Patent Application
20160287063
The presently disclosed subject matter relates to medical devices. Particularly, the presently disclosed subject matter relates to colposcopes having light emitters and image capture devices and associated methods.
Numerous studies have shown that the early detection and treatment of oral and cervical cancers significantly improve survival rates. Detection of precancerous and cancerous oral lesions is mostly accomplished through visual inspection followed by the biopsy of suspicious tissue sites. For cervical cancer screening, the Papanicolau test or Pap smear is the standard of care. If the Pap smear is positive, colposcopy (visualization of the acetic acid stained cervix with a low power microscope) and biopsy are performed. An effective cancer screening and diagnostic program often requires both sophisticated and expensive medical facilities with well-trained and experienced medical staff. In developing countries, however, there is often an absence of appropriate medical infrastructure and resources to support the organized screening and diagnostic programs that are available elsewhere. Therefore, there is a critical global need for a portable, easy-to-use, reliable and low cost device that can rapidly screen for oral and cervical cancer in low-resource settings. Accordingly, there is a need for effective and low-cost equipment and techniques for cancer screening and diagnosis.
Disclosed herein are colposcopes having light emitters and image capture devices and associated methods. According to an aspect, a colposcope includes an elongate body having a distal end, a proximate end, and an axis extending between the distal end and the proximate end. The colposcope also includes a balloon attached to the elongate body and configured to be inflated to expand in a direction away from the axis of the elongate body. Further the colposcope includes an image capture device attached to the distal end of the elongate body and positioned to capture images of an area outside the elongate body. The colposcope also includes one or more light emitters attached to the distal end of the elongate body and positioned to generate and direct light towards the area outside of the elongate body.
The foregoing aspects and other features of the present subject matter are explained in the following description, taken in connection with the accompanying drawings, wherein:
For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to various embodiments and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended, such alteration and further modifications of the disclosure as illustrated herein, being contemplated as would normally occur to one skilled in the art to which the disclosure relates.
Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
In accordance with embodiments, the present subject matter relates to colposcopy. For example, colposcopes are described herein that utilize the principle of a mechanical delivery method for insertion and stabilization into the vagina for imaging of the external cervix. The imaging may produce digital, color, high-resolution images at both full field and at high magnification of areas of interest. Colposcopes described herein may include an image capture device for capture and storage of high-resolution, multimodal images of the external cervix for post-hoc analysis by medical personnel at a centralized location.
In accordance with embodiments of the present disclosure, a colposcope and electronic device may be a part of a kit provided for use by medical personnel to allow for screening of patients. Captured images may be suitably stored and processed. In an example, the images may be communicated or downloaded to a server for remote expert diagnosis. The colposcope may be suitably sterilized and subsequently re-used.
In accordance with embodiments of the present disclosure, the colposcope and an electronic operative therewith may implement a multimodal imaging technique to leverage intrinsic contrast from changes in collagen content through auto-fluorescent imaging and narrow band imaging of the neo-vascularization associated with progressively worsening cervical lesions derived from spectroscopic and ratiometric methods.
The colposcope 100 includes an elongate body 106 having a distal end 108, a proximate end 110, and an axis indicated by broken line 112. The body 106 is generally tubular and rounded in shape. Alternatively, the body 106 may be of any suitable shape and size.
The colposcope 100 includes a balloon 114 attached to the elongate body 106. The balloon 114 is configured to be inflated to expand in a direction away from the axis 112 of the body 106. More particularly, the balloon 114 may be operative with suitable mechanisms and controls for selective inflation and deflation as described in further detail herein. The balloon 114 is shown in a deflated state in the example of
The balloon 114 may have one or more openings connected to a tube (not shown) for passage of air for inflation or deflation. The tube may be positioned within an interior space defined by the elongate body 106 and extend out from the proximate end 110 for connection to a mechanism to controllably inflate and deflate the balloon 114. The balloon 114 may be made of silicone rubber or a double-lumen, thin-walled membrane. Further, the colposcope 100 may include a one-way valve for retention of the dilation.
At the distal end 108, the body 106 may have attached thereto multiple light emitters 116 and an image capture device 118. In this example, the light emitters 116 are light emitting diodes (LEDs), although it should be understood that the light emitters 116 may be any suitable type of light emitter. The image capture device 118 may be a digital camera (e.g., a color CMOS sensor) configured to capture images and/or video. The image capture device 118 may be configured with one or more lenses and/or one or more filters. The light emitters 116 and the image capture device 118 may operate together for surveillance of the external cervix when the colposcope is positioned in the vaginal cavity. During image capture, the balloon 114 may be suitably inflated to expand the cavity. The balloon 114 may be automatically expanded during image capture and deflated otherwise. In an example, the balloon 114 may be suitably inflated or deflated by use of a syringe or valve. Such mechanisms may activate with sidewall compression to allow for removal of the colposcope.
