

In Eqn.

(2.1), the cos(2Δzk + φ) term represents the spectral oscillations that appear from interference of the reflected fields.

As the path length, Δz, increases, the frequency of spectral oscillations increases.

Optical path length, Δz, is related to physical thickness, t, in a sample by Δz = nt, where n is the index of refraction of the sample.

Figure 2.3 summarizes the Fourier transform relationship between spectral oscillations and reflector position.

18

–  –  –

Each reflection from a given layer in the sample will produce an interference pattern with a specific frequency of oscillation when mixed with a reference field.

The total interference spectrum incident on the detector is thus the sum of these interference patterns.

The signal is initially converted to the wavenumber domain, or k- space, from wavelength by the relationship k = 2π/λ.

Linearity is then restored using a spline interpolation of the wavenumbers.

A Fourier transform can then be used to separately analyze each frequency, resulting in an A- scan, or depth- scan, where the distance between the peaks in Fourier space reveals the OPL difference between the layers in the sample.

19 The actual raw Fourier transformed depth- scan contains three separate components that must be conditioned to recover the correct depth information, as seen in Eqn.

(2.1).

The desired component is the cross- correlation term, the third term in Eqn.

(2.1), which contains the distance information between reflectors.

The cross- correlation term is directly dependent on the OPL difference between a reflector in the sample and the reference mirror.

Two DC terms are also present in the signal, which are path length independent, and are proportional to the total reflectivity of the sample reflectors and that of the reference mirror respectively.

Finally, common- path, or autocorrelation, terms are also present resulting from interference occurring between reflectors in the sample.

However, by measuring the sample and reference fields independently, the autocorrelation and DC terms can be removed from the spectrum, leaving just the interference signal which may be analyzed to obtain a depth resolved reflection profile of the sample.

2.2.5 Measuring microbicide distribution with LCI Previous studies by Braun et al.

have verified the ability of LCI to measure microbicide gel thicknesses, with results comparable to fluorimetric methods.26 The initial LCI system utilized a fiber optic- based, common path geometry as shown in Figure 2.4.

Light from a superluminescent diode (SLD) was focused onto the sample with lens, L1.

The reflected light was split by a 1x2 fiber coupler and analyzed by a 20 spectrometer.

The reference field was generated by light reflected from the surface of a coverglass placed on top of the sample.

–  –  –

The initial common path LCI system was used to examine gel thickness in a calibration socket.

The common path geometry was easy to align, and was an effective method of measurement for simple samples such as the calibration socket.

However, for more complex samples, such as gel layers on tissues and tissue phantoms, the optical properties of the sample made the common path interferograms difficult to interpret because autocorrelation terms compromised the signal.

The second- generation LCI system utilized Michelson geometry in order to make the results easier to analyze, and this system is described in Figure 2.5.

21

–  –  –

The improved single channel LCI system had a separate sample and reference arm, which added complexity to the optical scheme but clarified the measurements, as each layer in the sample appeared in the correct physical arrangement in the signal.

To demonstrate the feasibility of measuring gel thickness atop tissue, a tissue phantom was developed which had optical properties similar to epithelial tissues.

The phantom consisted of 2 g agarose / 100 mL distilled water with 0.1 mL Intralipid (Liposyn II 20%).

The refractive index of the phantom was measured to be 1.344, and the scattering coefficient was found to be 26.5 cm- 1.

These values agree with published values for cervical tissue, and are similar to values published for general epithelial tissues.47, 48 Gel samples of known thickness were applied to the tissue phantom, and LCI measurements were made to assess the thickness distribution.

Scans of 10x8 points at 0.25 mm intervals were executed in order to determine the local gel distribution.

These studies concluded that area scanning of gel distribution on epithelial tissue was feasible with LCI, but the point- by- point method that was used for data collection was too slow for in vivo application.



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