The Invention relates to devices for the detection/diagnosis of cervical cancer. The Invention in particular provides smartphone based polarized fluorescence spectroscopic device for early detection of cervical cancer.
Background of the invention:
The following background discussion includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

Cancer has become one of the deadly diseases nowadays with a comparatively high mortality rate in developing countries. Cervical cancer is one of the leading causes of deaths for women in India with an estimated 1.04 lakh new cases and 60,000 deaths reported according to a report released by WHO in 2020. Apart from the conventional medical techniques including Pap smear, colposcopy and biopsy with histopathology, several optical techniques have shown promising results in diagnosing the abnormality at an early stage. Optical spectroscopy is seen to be effective with its ability to probe differences in the spectral response of native fluorophores (collagen, NADH, FAD & porphyrins) with disease progression. Fluorescence spectroscopy has the potential to discriminate among different grades of cervical cancer. However, the spectroscopic systems used are mostly limited to the controlled laboratory environment due to requirements of expensive light sources and spectrometers. As per assured, WHO recommended criteria: affordable, sensitive, specific, user friendly, rapid & robust, equipment free and deliverable to end users is the need of the hour. In recent years, an increasing interest has been seen in developing portable, low cost spectroscopic devices by integrating them with smartphones that replace the bulky spectrometers and data storage devices.

In recent studies, researchers have demonstrated the advantages of spectroscopic systems comprising of light collection geometry and diffraction grating in front of a smartphone. There is a need of a probe device that is efficient, cost effective, portable, user friendly which can replace bulky spectrometers and existing data storage devices.

Object of the invention:
Primary object of the present invention is to overcome the drawback associated with the prior art.
Another object of the present invention is to provide an efficient device useful for detecting cervical cancer.
Another object of the present invention is to provide handheld, miniaturized device for the early diagnosis of cervical cancer.
Another object of the present invention is to provide a device that does not require a separate module for imaging/ spectra collection and analysis.
Another object of the present invention is to provide a device that captures spectral changes associated with intrinsic fluorophores present in the different layers of the cervical tissue.

