KYAMBOGO UNIVERSITY

Faculty of Engineering
Department of Electrical and Electronics Engineering

SEMESTER 1, 2021/22

TEMB 3104 Design Methods for Engineers

EARLY DETECTION OF CERVICAL CANCER USING

OPTICAL BIOSENSORS
Group 38

KINENE IAN GARVIN 18/U/BIO/339/GV

SSEKITTO JOEL 18/U/BIO/6416/PD

MUKISA PATIENCE FAITH 18/U/BIO/6387/PD

May 2021

This is submitted in fulfilment of the requirement leading to the award of Bachelor

of Engineering in Mechatronics and Biomedical Engineering

STATEMENT OF ORIGINAL WORK

I declare that this proposal has never been submitted to any institution in partial or complete
form for the award of any diploma, degree, master or PhD. The work contained herein is the
original contribution of the author of this proposal. For any referenced work, the due citation and
acknowledgement has been given to the original author/s of that specific work.

ABSTRACT
Cervical Cancer is a disease in which normal cells in the cervix (the lower part of the uterus that
connects to the vagina) grow out of control or become abnormal cells. It develops from pre-
cancerous changes that occur in the cervix when normal cells turn into abnormal cells in the
presence of persisting HPV. Screening and diagnosis by the standard sequence of cytology,
colposcopy, biopsy, and histological confirmation of CIN. However, the readily available
screening tests such as the human papillomavirus (HPV) test, visual inspection with acetic acid
(VIA), and cytology (Pap test) all these have limitations which put women still at risk of
acquiring cervical cancer. Many treatment strategies have been put in place but still cervical
cancer is claiming a big number of women’s life hence screening highly recommended to
prevent all the circumstances that are a subject to a woman once she acquires cervical cancer. we
opt to come up with a more effective screening method for cervical cancer whose working
principle relies basically on optics which is a Bio-Nano Sensor. The earlier cervical cancer can
be detected, the better the chance of cure. This cancer still remains the most common cancer
affecting women worldwide. India alone contributes 25.41% and 26.48% of the global burden of
cervical cancer cases and mortality, respectively. Currently this cancer is diagnosed only after it
has metastasized throughout the cervix.

LIST OF FIGURES
LIST OF TABLES
LIST OF ABBREVIATIONS

ASCUS Atypical Squamous Cells of Undetermined Significance

CIN Cervical Intraepithelial Neoplasia
CKC Cold Knife Conisation
ERG External Review Group
FICA Flanders International Cooperation Agency
GAVI Global Alliance for Vaccines and Immunization
GDG Guideline Development Group
GRADE Grading of Recommendations, Assessment, Development and Evaluation
HPV Human Papilloma Virus
IARC International Agency for Research on Cancer
INCa Institute National du Cancer (France)
LEEP Loop Electrosurgical Excision Procedure (also LLETZ)
LLETZ Large Loop Excision of the Transformation Zone (also LEEP)
NCI National Cancer Institute (USA)
NIH National Institutes of Health (USA)
PAHO Pan American Health Organization
Pap test Papanicolaou test (cytology-based method for cervical cancer screening)
WHO World Health Organization
CHAPTER ONE: INTRODUCTION

This chapter introduces the early stages of cervical cancer, background study, its detection in the
early stages and symptoms.
Background

Cancer of cervix is one of the major cancers affecting women worldwide [who]. It has not only
been a problem that has affected over a thousand lives of women but has greatly led to death.
Cervical cancer usually arises from the pre-cancerous changes that occur in the cervix when
normal cells in the cervix are affected by the human papillomavirus (HPV), this virus causes a
wide range of cancers such as genital cancer cases, throat cancers and greatly the main cause of
almost all the cervical cancer cases reported. Cervical cancer is deadly hence prevention where
possible and early screening to ensure early treatment in case found is highly recommended but
due to limited access and false negative results of the current screen tests a lot more women are
subjected to cervical cancer and its associated risks. According to world health organization
guidelines in 2013, it was suggested that screening and treatment of precancerous lesion would
be paramount for cervical cancer prevention, this has however had loop holes due to the current
screening tests used that are ineffective.

Problem Statement.

