spectroscopic detection of skin cancer - google docs

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Detection of Skin Cancer with Raman Spectroscopy

Robert Xu, Kevin Yee, Jason Zhang

BME 314: Engineering Foundation of BME

December 5th, 2014



Background and Motivation:

One in five Americans will develop some form of skin cancer in the course of a lifetime 1.However, skin cancer is a highly treatable disease in most cases, provided that the patient

receive an early diagnosis. For patients whose melanoma is detected before metastasis to

regional lymph nodes and organs, the five year survival rate is a promising 98%2. However, the

survival rate falls to 62% when the cancer has spread to the lymph nodes, and it drops to 16%when it has spread to distant organs3. Thus, it is exceedingly important for the patient to receive

an early and accurate diagnosis when the first signs of skin cancer begin to show.

Spectroscopy, or the study of the interaction between matter and radiated energy, is inherently

noninvasive. Weak light is delivered to the tissue, and the re-emitted light is examined to glean

information about the biochemical state of the sample. This technique offers a rich amount of

information, including biochemical composition, morphology, epithelial architecture, and

hemoglobin concentration4. All of these parameters change as skin cancer develops, so it is

useful to look at changes in these measurements to diagnose or monitor disease progression.

A particular type of spectroscopy based on Raman scattered light is a popular analytic

technique that can be used to evaluate the chemical constitution of certain materials. A Raman

spectroscopic fingerprint can be used to identify chemical culprits of interest. As such, it can beutilized in the field of biomedical optics for diagnosing skin cancer due to its sensitivity in sensing

morphological and physiological changes.

Principles of Raman Scattering and Spectroscopy

Raman spectroscopy is the principle of spectroscopy applied to inelastically scattered light.When light interacts with any molecule, it is absorbed if the photon’s energy is exactly equal to

the energy difference between the ground state of a molecule and its excited state. In other

words, absorption occurs when , where corresponds to the difference in energy E h νΔ = E Δ

between the ground state and excited state, is Planck’s constant, and is the frequency of h ν

the incident photon. Any incoming light that hits the molecule and does not satisfy this equality is

said to be scattered. When the light that is scattered has the same energy as the incident light, it

is said to be elastically scattered, or Rayleigh scattered. On the other hand, if the light that is

scattered is of different energy it is said to be inelastically, or Raman, scattered.

The difference in energy of the photon is essentially caused by their interaction with molecular

vibrations, which can either give energy or receive energy from the photon. If energy from the

molecular vibrations is given off to the photon, then the scattered light is of higher energy,

shorter wavelength, and is said to be anti-Stokes shifted. Photons that lose energy to excite

vibrational modes of the molecule are of lower energy, longer wavelength, and are said to be

Stokes shifted5.

One can shine a laser onto a sample, isolate the Raman scattered light, and pass this light

through a spectroscope, thus separating the scattered light into its spectral components. The

end result is a spectrum that contains valuable information about the chemical structure of thesample. Because of Raman spectroscopy’s ability to generate data that is linked to the inherent

structure of certain molecules, it can be a valuable tool in attempting to characterize the

biochemical state of tissues(Figure 1)6. This makes it a potential diagnostic tool for any lesion

easily accessible by an optical system, such as skin cancer.

A typical optical system designed for Raman spectroscopy consists of components typically

seen in any spectrometer: a light source, a diffraction grating, mirrors, and some sort of detector.

The Raman spectroscope can be made clinically useful by coupling it with an optical



microscope, thus creating a Raman

microspectroscope system. This introduces

lenses and objectives into the optical path.

Furthermore, a dichroic mirror is needed to

separate as much of the Rayleigh scattering

from the Raman scattering as possible. An

optical fiber can also be coupled to the light

source to make the light delivery and signal

collection component flexible.

The calculations that need to be considered

when constructing these systems can be

based on the basic laws derived from ray

optics to laws rooted in advanced electromagnetic wave theory and quantum mechanics. It turns

out that most of these calculations are usually done by the component manufacturer, which

usually ends up providing the technical specifications of the product. However, this should not

preclude the engineer, doctor, or scientist from having an understanding of the most fundamental

equations in optics.For example, an important parameter to address when selecting an optical fiber is numerical

aperture (NA). For optical fibers, NA is a measure of the light gathering capacity of the fiber. An

expression for NA in terms of the indices of refraction of the core and cladding material can be

derived using Snell’s Law.

From figure 2, an application of Snell’s Law gives us:

sin i sin θ, where n 1 (air )n0 = n1 0 = (1)

The critical angle is smallest possible angle of that allowsθ′

for total internal reflection to occur. It is defined as the angle

, such that such that the angle of refraction becomes 90°θ′ c

at the cladding-core interface. sin θ sin 90n1 ′

c = n2

in θ⇒ s ′ c =

n1

n2 (2)

corresponds to a particular corresponding angle of ,θ′ c

im

which is the maximum angle of incidence light.

from (1). A n sin i sin θ N = 0 m = n1

n sin

(90 θ )n

cos

θn

= 1 − c = 1 ′

c = 1

√1

in θ−

s 2 ′

c

From (2),

A N = n n1√1 in θ− s 2 ′ c = 1√1 )− (

n1n2 2

= √ n12 − n 2

2

Pros and Cons:

Like many emerging technologies, there exists many advantages and disadvantages in utilizing

such science. A major benefit in using Raman spectroscopy to detect skin cancer is its



non-invasive property. Such a technique will prevent the patient from being exposed to

discomfort or adverse side effects. In addition to the non-destructive nature of this imaging

technique, Raman spectroscopy proves to be quite efficient. This is especially seen in the speed

of acquiring Raman spectra. With the development of ultra-fast Raman spectral imaging

modules, large area survey scans can be completed in seconds or minutes10.