Another object of the present invention is to provide a method of operation of the handheld, miniaturized probe for the early diagnosis of cervical cancer.
Summary of the invention:
In an aspect of the present invention there is provided a handheld miniaturized device for the early diagnosis of cervical cancer, the device comprising:
a) a smartphone holder, wherein the smartphone holder is configured to hold a smartphone around its edge;
b) a grating holder, wherein the grating holder is configured to hold the transmission grating which has been placed before the smartphone camera to disperse the resultant fluorescence intensity into spectral image;
c) a filter holder, wherein the filter holder is configured to hold 450nm long pass filter which is configured to eliminate the source signal and pass the light of wavelength above than 450nm;
d) an analyser holder, wherein the analyser holder is configured to hold the analyser where the analyser is configured to collect both co and cross polarized components of the fluorescence light emitted from the cervical tissue sample;
e) an analyser ring, wherein the analyser ring is configured to rotate the analyser for collecting co and cross polarized components of the resultant fluorescence light;
f) an output beam splitter holder, wherein the output beam splitter holder is configured to hold output beam splitter which reflects the incoming source light to the cervix sample and transmits the emitted fluorescence light towards the detector side;
g) an input beam splitter holder, wherein the input beam splitter holder is configured to hold the input beam splitter which transmits both the laser and white light towards the sample side;
h) a light emitting diode holder, wherein the light emitting diode holder is configured to hold the white light LED source.
i) a laser holder, wherein the laser holder is configured to hold the 405nm laser source;
j) a polariser holder, wherein the polariser holder is configured to hold the polarizer which is adapted to polarize the incoming source light; and
k) a cylindrical tube, wherein the cylindrical tube, 13cm long in length, is configured to provide easy access to the surface of the cervix through vagina.
In another aspect of the present invention there is provided a method of early diagnosis of cervical cancer by the handheld miniaturized device as claimed in claim 1, the method comprising steps of:
a) holding a smartphone by a smartphone holder, wherein the smartphone holder is configured to hold a smartphone around its edge;
b) separating the wavelengths by a plurality of slits, wherein the grating holder is configured to have a plurality of slit;
c) filtering the wavelength by 450nm long pass filter which is configured to eliminate the source signal and pass the light of wavelength above than 450nm;
d) collecting both co and cross polarized components of the fluorescence light emitted from the cervical tissue sample by an analyser;
e) collecting co and cross polarized components of the resultant fluorescence light by rotating analyser;
f) reflecting the incoming source light to the cervix sample and transmitting the emitted fluorescence light towards the detector side by an output beam splitter;
g) transmitting the laser and white light towards the sample side by an input beam splitter;
h) emitting the white light source by a light LED source;
i) holding a laser source of 405nm length;
j) polarising the incoming light source by a polarizer; and
k) providing easy access to the surface of the cervix through vagina by a cylindrical tube which is of 13cm long in length.
This together with the other aspects of the present invention along with the various features of novelty that characterized the present disclosure is pointed out with particularity in claims annexed hereto and forms a part of the present invention. For better understanding of the present disclosure, its operating advantages, and the specified objective attained by its uses, reference should be made to the accompanying descriptive matter in which there are illustrated exemplary embodiments of the present invention.
Brief Description of the drawings:
The foregoing detailed description of preferred embodiments, are better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there is shown in the drawings exemplary constructions of the invention; however, the invention is not limited to the specific methods and system disclosed. In the drawings:
Figure 1: illustrates view of the working set-up of smartphone-based device of the present invention
Figure 2: illustrates detail view of smartphone-based device of the present invention
Figure 3: illustrates view of laser source holder of smartphone-based device of the present invention
Figure- 4: illustrates view of white LED source holder of smartphone-based device of the present invention
Figure- 5: illustrates input and output beam splitter holder of smartphone-based device of the present invention
Figure 6: illustrates polarizer and analyser holder of smartphone-based device of the present invention
Figure 7: illustrates cylindrical tube of smartphone-based device of the present invention
Figure 8: illustrates analyser ring of smartphone-based device of the present invention
Figure 9: illustrates filter holder of smartphone-based device of the present invention
Figure 10: illustrates grating holder of smartphone-based device of the present invention
Figure 11: illustrates smartphone holder of smartphone-based device of the present invention
Figure 12: explains the entire wavelength calibration process and also the generation of the resultant spectra from the captured spectral images of smartphone-based device of the present invention
Figure 13 (a-b): show that device has been calibrated using four laser sources to cover entire visible range.
Figure14 (a-c): show the ability of the probe based on smartphone platform to capture the exact
peaks of the fluorophores in comparison with spectrometer spectra. Figure14 (d): shows the comparison between smartphone and spectrometer spectra from cervical tissue.
Figure 15(a-b) represent the collected co and cross polarized fluorescence and polarized elastic scattering spectra, and the extracted polarized fluorescence and intrinsic fluorescence spectra from the smartphone-based device.

Detailed description of the Invention:
For the purpose of promoting an understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications in the illustrated system, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates.
It will be understood by those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not intended to be restrictive thereof.
Reference throughout this specification to “an embodiment, “another embodiment, “an or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrase “in an embodiment, “in another embodiment, “in one and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

The Invention provides a handheld, miniaturized device for the early diagnosis of cervical cancer.

This device is based on polarized fluorescence which is used for the extraction of intrinsic fluorescence from the sample to discriminate different grades of abnormality.

In an embodiment, the device comprises smartphone for capturing the spectrum and for the analysis.

The Invention provides a smartphone based device that captures spectral changes associated with intrinsic fluorophores present in different layers of the cervical tissue. The device has potential to produce more reliable results than the existing screening devices.

The device of the present invention does not require a separate module for imaging/ spectra collection and analysis.