Cervical Cancer is a disease in which normal cells in the cervix (the lower part of the uterus that
connects to the vagina) grow out of control or become abnormal cells. These cells do not directly
change into cancer but first gradually develop pre-cancerous changes that influence them to turn
into cancer (Centres for Disease Control and Prevention, 2003). The main causes of cervical
cancer is the human papillomavirus (HPV)-16 and HPV-18(worldwide about 70% cervical
cancers cases are caused by these two). They are transmitted through genital to anal and genital
to genital contact. Persistent HPV infections induce cellular abnormalities that after sometime
develop into cervical cancer (States, 2010). Other causes include early onset of sexual activity
(younger than 18 years), multiple sexual partners, history of one or more sexually transmitted
infections ( Chlamydia infection or genital herpes or HIV), use of tobacco, having a partner
whose former partner had cervical cancer, having suppressed immune function, long-term use (5
or more years) of birth control pills, women whose mothers took diethylstilboestrol (DES) to
become pregnant or to sustain pregnancy and family history of cervical cancer (ACS, 2016).
Worldwide, Cervical cancer is the second most common cancer in women and about 300000
deaths occur annually due to cervical cancer out of the 530000 cervical cancer cases reported and
this is due to the cervical cancer screening limited access, more than 85% of these deaths are in
low and middle income countries, and still about 88% of those few who survive are in low and
middle income countries (States, 2010). In 2018, it was found that nearly 20% of women with
cervical cancer die within the first year of diagnosis and 5-year relative survival rate is 50%. A
conclusive evidence was proved that the majority of cervical cancer cases (95-98%) is caused by
the infection with cancerogenic strains of human papilloma virus (HPV). Most of these
infections are cleared by the immune system within one to two years which makes it hard to be
detected in early stage (Novikova, 2017). The high mortality rate from cervical cancer globally
can be reduced through a comprehensive approach that includes, prevention, early detection,
effective screening and treatment programmes. Cervical cancer screening is highly
recommended to lower the death rates due to cervical cancer and the general associated risks
once someone acquires cervical cancer, this is because precancerous changes of the cervix
usually do not cause pain or any other symptoms and are not detected unless a woman undergoes
screening, and usually symptoms appear when abnormal cervical cells become cancerous and
invade nearby tissue (Nandkishor Jha, 2017). It is the normal cells of cervix that when affected
by HPV that develop precancerous changes that then turn into cervical cancer. Screening is
really a paramount remedy to cub down the cervical cancer burden that helps detect cervical pre-
cancers and when presence confirmed to ensure treatment before cervical cancer develops
(Centres for Disease Control and Prevention, 2003).
This image shows us the stages of cervical cancer, how it develops from it early stage to
cancerous. If carcinogenic HPV infection is not cleared, the virus invades the cells at the junction
of squamous epithelium of the ectocervix and columnar epithelium of endocervical (cervical
squamocolumnar junction). The location of the squamocolumnar junction relative to the external
orifice, or external OS shifts over the lifetime of a women.

The international federation of Gynaecology and obstetrics (FIGO) believes that any staging
system should be universally feasible and applicable, as well as provide a worldwide
standardized classification that allows various medical centres to compare results. The major
categories are in the table below.

Stage Description

Stage 0 Carcinoma in situ. Abnormal cells in the innermost lining of

the cervix.

Stage I Invasive carcinoma that is strictly confined to the cervix.

Stage II Locoregional spread of the cancer beyond the uterus but not
to the pelvic sidewall or the lower third of the vagina.

Stage III Cancerous spread to the sidewall or the lower third of the
vagina, and/or hydronephrosis or a non-functioning kidney
that is incident to invasion of the ureter.

Stage IV Cancerous spread beyond the true pelvis or into the mucosa of
bladder or rectum.

The FIGO stages are further categorized as follows.

Stage Ia cervical carcinoma: Preclinical invasive carcinoma that can be diagnosed only by
means of microscopy.

Stage Ib cervical carcinoma: A clinically visible lesion that is confined to the cervix uteri

Stage IbI: Primary tumour not greater than 4.0cm in diameter.

Stage Ib2: Primary tumour greater than 4.0cm in diameter.

Stage IIa cervical carcinoma: spread into the upper two thirds of the vagina without parametrial
invasion.

Stage IIb cervical carcinoma: extension into the parametrium but not the pelvic sidewall.
Stage IIIa cervical carcinoma: extension into lower one third of the vagina, without spread to the
pelvic sidewall.

Stage IIIb cervical carcinoma: extension into the pelvic sidewall and/or invasion of the ureter,
with the latter resulting in a non-functioning kidney or hydronephrosis.

Stage Iva cervical carcinoma: extension of the tumour into the mucosa of the bladder or rectum.

Stage IVb cervical carcinoma: spread of the tumour beyond the true pelvis and/or by metastasis
into distant organs.

SYMPTOMS OF THE CERVICAL CANCER

These are the most common symptoms of cervical cancer but most of the time these show up
when the situation is already worse.

 Abnormal bleeding (between periods, with intercourse or after menopause)

 Unusual vaginal discharge
 Leg and pelvic pain
 Bleeding from the rectum or bladder
 Backache
 Or sometimes depending on a person, no symptoms is show

CURRENT SOLUTIONS

There are currently vaccines that protect against common cancer-causing types of human
papilloma virus and can significantly reduce the risks of cervical cancer. The way vaccines are
given depend on ages and one can take it only once in lifetime. Following table shows the
eligibility according to age range.

