WO2023163720A1

WO2023163720A1 - Handheld breast cancer probe and bioimpedance detection method

Info

Publication number: WO2023163720A1
Application number: PCT/US2022/018129
Authority: WO
Inventors: Harvey Wayne KO
Original assignee: Ko Harvey Wayne
Priority date: 2022-02-28
Filing date: 2022-02-28
Publication date: 2023-08-31

Abstract

A noninvasive handheld probe for breast cancer detection has an elongated housing with a sensor head at one end and microelectronics mounted within the housing. The microelectronics include a Colpitts oscillator module. A ferrite coil sensor is mounted within the sensor head. The sensor includes a ferrite core wrapped in a multi-turn coil. The coil generates a primary magnetic field and receives a secondary magnetic field generated by the electrical conductivity of biological tissue. The Colpitts oscillator detects a voltage change. The small, low-power probe is simple to use and does not require skin penetration nor skin contact by electric voltage probes. It detects the suspected presence of a breast tumor which has a larger electrical conductivity than normal breast tissue.

Description

HANDHELD BREAST CANCER PROBE AND BIOIMPEDANCE DETECTION METHOD

BACKGROUND OF THE INVENTION

The present invention relates to breast cancer detection and, more particularly, to a handheld bioimpedance probe and breast cancer detection method.

Breast cancer is the second leading medical cause of death for women in the United States (US). Approximately 250,000 new cases of invasive breast cancer are documented each year. Early detection, diagnosis, and treatment are sought especially for those aged 15 to 39 years old because these people have “dense” breasts that render normal mammography less useful. The currently available diagnosis and procedures range from private self-examination to complex, uncomfortable (and often painful) imaging facilities [e.g., magnetic resonance imaging (MRI), computer-aided tomography (CT), and positron emission tomography (PET)] and biopsy. CT scanning often requires the painful compression of the breasts that not only distorts breast geometry but also blurs or hides microcalcification returns. Newer exploratory laboratory methods now employ several investigators, expensive and complex equipment, patient tables with breast fitting contact “wells” (into which the woman must try to insert her breasts while lying face down on a device table), and new, less understood signal processing. For example, Raman spectroscopy, Electric Impedance Spectroscopy (EIS), and Electric Impedance Tomography (EIT) are on the horizon for expensive and detailed diagnostics. Each method shows potential diagnostic benefits along with specific uncertainties that dictate the tumor identification and subsequent treatment for each individual. For example, almost all the EIT/EIS methods require excellent electrical contact with the breast and contain errors due to imperfect contact, electrical voltages, and circuitous electrical currents due to perspiration. Furthermore, EIT/EIS methods often require multiple signal sites to obtain tomographic images that might be compared to MRI or CT images.

So far, the common breast tumor types are characterized/defined with respect to whether the cancer has spread or not. Ductal Carcinoma In Situ (DCIS) refers to a cancer starting in a milk duct that has not grown/spread to other breast tissue (i.e. not invasive or pre-invasive). About 20% of new breast cancers are DCIS, and nearly all can be cured if discovered early. All women with DCIS are treated because it is unknown whether/how DCIS becomes invasive. Invasive/lnfiltrating Lobular Carcinoma (ILC) is an invasive/infiltrating cancer that spreads to surrounding breast tissue. Invasive/lnfiltrating Ductal Carcinoma (IDC) represents about 70% to 80% of all breast cancers. Metastatic breast cancer (also called Stage IV) refers to breast cancer that has spread to another part of the body.

As can be seen, there is a need for a reliable, inexpensive, and comfortable breast cancer detection device, especially one that can be used easily at home for early warning.

Recent discoveries have shown that high electrical conductivity of a malignant breast tumor is linked to cell necrosis, and the conductivity of calcium and complex calcium hydroxyapatite (CHA), a chemical mineral compound related to both, is amenable to measurement.

CHA formation is strictly associated with malignant lesions, whereas the amber-colored calcium oxalate (often called Type II) has much smaller electrical conductivity and is mainly reported in benign lesions. Researchers elsewhere have discovered a possible linkage between calcium hydroxyapatite and breast cancer (BC) bioimpedance. Gittings, J.P., et al (2009). “Electrical Characterization of Hydroxyapatite-based Receptors.” Acta Biomaterialia, 5, 743-754 describes the electrical conductivity of a component of CHA, hydroxyapatite (HA), as quite high with a value of almost 0.1 Siemens/meter (1.0 milliSiemens/cm) at frequencies as high as 10 MHz. Gittings, however, explores the use of HA for the development of porous ceramic compounds in bone grafting and is unrelated to breast cancer. Calcium, the other component of CHA, also has a high conductivity (almost as high as aluminum) of 300 mS/cm.