In an embodiment, a handheld miniaturized device for the early diagnosis of cervical cancer, the device comprising:
a) a smartphone holder, wherein the smartphone holder is configured to hold a smartphone around its edge;
b) a grating holder, wherein the grating holder is configured to hold the transmission grating which has been placed before the smartphone camera to disperse the resultant fluorescence intensity into spectral image;
c) a filter holder, wherein the filter holder is configured to hold 450nm long pass filter which is configured to eliminate the source signal and pass the light of wavelength above than 450nm;
d) an analyser holder, wherein the analyser holder is configured to hold the analyser where the analyser is configured to collect both co and cross polarized components of the fluorescence light emitted from the cervical tissue sample;
e) an analyser ring, wherein the analyser ring is configured to rotate the analyser for collecting co and cross polarized components of the resultant fluorescence light;
f) an output beam splitter holder, wherein the output beam splitter holder is configured to hold output beam splitter which reflects the incoming source light to the cervix sample and transmits the emitted fluorescence light towards the detector side;
g) an input beam splitter holder, wherein the input beam splitter holder is configured to hold the input beam splitter which transmits both the laser and white light towards the sample side;
h) a light emitting diode holder, wherein the light emitting diode holder is configured to hold the white light LED source.
i) a laser holder, wherein the laser holder is configured to hold the 405nm laser source;
j) a polariser holder, wherein the polariser holder is configured to hold the polarizer which is adapted to polarize the incoming source light; and
k) a cylindrical tube, wherein the cylindrical tube,13cm long in length, is configured to provide easy access to the surface of the cervix through vagina.

In an embodiment, the smartphone holder is attached to the grating holder in a way such that the smartphone is able to take photo.
In an embodiment, the grating holder have different type of slit for transmission of light.
In an embodiment, the filter holder comprises a long pass filter to remove the portion of the incident light.
In an embodiment, the cylindrical tube is configured to have a small collecting lens at its tip to collect maximum fluorescence from the sample.
In an embodiment, early diagnosis of cervical cancer by the handheld miniaturized device as claimed in claim 1, the method comprising steps of:
a) holding a smartphone by a smartphone holder, wherein the smartphone holder is configured to hold a smartphone around its edge;
b) separating the wavelengths by a plurality of slits, wherein the grating holder is configured to have a plurality of slit;
c) filtering the wavelength by 450nm long pass filter which is configured to eliminate the source signal and pass the light of wavelength above than 450nm;
d) collecting both co and cross polarized components of the fluorescence light emitted from the cervical tissue sample by an analyser;
e) collecting co and cross polarized components of the resultant fluorescence light by rotating analyser;
f) reflecting the incoming source light to the cervix sample and transmitting the emitted fluorescence light towards the detector side by an output beam splitter;
g) transmitting the laser and white light towards the sample side by a input beam splitter;
h) emitting the white light source by a light LED source;
i) holding a laser source of 405nm length;
j) polarising the incoming light source by a polarizer; and
k) providing easy access to the surface of the cervix through vagina by a cylindrical tube which is of 13cm long in length.

In an embodiment, the device comprises following components:

1. Input chamber: It consists of two ports for light sources (Laser and white light source), one pair of collimating lenses for each source, a polarizer to pass polarized light and a beam splitter for simultaneous reflection and transmission of incident light.

2. Output chamber: It has several components such as a beam splitter to reflect light to the sample and pass the emitted fluorescence signal to analyzer, a long narrow cylindrical tube for easy access to the surface of the cervix through the vagina, a long pass filter to remove the portion of the incident light and at the end, the collection assembly which comprises of a transmission grating and a smartphone to record and analyze the resultant polarized spectrum.