The electronic device 102 may be configured to control the operation of the colposcope 100, to process captured images, and to interface with a user, such as medical personnel. In this example, the electronic device 102 is a smartphone, although it should be understood that the electronic device 102 may alternatively be any other type of computing device. It is noted that the term “electronic device” should be broadly construed. It can include any type of device capable of presenting electronic text to a user. For example, the electronic device may be a mobile device such as, for example, but not limited to, a smart phone, a cell phone, a pager, a personal digital assistant (PDA, e.g., with GPRS NIC), a mobile computer with a smart phone client, or the like. An electronic device can also include any type of conventional computer, for example, a desktop computer or a laptop computer. A typical mobile device is a wireless data access-enabled device (e.g., an iPHONE® smart phone, a BLACKBERRY® smart phone, a NEXUS ONE™ smart phone, an iPAD® device, or the like) that is capable of sending and receiving data in a wireless manner using protocols like the Internet Protocol, or IP, and the wireless application protocol, or WAP. This allows users to access information via wireless devices, such as smart phones, mobile phones, pagers, two-way radios, communicators, and the like. Wireless data access is supported by many wireless networks, including, but not limited to, CDPD, CDMA, GSM, PDC, PHS, TDMA, FLEX, ReFLEX, iDEN, TETRA, DECT, DataTAC, Mobitex, EDGE and other 2G, 3G, 4G and LTE technologies, and it operates with many handheld device operating systems, such as PalmOS, EPOC, Windows CE, FLEXOS, OS/9, JavaOS, iOS and Android. Typically, these devices use graphical displays and can access the Internet (or other communications network) on so-called mini- or micro-browsers, which are web browsers with small file sizes that can accommodate the reduced memory constraints of wireless networks. In a representative embodiment, the mobile device is a cellular telephone or smart phone that operates over GPRS (General Packet Radio Services), which is a data technology for GSM networks. In addition to a conventional voice communication, a given mobile device can communicate with another such device via many different types of message transfer techniques, including SMS (short message service), enhanced SMS (EMS), multi-media message (MMS), email WAP, paging, or other known or later-developed wireless data formats. Example functions described herein may be implemented on any suitable electronic device, such as a computer or smartphone.
The electronic device 102 may include a touchscreen display 120 and/or other user interface for interacting with a user and for present information and images. As referred to herein, a “user interface” (UI) is generally a system by which users interact with an electronic device. An interface can include an input for allowing users to manipulate an electronic device, and can include an output for allowing the system to present information (e.g., e-book content) and/or data, indicate the effects of the user's manipulation, etc. An example of an interface on an electronic device includes a graphical user interface (GUI) that allows users to interact with programs in more ways than typing. A GUI typically can offer display objects, and visual indicators, as opposed to text-based interfaces, typed command labels or text navigation to represent information and actions available to a user. For example, an interface can be a display window or display object, which is selectable by a user of a mobile device for interaction. The display object can be displayed on a display screen of an electronic device and can be selected by and interacted with by a user using the interface. In an example, the display of the electronic device can be a touch screen, which can display the display icon. The user can depress the area of the display screen at which the display icon is displayed for selecting the display icon. In another example, the user can use any other suitable interface of a mobile device, such as a keypad, to select the display icon or display object. For example, the user can use a track ball or arrow keys for moving a cursor to highlight and select the display object.
Operating environments in which embodiments of the present disclosure may be implemented are also well-known. The electronic device 102 may be communicatively connected to a remote server for communication of data and captured images for processing in accordance with embodiments of the present disclosure. Further, the electronic device 102 may suitably power the light emitters 116 and the image capture device 118 via the cable 104. In a representative embodiment, an electronic device, such as an e-book reader, is connectable (for example, via WAP) to a transmission functionality that varies depending on implementation. Thus, for example, where the operating environment is a wide area wireless network (e.g., a 2.5G network, a 3G network, or a 4G network), the transmission functionality comprises one or more components such as a mobile switching center (MSC) (an enhanced ISDN switch that is responsible for call handling of mobile subscribers), a visitor location register (VLR) (an intelligent database that stores on a temporary basis data required to handle calls set up or received by mobile devices registered with the VLR), a home location register (HLR) (an intelligent database responsible for management of each subscriber's records), one or more base stations (which provide radio coverage with a cell), a base station controller (BSC) (a switch that acts as a local concentrator of traffic and provides local switching to effect handover between base stations), and a packet control unit (PCU) (a device that separates data traffic coming from a mobile device). The HLR also controls certain services associated with incoming calls. Of course, embodiments in accordance with the present disclosure may be implemented in other and next-generation mobile networks and devices as well. The mobile device is the physical equipment used by the end user, typically a subscriber to the wireless network. Typically, a mobile device is a 2.5G-compliant device, 3G-compliant device, or 4G-compliant device that includes a subscriber identity module (SIM), which is a smart card that carries subscriber-specific information, mobile equipment (e.g., radio and associated signal processing devices), a user interface (or a man-machine interface (MMI)), and one or more interfaces to external devices (e.g., computers, PDAs, and the like). The electronic device may also include a memory or data store.
The colposcope 100 may include an interface 122 at the proximal end 110 for receipt of the tubing for the balloon 114 and any cabling for the light emitters 116 and the image capture device 118. The interface 122 may be suitably configured for connection to the cable 104.
Now turning to
As an alternative to a balloon, a colposcope in accordance with the present disclosure may use a cavity expander having one or more members for opening to expand a human cavity. As an example,
The colposcope 100 includes a mechanism for controlling movement of the members 602 and 604 between the open and closed positions. For example, the members 602 and 604 may be attached to an actuating ring 606 via wires 608 and 610 such that when the ring is moved between a position shown in
The colposcope 100 may include a biopsy forcep 612 attached to the distal end 108. The forcep 612 may be covered when the members 602 and 604 are in the closed position, and exposed when the members 602 and 604 are in the open position.
The members 602 and 604 may form an opening 616 at an end when in the closed position shown in
In accordance with embodiments, the members 602 and 604 may include brushes or other features for clearing bodily fluid (e.g., mucous or blood) from the cervix. The brushes may be made of, for example, pliable, plastic fibers or the like). The brushes may be located at a tip of the members 602 and 604 such as near where the opening 616 is formed.
In another example,
The colposcope 100 includes a mechanism for controlling movement of the mechanical components 800 and the flexible membrane 802 between the open and closed positions. For example, the mechanical components 800 and the flexible membrane 802 may be attached to wires 608 and 610 such movement of the wires can cause the mechanical components 800 and the flexible membrane 802 to move between the open and closed positions.
In another example,
The colposcope 100 includes a mechanism for controlling movement of the mechanical components 800 and the flexible membrane 802 between the open and closed positions. For example, the mechanical components 800 and the flexible membrane 802 may be attached to wires 608 and 610 such movement of the wires can cause the mechanical components 800 and the flexible membrane 802 to move between the open and closed positions.