Although Raman spectra can be acquired quickly, the Raman effect itself is very weak. Whenlight strikes a molecule, roughly one in 10 million photons hitting the area will experience a

change in frequency that can be used to determine the characteristics of a sample11. As a result,

these systems require highly sensitized and optimized components costing up to tens of

thousands of dollars to capture, refine, and analyze the signal. However, in the long run, the cost

of Raman spectroscopy would be far less than that of the current diagnostic methods 4.

Competing Technologies:

Currently the gold standard for diagnosis is clinical examination, followed by skin biopsy and cell

staining. This is an expensive, time-consuming, and invasive process. Furthermore, many

patients, who tend to err on the side of caution, undergo biopsies of suspicious lesions and end

up receiving a negative result for skin cancer 4. This leads to more financial burden and

unnecessary discomfort for the patient. So, there is a pressing need for developing better

techniques for diagnosis of skin cancer .

There are several technologies that compete with Raman scattering, one of them being

multispectral multiphoton fluorescence lifetime imaging. This is also a spectroscopic technique,

but it differs slightly in the mechanism of light-absorption and reemission.

Multispectral multiphoton fluorescence lifetime imaging (MPT) is a technique that excites

fluorescence through absorption of two or more photons of infrared light. A high intensity laser is

used to gather information from specific points, and then images are generated using a raster

scanning technique. Raster scanning is a technique in which many points are scanned, and then

a spectral array is assembled from those individual points 12. This is different from Raman

scattering in that Raman spectroscopy generates a spectrum from inelastically scattered light,while MTP is concerned with fluorescence spectra.

Future trends and developments:

In the future, we hope to integrate Raman spectroscopy into modular systems that can be used

in the clinic. Sharma et al. have developed a novel fiber-optic probe that utilizes Raman

spectroscopy, as well as two other types of spectroscopy, to make accurate measurements of

liquid phantoms with less than 10% error 7. Furthermore, by integrating a confocal Raman

microspectroscope into a probe, it could be used in a wide variety of clinical settings and

situations with higher resolution.

Ideally, this probe would be able to be used in applications such as Mohs surgery, where the

surgeon removes cancerous tissue slice by slice. After every slice is removed, a pathologistmust look at the sample and decide whether it is still necessary to remove more tissue. This

process can be made more efficient by using a fiber-optic probe system as described above.

With further research, one could go to the dermatologist with suspicious moles or lesions and

know the biochemical composition. morphology, and physiology of the lesion within a few

minutes. The dermatologist could then make the appropriate diagnosis based on these

measurements.



References

1. Robinson, J. K. Sun exposure, sun protection, and vitamin D.

2. Ries, L. A. G., Melbert, D. & Krapcho, M. SEER Cancer Statistics Review, 1975-2004. at

<http://seer.cancer.gov/csr/1975_2004/>

3. American Cancer Society. Cancer Facts & Figures. (2014).

4. Lim, L. Clinical, non-invasive in vivo diagnosis of skin cancer using multimodal Spectral

Diagnosis. (2013). at <http://repositories.lib.utexas.edu/handle/2152/23196>

5. Opilik, L., Schmid, T. & Zenobi, R. Modern Raman Imaging: Vibrational Spectroscopy on the

Micrometer and Nanometer Scales. Annu. Rev. Anal. Chem. 6, 379–398 (2013).

6. Feng, X. Confocal Raman Microspectroscope for the Assessment of Human Skin. (2014)

7. Woodward, Bill and Emile B. Husson. Fiber Optics and Technicians Installer Study Guide.

San Francisco: Sybex, 2005.

8. Downing, James. Fiber Optic Communications. Clifton Park: Thomson Delmar Learning,

2004.

9. Prakash, Satya. Physics: Vol. 1,2. City: V K Publications, 2008.

10. Poll, S. et al. On-line detection of cholesterol and calcification by catheter based Ramanspectroscopy in human atherosclerotic plaque ex vivo. Heart 89, 1078–1082 (2003).

11. Savage, N. Raman Laser Could Identify Explosives at a Distance - IEEE Spectrum. at

<http://spectrum.ieee.org/tech-talk/semiconductors/optoelectronics/raman-laser-could-id-exp

losives-at-a-distance>

12. Patalay, R. et al. Multiphoton Multispectral Fluorescence Lifetime Tomography for the

Evaluation of Basal Cell Carcinomas. PLoS ONE 7, 1–9 (2012).

13. Garcia-Uribe, A. et al. In Vivo Diagnosis of Melanoma and Nonmelanoma Skin Cancer Using

Oblique Incidence Diffuse Reflectance Spectrometry. Cancer Research 72, 2738–2745

(2012).

14. Sharma, M., Marple, E., Reichenberg, J. & Tunnell, J. W. Design and characterization of a

novel multimodal fiber-optic probe and spectroscopy system for skin cancer applications.

Rev. Sci. Instrum. 85, 083101 (2014).

spectroscopic detection of skin cancer - google docs

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