In an embodiment, the specifications of different parts (sources and optical components) of the device are given below:
• Laser: 405nm (50mW), Adlabs Instruments, New Delhi
• White light: 10W white LED, CREE XM-L T6
• Collimating lenses: 12mm focal length, Thorlabs, LA1576
• Polarizer and Analyser: 25.4mm diameter, Glan-Thompson 10GT04AR.14, Newport
• Beam splitters: 10mm non-polarizing cubic beam splitter, BS010, Thorlabs
• Collecting lens: 6mm diameter x 12mm focal length, Plano convex lens, Edmund optics
• Filter: 450nm long pass filter, 12.5mm diameter, OD 4.0 LPF, Edmund optics
• Grating: 12.7mm x 12.7mm, visible transmission grating, GT 13-12, Thorlabs:

In an embodiment, the device of the present invention has the overall dimension (L x B x H) of the device is approximately 26 cm x 15 cm x 4 cm and average weight is ~ 300 grams. The low weight of the device makes its user friendly, user can use the device for longer time without having any tiredness.

In an embodiment, the device is based on the extraction of intrinsic fluorescence using polarized fluorescence and elastic scattering spectra recorded from smartphone’s camera. The inclusion of the smartphone for data collection and analysis makes it cost effective, user friendly and portable.

In an embodiment, the device captures the polarized fluorescence and elastic scattering spectral images in both co and cross polarized modes. All the collected images are in a RAW image format with .dng extension which is considered as a standard format to process images without any further processing. These images are then converted into a readable .tiff format and eventually typical spectra are generated as resultant for further analysis.

Wavelength calibration of the present system is very crucial as it defines the efficacy of the device to capture the accurate spectra for the specimen. Four lasers (violet, blue, green and red) have been used to calibrate the system for the entire visible wavelength range (400-700 nm). Fluorescence spectra of some known fluorophores such as fluorescein, FAD, rhodamine have been recorded using the device to cross verify the entire I v/s pixel to I v/s wavelength conversion in comparison with spectra collected from a commercial spectrometer. Polarized fluorescence spectra of few cervical tissue samples have also been tested in-vitro to proof its applicability for cervical cancer diagnosis.

Initial testing has been done with some known fluorophores like FAD, fluorescein, etc. for the validation of the device. Testing with cervical tissue samples is going on.

The Invention is further described with the help of non-limiting examples:
Example 1:
The handheld probe is calibrated using four lasers (violet, blue, green, and red) covering the
whole visible region (400-700nm) so that one can obtain its correct spectral response in this
wavelength range. The corrected spectrum captured from the smartphone and the one recorded using a commercial spectrometer have been shown in Fig 13 (a, b). In the figure, the spectral plots display the ability of the probe based on a smartphone platform to capture the exact peaks of the fluorophore in comparison spectrometer spectra. Spectra of some fluorophores have been captured and compared with the output spectra of a commercial spectrometer (Fig 14 (a-c)) to validate its performance on fluorescent dyes. Fluorescence spectra of cervical tissue samples have also been recorded, analysed and compared with the spectra from spectrometer (Fig 14(d)) to prove its applicability for fluorescence collection from biological samples. Figure 14 (a), (b) and (c) show the comparison between smartphone and spectrometer spectra for different fluorophores. Figure 14 (d) shows the cervical tissue spectra from smartphone and spectrometer.

In an embodiment, Intrinsic fluorescence is extracted from the simultaneously collected polarized fluorescence and elastic scattering spectra from cervical tissue samples using the below given equation:
IF= [I_vv (?)-G(?)*I_vh (?)]_fl/[I_vv (?)-G(?)*I_vh (?)]_scat
Where, I_vv (?) and I_vh (?) are intensities of co and cross polarized signals, G(?) is the ratio of the sensitivity of the proposed system for vertically and horizontally polarized light. Here, the subscripts ‘fl’ and ‘scat’ notify the fluorescence and elastic scattering respectively. Intrinsic fluorescence is free from the wavelength dependent absorption and scattering properties of a turbid medium like tissue which affect the bulk fluorescence from tissue and eventually mask the discriminatory signatures of fluorophores present in its layered structure.

Referring to figure 15(a-b), represents the collected co and cross polarized fluorescence and polarized elastic scattering spectra, and the extracted polarized fluorescence and intrinsic fluorescence spectra from the smartphone-based device. Further, from figure 15(b) it can be noticed that intrinsic fluorescence eliminates all the distortions present due to absorption and scattering properties which are visible in polarized fluorescence spectra.