In another example,
In another example,
Now turning to
With continuing reference to
The colposcope 100 shown in
Colposcopes disclosed herein may be used for applying Lugol's iodine and/or acetic acid (5%) for aiding in the visual inspection of the cervix. In accordance with embodiments, a colposcope may include a working channel or spray channel for applying a desired amount of stain to the cervix. For example,
With continuing reference to
In accordance with embodiments of the present disclosure, light emitters disclosed herein may be used for illuminating the cervix or other area of interest. For example,
Table 1 below shows a comparison of an example colposcope in accordance with embodiments of the present disclosure and a commercially-available colposcope.
For defogging, commercial off-the-shelf anti-fog wipes (i.e. Bausch & Lomb Fogshield XP) may be applied prior to each procedure to the outermost lens or optical window and the system has a hydrophobic optically-clear window are used to minimize obscuration of the cervix due to internal body cavity humidity induced condensation on the lens.
In accordance with embodiments of the present disclosure, a suitable imaging processing technique may be applied for the capture and analysis of cervix images. In an example, an automated imaging sequence may be implemented that transitions through the following illumination stages: white light illumination (WLI), green light illumination (green filter), and narrow band imaging (green and blue). This sequence may capture between 10 and 15 images per type of illumination strategy and may include an auto-focusing mechanism. The initial white light images may aid in characterization of the mosaicism, with enhanced mosaicism visualization with the green-light only illumination stage. Lastly, in this example, a narrow band of illumination of narrow green and blue spectra can provide important information for the vasculature of the cervix. These three components may be combined for a mathematical algorithm to aid in a probabilistic heat map for highly suspicious lesion locations as well as high-resolution color images of the cervix for reading by medical personnel, such as an obstetrician gynecologist.
With continuing reference to
The microcontroller 2202 may also be communicatively connected to a color CMOS detector 118 and a graphics processing unit (GPU) 2206 (operatively connected to the detector 118) for capture of images. The microcontroller 2202 may control flash memory 2208 to store the captured images. The flash memory 2208 may store the captured images until communicated to an electronic device via a USB-to-serial interface 2210. Alternatively, the colposcope may suitably communicate captured image data via a wireless technique.
The colposcope circuit 2200 may include a battery power source 2212 configured to supply power to the LED (light source) constant current driver(s) 2204, the microcontroller 2202, and a solenoid valve 2214. Further, the colposcope circuit 2200 may include a pressure sensor 2216, a position sensor 2218, air pump (not shown) and a timer 2220. This microcontroller uses an external timer to precisely control the length of time the pump and/or solenoid valve are activate based on real-time readings from the pressure sensor to control inflation and deflation of the vaginal wall dilator mechanism and pressurize the acetic acid and/or Lugol's Iodine spray for enhancing visual contrast in the cervix.
Disclosed herein are UV-visible (UV-VIS) diffuse reflectance spectroscopy systems, which can be used to measure tissue absorption and scattering. These systems may be used for the early diagnosis of cancers in the cervix and oral cavity. The absorption and scattering coefficients of epithelial tissues reflect the underlying physiological and morphological properties. In the UV-VIS band, the dominant absorbers in oral and cervical tissues are oxygenated and deoxygenated hemoglobin, arising from blood vessels in the stroma. Light scattering is primarily associated with cell nuclei and organelles in the epithelium, as well as collagen fibers and crosslinks in the stroma. Neoplastic tissues exhibit significant changes in their physiological and morphological characteristics that can be quantified optically. The contribution of absorption in the stromal layer can be expected to increase with neovascularization and angiogenesis, and the oxygen saturation in blood vessels is expected to decrease as the neoplastic tissue outgrows its blood supply. Stromal scattering can be expected to decrease with neoplastic progression due to degradation of extracellular collagen networks. However, epithelial scattering can be expected to increase due to increased nuclear size, increased DNA content, and hyperchromasia. UV-VIS diffuse reflectance spectroscopy has a penetration depth that can be tuned to be comparable to the thickness of the epithelial layer or deeper to probe both the epithelial and stromal layers.
In accordance with embodiments disclosed herein, a UV-VIS diffuse reflectance spectroscopy system is provide having a colposcope geometry that is most sensitive to changes in the stroma and a scalable inverse Monte Carlo (MC) reflectance model to rapidly measure and quantify tissue optical properties. In one study, it was shown that a spectroscopic system and the MC model may be used to identify optical biomarkers that vary with different grades of cervical intraepithelial neoplasia (CIN) from normal cervical tissues. In another study, total hemoglobin was found to be statistically higher in high-grade dysplasia compared with normal and low grade dysplasia (P,0.002), whereas scattering was significantly reduced in dysplasia compared with normal tissues (P,0.002). Further, in another study, the same UV-VIS diffuse reflectance spectroscopy system was applied in an in vivo in which 21 patients with mucosal squamous cell carcinoma of the head and neck were evaluated. All 21 patients underwent panendoscopy and biopsies were taken from the malignant and the contralateral normal tissues. Diffuse reflectance spectra were measured prior to biopsy. The vascular oxygen saturation (SO2) was found to be statistically higher in malignant tissues compared to non-malignant tissues (P=0.001).
It is known that the most efficient and effective strategy for the prevention of advanced cervical or oral cancers in resource-limited settings is to see and treat the patient in a single-visit, thus obviating the need for a multi-tiered system such as that in the U.S. where screening, diagnosis, and treatment entail three or more visits to the healthcare facility. For example, guidelines have been written by the Alliance for the Prevention of Cervical Cancer (APCC) on strategies for screening cervical cancer in resource-limited settings. Their recommendation is visual inspection with acetic acid (VIA), followed by treatment of the precancerous lesions using cryotherapy (freezing), which can be carried out by physicians, nurses or midwives. An effective screening/diagnostic strategy that can allow for immediate treatment intervention needs to be able to survey the entire region of interest. Further, the detection strategy should be minimally affected by operator bias or subjective interpretation of images collected from the region of interest. Systems disclosed herein can enable quantitative determination of tissue physiological endpoints, but may be limited to evaluating localized regions of the tissue. To survey the entire field of view, it is important to scale the single-pixel fiber-based system into an imaging platform and develop algorithms that can quantify these spectral images. However, development of simple imaging systems may require a significant consolidation of the number of wavelengths, so that imaging spectrographs and broad-band thermal sources can be replaced by simple cameras and LEDs.