Girls 9-10 Girls 11-12 Girls 13-18

 Eligible to the vaccine Recommended age group to Eligible to receive the
receive the cervical cancer vaccine, if not previously
vaccine vaccinated

Women 19-26 Women 27-Older Men

Eligible to receive the Not approved by FDA Not approved by FDA

vaccine, if not previously
vaccinated

Also, the tests that are being used to screen cervical cancer include pap tests or pap smears also
known as cytology that finds abnormal cells in the cervix that develop due to HPV, it is done
using a speculum to make the vagina wider and enable the physician to examine the cervix and
vagina, and then collect a few mucus and cells from the cervix which are then placed on the slide
to be taken to the laboratory to analyse it for abnormal cells. It has a limitation of high degree of
false- negative results (States, 2010) (Khanna, 2012) and cannot be used on women whose cervix
has been removed during hysterectomy which is a process of removing the uterus. Human
papillomavirus (HPV) test is a test which collects cells from the surface of the cervix to check
for HPV and for this test the cells are collected the same way as for a Pap test, results can help
the doctor decide if more testing is needed. And visual inspection with acetic acid (VIA) is
another test done in case HPV is confirmed positive and treatment is being done, aiming at
ensuring that the treatment given is effectively working (Centres for Disease Control and
Prevention, 2003) (ACS, 2016).

NOVELTY OF THE SOLUTION

The ability to detect pathogenic and physiologically relevant molecules in the body with high
sensitivity and specificity offers a powerful opportunity in the early diagnosis and treatment of
cervical cancer. Early detection and diagnosis can be used to greatly reduce the cost of patient
care associated with the advanced stages of cervical cancer and other associated risks, that is a
reason we are hoping to engineer a prototype optical Bio Nano sensor composed of an antibody
functionalized carbon nanotube complex which will respond quantitatively to HPV via
modulation of the nanotube optical band gap (Reitzig, Katzmann, Schuster, & Härtling, 2015).

The reasons as to why we choose to go with an optical Nano sensor is because of its great
features such as cost-effective making it available even to low income earners, portable ensuring
mobility, selectivity and high sensitivity since it utilizes optical properties to improve the
detection limits of analytes (Large surface area to volume ratio, composition, charge, reactive
sites, physical structure and potential) (Nano sensors for diagnosis with optical,...ducers - RSC
Advances (RSC Publishing).pdf, n.d.). It also enables the direct, real-time and label-free detection
of many biological and chemical substances (Optical biosensors.pdf, n.d.). It is generally less
likely to give negative results unlike the other tests.

PRINCIPLE TO BE USED

This optical Bio-Nano sensor will have three components: the detector for identifying the
stimulus, optical transducer for converting this stimulus to a useful output, and finally the signal
processing system which will involve amplification and display of the output in an appropriate
format. It will be designed in such a way to detect the biomarker of cervical cancer which is
produced in a cervix region, by using a detector to identify a bio-recognition element such as a
protein, enzyme, receptor, antigen and antibodies, and an optical transducer to send a signal to
the signal processing system (Nandkishor Jha , 2017). This optical Nano sensor will be an
implant placed into cervix aiming to quantify precancerous biomarker (elevated cancer antigen
CA 125) via devices that normally remain stationary in the body (High-sensitivity Nano sensors
for biomarker detection.pdf, n.d.).

The optical Bio-Nano sensor will made of a semiconducting carbon nanotubes which emit near-
infrared (NIR) band gap photoluminescence (PL) between 900 and 1800nm, which can penetrate
living tissues to a distance in the centimetre range (Reitzig et al., 2015) . We shall also have to
test for potential biocompatibility of the Bio-Nano sensor membranes and in case they are not
biocompatible we then coat the membrane with either polyethylene glycol or another antifouling
material, or else we embed it directly in a hydrogel matrix, this will help eliminate local
inflammation (Rogers, 2003). Our implant will be free of Nano particles that arise during
fabrication since we to consider different techniques to help eliminate the errors that are brought
by such unused Nano particles there by ensuring more accurate results (Non-invasive ovarian
cancer biomarker de... Nano sensor implant _ Science Advances.pdf, n.d.).

Below is a diagram showing the Optical Bio-Nano Sensor with the Detector consisting of the
input and the Bio-recognition element, Transducer and the data processing system.

RECEPTORS

ANTIGENS
OPTICAL-

ANTIBODIES LUMINESCENCE,
INPUT OUTPUT

ENZYMES CALORIMETRY
AND
NUCLEIC ACID
FLUORESCENCE
Sample Analyte
PROTEINS

Bio-Recognition Element
Optical Transducer
Figure 4: Detecting process of the Nano sensor

Figure 5: Illustration of optical molecular-targeted imaging with

nanoparticles. Adopted from (Novikova, 2017)

AIMS OF THE STUDY

Since currently , in many low resource settings, the disease is often not identified until it is further
advanced or treatment is inaccessible resulting in a high rate of death from cervical cancer. All
women should endeavor to go for screening to detect precancerous changes before they become real
cervical cancer. Always Prevention is better than cure women should acquire Knowledge on how
best they can achieve this. Understanding and identifying the symptoms of cervical cancer will
ensure seeking for treatment as early as possible lowering death rates.

Figure 6: Key steps for addressing cervical cancer as public health cancer(Novikova, 2017
CHAPTER TWO