In an embodiment, device works as a smartphone-based spectrometer which has the ability to capture unprocessed RAW images and convert them in to a typical I v/s ? graph with further processing. Polarized fluorescence and elastic scattering spectra are utilized to finally extract the intrinsic fluorescence spectra and enhance its efficacy to produce more reliable and accurate results than the existing commercial screening devices.

WE CLAIM:

1. A handheld miniaturized device for the early diagnosis of cervical cancer, the device comprising:
a) a smartphone holder, wherein the smartphone holder is configured to hold a smartphone around its edge;
b) a grating holder, wherein the grating holder is configured to hold the transmission grating which has been placed before the smartphone camera to disperse the resultant fluorescence intensity into spectral image;
c) a filter holder, wherein the filter holder is configured to hold 450nm long pass filter which is configured to eliminate the source signal and pass the light of wavelength above than 450nm;
d) an analyser holder, wherein the analyser holder is configured to hold the analyser where the analyser is configured to collect both co and cross polarized components of the fluorescence light emitted from the cervical tissue sample;
e) an analyser ring, wherein the analyser ring is configured to rotate the analyser for collecting co and cross polarized components of the resultant fluorescence light;
f) an output beam splitter holder, wherein the output beam splitter holder is configured to hold output beam splitter which reflects the incoming source light to the cervix sample and transmits the emitted fluorescence light towards the detector side;
g) an input beam splitter holder, wherein the input beam splitter holder is configured to hold the input beam splitter which transmits both the laser and white light towards the sample side;
h) a light emitting diode holder, wherein the light emitting diode holder is configured to hold the white light LED source.)
i) a laser holder, wherein the laser holder is configured to hold the 405nm laser source;
j) a polariser holder, wherein the polariser holder is configured to hold the polarizer which is adapted to polarize the incoming source light; and
k) a cylindrical tube, wherein the cylindrical tube is 13cm long in length is configured to provide easy access to the surface of the cervix through vagina.

2. The device as claimed in claim 1, wherein the smartphone holder is attached to the grating holder in a way such that the smartphone is able to take photo.
3. The device as claimed in claim 1, wherein the grating holder have different type of slit for transmission of light.
4. The device as claimed in claim 1, wherein the filter holder comprises a long pass filter to remove the portion of the incident light.
5. The device as claimed in claim 1, Wherein the cylindrical tube is configured to have a small collecting lens at its tip to collect maximum fluorescence from the sample.

6. A method of early diagnosis of cervical cancer by the handheld miniaturized device as claimed in claim 1, the method comprising steps of:
a) holding a smartphone by a smartphone holder, wherein the smartphone holder is configured to hold a smartphone around its edge;
b) separating the wavelengths by a plurality of slits, wherein the grating holder is configured to have a plurality of slit;
c) filtering the wavelength by 450nm long pass filter which is configured to eliminate the source signal and pass the light of wavelength above than 450nm;
d) collecting both co and cross polarized components of the fluorescence light emitted from the cervical tissue sample by a analyser;
e) collecting co and cross polarized components of the resultant fluorescence light by rotating analyser;
f) reflecting the incoming source light to the cervix sample and transmitting the emitted fluorescence light towards the detector side by an output beam splitter;
g) transmitting the laser and white light towards the sample side by a input beam splitter;
h) emitting the white light source by a light LED source;
i) holding a laser source of 405nm length;
j) polarising the incoming light source by a polarizer; and
k) providing easy access to the surface of the cervix through vagina by a cylindrical tube is of 13cm long in length.
7. The method as claimed in claim 6, wherein the smartphone holder is attached to the grating holder in a way such that the smartphone is able to take photo.
8. The method as claimed in claim 6, wherein the grating holder have different type of slit for transmission of light.
9. The method as claimed in claim 6, wherein the filter holder comprises a long pass filter to remove the portion of the incident light.
10. The method as claimed in claim 6, Wherein the cylindrical tube is configured to have a small collecting lens at its tip to collect maximum fluorescence from the sample.