Systems disclosed herein can use a ratiometric analysis for the quantitation of tissue SO2 and total hemoglobin concentration ([THb]) using a small number of wavelengths in the visible spectral range as a strategy for implementation of rapid surveillance of pre-cancers and cancers in a screening population in resource-limited settings. For example, the analysis may be used by colposcopes and associated electronic devices disclosed herein. Ratiometric analyses may be used to compute [THb] or SO2 from reflectance spectra. For example, ratiometric analyses may be used to extract SO2 using ratios at two wavelengths, one where the local differences between the extinction coefficients of oxy- and deoxy-hemoglobin are maximal, and one isosbestic wavelength, where the extinction coefficients of oxy- and deoxy-hemoglobin are the same. A ratiometric analysis is disclosed which computes reflectance ratios at the isosbestic wavelengths of hemoglobin, and this analysis may be used to rapidly calculate [THb] independent of tissue scattering and SO2. For this particular ratiometric analysis, the ratio of the intensities at one visible wavelength (452, 500, or 529 nm) to one ultraviolet wavelength (390 nm) from a diffuse reflectance spectrum was used to extract [THb] using a linear analytical equation. This analysis may require an ultraviolet source, which is relatively expensive compared to ubiquitous visible wavelength light sources. Herein, an analytical ratiometric analysis is provided for extracting both [THb] and SO2 in the visible wavelength range. It utilizes two or more intensities at different wavelengths from a diffuse reflectance spectrum and calculates appropriate ratios from them. The derived ratios may then be converted to [THb] or SO2 using analytical equations. The analysis, in one example, utilizes only three wavelengths (539, 545 and 584 nm), all in the visible part of the spectrum where light emitting diodes (LEDs) are readily available. This ratiometric analysis was tested with full spectral MC simulations and experimental phantoms to ensure minimal sensitivity to scattering. In addition, the ratiometric analysis may also account for [THb] when computing SO2.
In an example study, wavelengths were chosen from 500 nm to 600 nm (visible spectrum) in order to leverage relatively low priced light sources such as LEDs. In addition, deoxy- and oxy hemoglobin have distinct absorption features in the visible spectrum. Five isosbestic wavelengths and five other wavelengths where the difference of extinction coefficients between deoxy- and oxy-hemoglobin are largest were used to calculate [THb] and SO2, respectively. Table 2 below lists these wavelengths, which provide a total of ten possible combinations (pairs of isosbestic wavelengths), at which ratios were tested for extraction of [THb] and 25 wavelength combinations at which the reflectance ratios were tested (one isosbestic and one maximal difference wavelength) for extraction of SO2.
Analytical equations to convert appropriate ratios into [THb] and SO2 values may be determined using full spectral MC simulations. A suitable forward full spectral MC model may be used to generate 24805 unique diffuse reflectance spectra. These reflectance spectra may serve as the simulated master set. Diffuse reflectance spectra may be simulated by calculating the absorption and scattering spectrum between 350-600 nm. The absorption coefficients may be calculated with the assumption that oxy- and deoxy-hemoglobin are the dominant absorbers in tissue. The sum of these two absorber concentrations may provide the resulting [THb], which was varied between 5 and 50 mM in increments of 0.1 mM in the master set. The concentration of each hemoglobin species may be varied to span the range of SO2 values from 0 to 1, in steps of 0.1. The reduced scattering coefficients, ms′, across the spectral range may be determined using Mie theory for 1 mm polystyrene microspheres. Five different scattering levels may be generated by increasing the number density of sphere concentrations. The wavelength-averaged (between 350,600 nm) mean reduced scattering coefficients for these five scattering levels were 8.9, 13.3, 17.8, 22.2, and 26.6 cm−1. The resulting master set consisted of 24805 reflectance spectra, which represent the combination of all possible [THb] levels, with all SO2 levels, and all scattering levels (45161165=24805). These optical properties are similar to those previously used. The simulated reflectance spectra for the master set may be created for a fixed fiber-probe geometry in a suitable manner. Finally, an experimentally measured diffuse reflectance spectrum with the same fiber-geometry may be used as a “reference” to calibrate the scale of the simulated spectra to be comparable to that of measured spectra.
To study the impact on extraction accuracy of the ratiometric analysis with increasing spectral bandpasses, additional bandpasses in the master set were simulated. The reflectance spectra were simulated for three different bandpasses (2 nm, 3.5 nm and 10 nm full width-half-maximum (FWHM) bandwidths) and resulted in 3 modified master diffuse reflectance sets (each containing 24,805 spectra). This was done by assuming each wavelength had a certain Gaussian bandpass of specified FWHM. Specifically, the reflectance at each wavelength in the simulated spectrum was convolved with a Gaussian distribution function with the specific bandpass. Equations to convert reflectance ratios into [THb] and SO2 were then generated separately for each of the three bandpass-modified master diffuse reflectance spectral sets.
In order to convert the reflectance ratio computed at a given SO2 wavelength-pair into an SO2 value, a non-linear logistic (Hill curve) equation was used. A unique Hill equation was generated for each of the 451 [THb] (5-50 mM in 0.1 increment steps) in the modified master set. The reflectance ratio for a given SO2 wavelength-pair, at a given [THb], was averaged across the five scattering levels (
A total of 8 sets of reflectance spectra were used to validate the ratiometric analysis. The optical properties and collection parameters for these 8 phantom sets are summarized in Table 3 shown below.
Phantom sets 1-3 were simulated with the scalable MC model, as described above. Phantom sets 4-8 were experimentally measured data. Briefly, Phantom Set 4 consisted of 51 phantoms with varying SO2 levels but with a fixed [THb] (14.8 mM), and μs″ level (12.6 cm−1). Phantom Set 5 consisted of two subsets of phantoms with a low scattering level (μs′=13.5 cm−1) and high scattering level (μs′=22.52 cm−1). Each set in Phantom Set 5 consisted of 4 phantoms. Each phantom in the low scattering level was paired with a phantom in the high scattering level and the [THb] value of each paired phantom was the same. The standard deviation of the reflectance for each wavelength-pair in each paired phantoms were computed. Phantom Set 6 consisted of 13 phantoms with increasing [THb] from 5.86-35.15 mM. The averaged μs′ levels decreased for each phantom from 23.63 to 17.30 cm−1. A second instrument was used to measure the phantoms for Phantom Set 7 and Set 8 to validate the instrument independence of the ratiometric analysis. Phantom Set 7 was similar to Phantom Set 5 in that it contained two sets of 4 phantoms with low and high scattering levels (μs′=13.5 cm−1 and 22.89 cm−1 respectively) and paired phantoms from each level contained the same [THb]. The standard deviation of the reflectance for each wavelength-pair in each paired phantoms were also computed. Phantom Set 8 consisted of 16 phantoms with increasing [THb] from 5-50 mM. The μs′ level of each phantom was lower than the previous phantom, ranging from 28.56 to 17.02 cm−1, due to serial dilutions of the phantom solution. The combination of all of these experimental tissue phantoms measured serves to determine the best ratios to estimate [THb] and SO2 for a wide range of optical properties measured by different instruments.
The ratiometric analysis was first tested on the simulated reflectance. Linear analytical equations for [THb] ratios and the non-linear logistic equations for SO2 ratios were generated from Phantom Sets 1-3. The extracted values of [THb] using the ratiometric analysis were compared to the true values for each diffuse reflectance spectrum and the absolute errors between the predicted and true values were calculated. Next, the sensitivity of each [THb] ratio to scattering was computed using the standard deviation of the reflectance ratio at each [THb].
The calculation of [THb] using the ratiometric analysis was also validated in Phantom Sets 4-8. Since every reflectance spectrum simulated by the MC model needs to be scaled by a calibrating phantom, the choice of the calibrating phantom can introduce systematic errors. To account for these effects on the extracted [THb], 3 different phantoms in Phantom Set 4, Set 6 and Set 8 and 2 different phantoms in Sets 5 and 7 were selected as the calibrating phantoms. The SO2, [THb] and μs′ of the calibrating phantoms are summarized in Table 4 below.
Each time a calibrating phantom was selected, a new master set of reflectance was generated with the scalable MC model, and new coefficients for analytical equations were generated from these phantom sets. The generated analytical equations were used to extract the [THb] or SO2 values in the same experimental phantom sets from which the calibrating phantoms were selected. This ensured that the systematic errors or titration errors in one experimental phantom study were restricted to the same experimental phantom study and were not carried to another experimental phantom study. The probe geometries and bandpasses for the simulated master sets were matched to the experimental system. The ratiometrically extracted [THb] were compared to the MC extracted [THb] of the experimental phantoms for each phantom in Sets 4-8 to compute the absolute errors. The ratio spreads of the ten possible isosbestic wavelength pairs were computed from the paired phantoms in Set 5 and Set 7. The best ratio for [THb] was determined from the error and ratio spread rankings both with the simulated data and with the experimental data.
The ratiometric analysis for SO2 was validated in Phantom Set 4, which consisted of phantoms with varying SO2 levels. For each experimental phantom in this set, [THb] was first computed using the best isosbestic wavelength-pair using the ratiometric analysis. This extracted [THb] was then used to select the corresponding Hill curve coefficients for a given SO2 wavelength-pair. The reflectance ratio of each SO2 wavelength-pair was first computed and then converted to a SO2 value with the corresponding Hill curve coefficients. The ratiometrically extracted SO2 values were compared against the SO2 values measured with a pO2 electrode. To evaluate the sensitivity of each SO2 ratio to scattering, the reflectance ratios of each SO2 wavelength-pair were first computed in every phantom of Phantom Sets 5 and Set 7. The standard deviations were then computed from each paired reflectance ratios for each SO2 wavelength-pair since only the scattering was different within each paired phantom. The derived standard deviations from every paired phantom in Phantom Set 5 and Set 7 were averaged for each SO2 wavelength-pair.
Three instruments were used to validate the ratiometric analysis in this manuscript. Instrument A was used in the experimental phantom studies (Set 4-6) and in an in vivo cervical study. Instrument B was also used in the experimental phantom studies (Set 7-8), and also in the in vivo cervical study and in an in vivo breast cancer study. Instrument C was used for an in vivo head and neck cancer study. The details of Instruments A, B and C and the probe geometries were determined. Briefly, Instrument A consisted of a 450 W xenon (Xe) arc lamp (JY Horiba, Edison N.J.), double excitation monochromators (Gemini 180, JY Horiba, Edison, N.J.), and a Peltier-cooled open electrode charge-coupled device (CCD) (Symphony, JY Horiba, Edison, N.J.). Instrument B was a fibercoupled spectrophotometer (SkinSkan, JY Horiba, Edison, N.J.), which consisted of a 150 W Xe arc lamp, a double-grating excitation monochromator, an emission monochromator, and an extended red photomultiplier tube (PMT). Instrument C was a portable system, which consisted of a 20 W halogen lamp (HL2000HP; Ocean Optics, Dunedin, Fla.), heat filter (KG3, Schott, Duryea, Pa.), and an USB spectrometer (USB4000, Ocean Optics, Dunedin, Fla.). Illumination and collection for all instruments were achieved by coupling to fiber optic probes. The instrument parameters are listed in
The power law (μs′=a·λ−b) was used to model the reduced scattering coefficients where a determines the overall magnitude of scattering, 1 is wavelength, and b is the scattering power. A new set of 1500 reflectance spectra (10 [THb] levels, 5 SO2 levels, and 10 different scattering powers with the scattering values equal to 2, 6, or 10 cm2−1 at 600 nm) were simulated with the forward Monte Carlo model using the scattering coefficient generated from the power law. The scattering power was varied from 0.2 to 2 with steps of 0.2. The [THb] were range from 5 to 50 mM in steps of 5. The SO2 levels were range from 0 to 1 with increment of 0.25. Table 4 summarizes the optical properties used for testing the ratiometric analysis with various scattering powers. The [THb] and the SO2 were extracted with the ratiometric analysis for the best ratios determined herein. The absolute [THb] and SO2 errors were computed. In addition, the scattering powers of the clinical data in this manuscript were computed by fitting the Monte Carlo-extracted wavelength-dependent scattering coefficients to the scatter power model.
To compare the computational performance of the ratiometric analysis and the full spectral MC analysis for extraction of [THb] and SO2, 100 diffuse reflectance spectra with randomly selected [THb] and SO2 values were simulated with the forward MC model. Random white noise was also added to each simulated reflectance spectrum before the fitting process. The amplitude of the generated random noise was limited to two percent of the difference between the simulated maximum and the minimum values of each reflectance spectrum. The noise level was determined from a previous study in which the worst SNR of instrument A is 44.58 dB. This means the amplitude of the noise is about two percent of the amplitude of the signal. These spectra were then analyzed using both the inverse full spectral MC analysis and the ratiometric analysis. The ratiometric analyses on these samples used the best ratios, which are described in the subsequent sections of this manuscript, for [THb] and SO2. The extracted [THb] and SO2 values for the full spectral MC analysis and the ratiometric analysis were compared to the expected (input) values and absolute errors were computed. The data processing time for both analyses were also compared.
To test the robustness of the ratiometric analysis in in vivo clinical settings, the ratiometric analysis was applied in three separate studies conducted on three different tissue sites. These clinical studies used diffuse reflectance spectroscopy to differentiate normal versus malignant or precancerous tissues in vivo in the cervix, in the breast, and in the head and neck. The samples from these studies represent different optical absorption scenarios. Head and neck and breast tissues have relatively high [THb] while the cervix has [THb] values at the lower end of the spectrum. The ranges of [THb] from previous results were 2.6-208.9 mM, 0.79-63.7 mM and 0.99-44.06 mM, for the head and neck, breast, and cervical tissues, respectively. In addition, breast tissue contains not only [THb] but also b-carotene as an additional absorber. Data previously collected for the clinical studies and analyzed with the scalable full spectral MC analysis were used to evaluate the ratiometric analysis. The averaged diffuse reflectance spectrum for each site from each study was analyzed with both the inverse full spectral MC analysis and the ratiometric analysis. Pearson correlation coefficients between the full spectral MC and ratiometric analysis extracted [THb] and SO2 values were calculated for each clinical study. In the cervical study, patients referred from the Duke University Medical Center (DUMC) Colposcopy Clinic after abnormal Papanicolaou tests were recruited. A fiber optic probe was used to deliver and collect the diffuse reflectance (350-600 nm) from one to three visually abnormal sites immediately after colposcopic examination of the cervix with the application of 5% acetic acid. This was followed by an optical measurement on a coloposcopically normal site from the same patient. Optical measurements of colposcopically normal and abnormal sites were taken prior to biopsy to avoid confounding absorption due to superficial bleeding. Diffuse reflectance from 76 sites in 38 patients were normalized by a reflectance standard and interpolated prior to calculating the reflectance ratios. Reduced scattering coefficients, [THb] and SO2 were also extracted from the same data using the inverse full spectral MC analysis.
For the head and neck cancer in vivo study, 42 enrolled patients had undergone panendoscopy with biopsy. After the consented patient was under general anesthesia, the optical probe was placed on at least two sites: a clinically suspicious site and a distant normal site with normal mucosa appearance whose location was contralaterally matched to the suspicious site. At least 5 diffuse reflectance spectra were measured for each site. The biopsies were obtained immediately after the probe was removed from the measured clinical suspicious sites. All measurements were calibrated to the reflectance standard measured on the day of the surgery. In this head and neck study, the utility of the physiological and morphological endpoints obtained via the quantitative diffuse reflectance spectroscopy technique was investigated for the classification of head and neck squamous cell carcinoma at the time of staging panendoscopy. Malignant and non-malignant tissues were initially stratified by diagnosis and further classified by anatomical and morphological groupings to determine the most effective approach to discriminate squamous cell carcinoma (SCC) from its benign counterparts.
In the breast cancer study, thirty-five patients undergoing either a modified radical mastectomy or partial mastectomy for invasive and noninvasive breast malignancies were recruited. The surgeon first located the lesion under ultrasound guidance; then, either a 10-gauge or 14-gauge biopsy needle coaxial cannula was guided through a small incision in the skin into the region of interest. A diffuse reflectance measurement (350-600 nm) was collected at a distance of 2 mm past the cannula with a fiber-optic probe after the removal of the needle and residual blood in the field. The optical probe was then retracted, and a biopsy needle was inserted through the cannula and a biopsy sample was removed. This resulted in the removal of a typically 20-mm-long cylinder of tissue, the proximal end of which corresponded to the volume optically measured by the probe. Tissue reflectance spectra from biopsies were normalized by the diffuse reflectance measured from an integrating sphere (Labsphere. Inc. North Sutton. N.H.) at the same day of the surgery for each patient. Biopsy samples were further processed through standard histologic procedures for pathological information.
To compare the classification performances of the full spectral MC and ratiometric analyses, w the area under the receiver operating curves (AUC) calculated from the logistic regression models built were compared based on the optical biomarkers extracted from the two analyses. The AUC may be more representative for the classification performance since the AUC is generated from various cut-off criteria. Since the full spectral MC model is able to extract optical biomarkers rather than just [THb] and SO2, μs′ extracted with the for the full spectral MC model to build the logistic regression model for the cervix, breast and the head and neck groups. Beta-carotene concentrations extracted with the full spectral MC model were also included to build the logistic regression model for the breast group. The extracted [THb], μs′ and the beta-carotene concentrations were log transformed before building the logistic regression model. The p values were computed based on a suitable method for comparing the ROC curves. All logistic regression models and the p values were computed with the SAS software (SAS Institute Inc., Cary, N.C., USA).
The accuracy of the 10 isosbestic wavelength-pairs to extract [THb] was evaluated in both simulated and experimental phantoms. Errors in extracted [THb] for each ratio were calculated. Next, the standard deviation of each ratio for changes in tissue scattering and SO2 was computed using only the simulated data. The 10 ratios were then ranked using both the standard deviations and the errors. The best ratio should be able to accurately extract [THb] with low sensitivity to both tissue scattering and SO2. A total of 25 wavelength-pairs were available for the calculation of SO2. The accuracy of these wavelength-pairs to determine SO2 was also ranked using an identical metric as was used for [THb]. Again, the best ratio should be able to accurately extract SO2 with low sensitivity to tissue scattering.
Correlation coefficients were computed between the optical endpoints extracted using both analyses for each tissue group in each of the three clinical studies. Table 5 below summarizes the Pearson correlation coefficients between the full spectral MC analysis and the ratiometric analysis for [THb] and SO2 of each tissue group in the cervical pre-cancer, head and neck squamous cell carcinoma, and breast cancer studies.
The normal samples in the breast cancer study were further classified into the benign and adipose group, depending on the adipose percentage of the normal sample. The overall correlation coefficient for each study was also computed when all samples in each study were used.
[THb] was extracted using the inverse full spectral MC analysis from a total of 76 samples from 38 patients, as published previously. The samples were classified as normal, low-grade cervical intraepithelial neoplasia (CIN 1) and high-grade cervical intraepithelial neoplasia (CIN 2+).
The combinations of the optical biomarkers used for building the logistic regression models and the area under the receiver operating curve (ROC) are summarized in Table 6 below.
No significant p values were observed when comparing the AUC calculated between the two analyses. Representative ROC curves built based on the optical biomarkers extracted from the lymphoid tissues using the full spectral MC and the ratiometric analyses are also shown in
A simple and fast analysis for quantitative extraction of [THb] and SO2 of tissues is disclosed. The analysis may use a look-up table that allows conversion of the ratio of the diffuse reflectance at two selected wavelengths into [THb] and SO2 values. This ratiometric analysis uses two isosbestic wavelengths for the calculation of [THb] and one isosbestic wavelength along with a wavelength where a local maximum difference in the extinction coefficients of deoxy- and oxy-hemoglobin exists for SO2. A total of 10 wavelength-pairs were tested for extraction of the [THb] while 25 wavelength-pairs were tested for SO2. The wavelength-pairs with the least dependence on tissue scattering were selected through rigorous tests on a total of 24805 spectra. The look-up tables may be used to translate the reflectance ratio into quantitative values were built for specific experimental probe-geometries and theoretically can be extended to any given source-detector configuration. Further, calibration using specific experimental phantoms ensured that the ratiometric analysis could directly be used on experimentally measured data. Once analytical equations for the ratiometric analysis were generated, extraction of [THb] and SO2 values from experimentally measured diffuse reflectance was over 4000 times faster than the scalable inverse full spectral MC analysis with minimal loss in accuracy. Even though the ratiometric analysis is not expected be as accurate as the inverse full spectral MC analysis, the ratiometric analysis achieves similar contrast between malignant and the benign tissues in three different organ sites for a wide range of tissue vascularity and for tissues with multiple absorbers.
A prominent hemoglobin absorption feature (Soret band) occurred around 410-420 nm in the visible spectrum. However, the absorption peaks of hemoglobin were omitted around the 410-420 nm since most silicon-based detectors have lower sensitivities in this region. In order to detect the hemoglobin absorption around 410-420 nm, higher power light sources or more sensitive detectors may be required. In order to leverage relatively low priced light sources, the wavelengths were chosen from 500 nm to 600 nm (visible spectrum) in this example.
The purpose of the bandpass simulations was to understand if the best [THb] or the SO2 ratios would change for the different systems used. Results show that 584/545 and 539/545 are the best ratios for the simulated results with three different bandpass values. Both 584/545 and 539/545 can extract [THb] or SO2 with low errors and both ratios have low sensitivity to scattering. Although different systems might have different bandpasses, the relative rankings of the [THb] ratios and SO2 ratios for error and the sensitivity to scattering remain the same. The clinical data has three different bandpasses. The band passes were 1.5 nm and 1.9 nm for the head and neck and breast data, respectively. The bandpasses were 1.9 nm or 3.5 nm for the cervical data. The extracted data with the ratiometric analysis show good agreement with the full spectral MC extracted values. In addition, the simulated [THb] results in
The sensitivities of the ratiometric analysis to the scattering power were tested since the scattering power is likely to change in the real tissues. As can be seen in
Although the ratiometric analysis was developed by assuming that hemoglobin was the primary absorber in tissue, the experimental measurements on human tissue can be influenced by absorbers other than hemoglobin. However, SO2 and [THb] are the hallmarks of carcinogenesis and represent the features of a growing tumor. This has been published on widely and is useful in diagnostics and therapeutics. For example, neovascularization increases with the development of cancer, and tumor hypoxia occurs as tumors outstrip their blood supply. Thus, being able to measure these endpoints with an optical technology that is optimized for speed and cost will have applications in early detection, diagnostics and response to therapy. Although some tissues may have multiple absorbers in addition to Hb, the classification performances were not significantly affected when using only [THb] and SO2 as parameters (in cervix and head & neck only). Further, optical technologies have a significant potential to have an impact in global health. The ratiometric analysis still worked well in breast tissue, where beta-carotene is a known absorber in the wavelength range used. The presence of beta-carotene may be one reason why a slightly lower correlation coefficients between the ratiometric and full spectral MC analysis was obtained in the breast study, relative to the head and neck study. Overall, in all of the clinical studies, the [THb] extracted from the ratiometric analysis were better correlated to full spectral MC values, in comparison to the SO2 values. The effect of beta-carotene is more obvious in the SO2 estimation than in the [THb] estimation. This may possibly be due to the absorption of beta-carotene being 8.5 times lower in the 550-600 nm compared to 500-550 nm. However, despite the lower correlation for the SO2 estimation in the breast tissues, the ratiometric analysis is still able to preserve the contrast between the malignant and non-malignant breast tissues observed with the results using the full spectral MC analysis.
Herein, it is shown the potential utility of the ratiometric analysis for diffuse reflectance imaging. Since the ratiometric analysis only involves wavelengths at 539, 545 and 584 nm, this analysis can be incorporated into any system with the use of a simple white LED and appropriate bandpass filters as disclosed by the examples provided herein. With appropriate optimization for wavelength and illumination and collection geometries, the ratiometric analysis might be applied to a variety of spectral imaging systems. For example, this analysis can be incorporated into previously developed fiber-less technology, where a Xenon lamp and light filters are used to illuminate the tissue at different wavelengths of light. The illumination light was delivered through free space with a quartz light delivery tube. A custom photodiode array is in contact with the tissue to directly measure diffuse reflectance from a large area of tissue. With proper modifications of this system and combined with the ratiometric analysis, real-time [THb] and SO2 imaging is possible.
A rapid analytical ratiometric analysis for determining [THb] and SO2 in head and neck, cervical, and breast tissues was presented. This analysis is non-invasive, label-free, quantitative, and fast. The ratiometric analysis requires the diffuse reflectance only from three selected wavelengths to calculate both [THb] and SO2. Thus, the system design can be simple, portable, and potentially useful for global health applications. The fast computation speed allows near real-time [THb] and SO2 mapping of tissue. This can provide important physiological information for many clinical applications, from cancer screening to diagnostics to treatment.
The present disclosure may be a system, a method, and/or a computer program product. The computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for causing a processor to carry out aspects of the present disclosure.
The computer readable storage medium can be a tangible device that can retain and store instructions for use by an instruction execution device. The computer readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing. A non-exhaustive list of more specific examples of the computer readable storage medium includes the following: a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon, and any suitable combination of the foregoing. A computer readable storage medium, as used herein, is not to be construed as being transitory signals per se, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission media (e.g., light pulses passing through a fiber-optic cable), or electrical signals transmitted through a wire.
Computer readable program instructions described herein can be downloaded to respective computing/processing devices from a computer readable storage medium or to an external computer or external storage device via a network, for example, the Internet, a local area network, a wide area network and/or a wireless network. The network may comprise copper transmission cables, optical transmission fibers, wireless transmission, routers, firewalls, switches, gateway computers and/or edge servers. A network adapter card or network interface in each computing/processing device receives computer readable program instructions from the network and forwards the computer readable program instructions for storage in a computer readable storage medium within the respective computing/processing device.
Computer readable program instructions for carrying out operations of the present disclosure may be assembler instructions, instruction-set-architecture (ISA) instructions, machine instructions, machine dependent instructions, microcode, firmware instructions, state-setting data, or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like, and conventional procedural programming languages, such as the “C” programming language or similar programming languages. The computer readable program instructions may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider). In some embodiments, electronic circuitry including, for example, programmable logic circuitry, field-programmable gate arrays (FPGA), or programmable logic arrays (PLA) may execute the computer readable program instructions by utilizing state information of the computer readable program instructions to personalize the electronic circuitry, in order to perform aspects of the present disclosure.
Aspects of the present disclosure are described herein with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the disclosure. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer readable program instructions.
These computer readable program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks. These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.
The computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.
The flowchart and block diagrams in the Figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present disclosure. In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s). In some alternative implementations, the functions noted in the block may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of the present disclosure has been presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the present disclosure in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the present disclosure. The embodiment was chosen and described in order to best explain the principles of the present disclosure and the practical application, and to enable others of ordinary skill in the art to understand the present disclosure for various embodiments with various modifications as are suited to the particular use contemplated.
The descriptions of the various embodiments of the present disclosure have been presented for purposes of illustration, but are not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein was chosen to best explain the principles of the embodiments, the practical application or technical improvement over technologies found in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
This application is a 35 USC 371 application of International PCT Patent Application No. PCT/US2014/067038, filed on Nov. 24, 2014 and titled COLPOSCOPES HAVING LIGHT EMITTERS AND IMAGE CAPTURE DEVICES AND ASSOCIATED METHODS, which claims the benefit of and priority to U.S. Provisional Patent Application No. 61/907,474, filed Nov. 22, 2013 and titled SYSTEMS AND METHODS FOR DETERMINING OXYGEN SATURATION AND VASCULARITY, and U.S. Provisional Patent Application No. 61/907,442, filed Nov. 22, 2013 and titled TRANS-VAGINAL DIGITAL COLPOSCOPE AND METHODS OF USE; the disclosures of which are incorporated herein by reference in their entireties.
This invention was made with government support under grant numbers 1R21CA162747-01 entitled “Smart Optical Sensor for Detection of Cervical Cancer in the Developing World” and 5R01EB011574-03 entitled “A Novel Optical Spectral Imaging System for Rapid Imaging of Breast Cancer,” both awarded by the National Institute of Health (NIH). Accordingly, the government may have certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2014/067038 | 11/24/2014 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61907442 | Nov 2013 | US | |
| 61907474 | Nov 2013 | US |