Measurements at the radio frequencies of 10kHz and 10MHz with invasive electrodes have yielded the breast cancer malignant tumor electrical conductivity values between 3.98 and 7.24 mS/cm, (see Ain, K., et al (2017). “Modeling of electrical impedance to detect breast cancer by finite volume methods.” IOP Conference Series, Journal of Physics: Conference Series, 853) which are consistent with the high metastatic prostate tumor values (approximately 3 mS/cm at 2.1 MHz) measured with a biomagnetic noninvasive probe by the applicant [see Smith, D., Ko, H. W., et al (2000). “In vivo measurement of tumor conductivities with the bioimpedance method.” IEEE Transactions on Biomedical Engineering, 47 with a bioimpedance sensor invented by applicant (Guo, Y., Ko, H. W. (1998). “3D Localization of Buried Objects by Nearfield Electromagnetic Holography.” Geophysics, 63, 880-889]. Applicant’s prostate cancer sensor has been difficult to bring to practice because the prostate tumor impedance/conductivity is embedded within the blood-filled normal prostate tissue, thereby making the tumor contrast- call/discrimination difficult. The conductivity of blood is also frequency-dependent and might mask tumor conductivities in certain frequency regimes (Schwan, H.P. (1983). “Electrical properties of blood and its constituents: alternating current spectroscopy.” Blut, 46; Abdalla, S., et al (2010). “Electrical properties with relaxation through human blood.” Biomicrofluidics, 4.)

However, Ain also gave conductivity measurements of the non-malignant tissue (fat) of about 0.2 mS/cm which makes the tumor-to-healthy-tissue ratio (i.e., S/N ratio) contrast robust enough to declare the potential tumor presence. Other investigators have reported similar malignant lobular (ILC) and malignant ductal (IDC) conductivity values and contrast with healthy tissue at radio and microwave frequencies using electric field measurements.

Other than applicant’s own 1999-2000 work, no such cancer tumor results use a noninvasive electromagnetic induction method using magnetic coils. [See Smith, D., Ko, H. W., et al (2000). “In vivo measurement of tumor conductivities with the bioimpedance method.” IEEE Transactions on Biomedical Engineering, 47.] Consistent with breast cancer efforts dating back to 1926 and with standard bioelectrical engineering investigations with electric (E) field electrodes, several reports of modern measurements for the electrical conductivities of breast tumor and surrounding non-cancerous tissue, using invasive E field electrodes, form a basis for measurements and sensor developments described herein using the noninvasive magnetic (H) field probe.

The geometry/location of the breast lobule/duct complex relative to and adjacent to breast fat makes the potential tumor identification even more promising.

Additional research investigations [e.g., Torti, F., et al; “Iron regulating protein (ferroportin) is strong predictor of breast cancer prognosis, study shows”, Wake Forrest Univ. Sci. News, 10 Aug 2010; Orlandi, R., et al, "Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer”, Annals of Oncology, 25, 352-357, 2014] cite the increased presence of iron-based proteins (e.g., ferritin, ferroportin) and associated regulators of iron transmembrane processes (e.g., hepcidin) in breast tumor tissue. The electrical conductivity of these substances may also be contributors to the reported increase of electrical conductivity in breast tumors and would add to the efficacy of applicant’s biomagnetic approach because of the intrinsic iron content in ferritin and ferroportin.

SUMMARY OF THE INVENTION

In one aspect of the present invention, a noninvasive handheld probe for breast cancer detection is provided, comprising: an elongated housing having a sensor head at a first end; a ferrite coil sensor mounted within the sensor head, said ferrite coil sensor (i.e., antenna) comprising a ferrite core wrapped in a multi-turn coil; and microelectronics mounted within the elongated housing including a Colpitts oscillator module electrically communicating with the multi-turn coil; wherein the ferrite coil sensor is operative to generate a primary magnetic field and to receive a secondary magnetic field generated by electrical conductivity of biological tissue, and the Colpitts oscillator module is operative to detect a voltage change due to the secondary magnetic field.

In another aspect of the present invention a method of detecting breast cancer is provided, comprising: providing a noninvasive handheld probe comprising a ferrite coil sensor and microelectronics mounted within a housing, having a conductivity indicator; projecting an electromagnetic field from the noninvasive handheld probe at a frequency between about 10 kilohertz and about 10 Megahertz through a subject’s skin and into the subject’s breast tissue; moving the noninvasive handheld probe in a search pattern across the subject’s skin while observing the conductivity indicator; and documenting a location of the subject’s breast tissue where the conductivity indicator indicates a conductivity consistent with breast tumor values using the hydroxyapatite phantom.

These and other features, aspects and advantages of the present invention will become better understood with reference to the following drawings, description, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a breast cancer probe according to an embodiment of the present invention, shown in use;

FIG. 2 is a perspective view of a ferrite core sensor coil according to an embodiment of the present invention;

FIG. 3 is a side elevation view of a ferrite core sensor coil according to an alternate embodiment of the present invention;

FIG. 4 is a perspective view of a coil configuration for gradiometer measurements according to an embodiment of the present invention; FIG. 5 is a perspective view of a coil configuration for gradiometer measurements according to an alternate embodiment of the present invention;

FIG. 6 is a side elevation view of a breast cancer probe according to another embodiment of the present invention, shown in use;

FIG. 7 is a schematic view of microelectronics embedded therein; and

FIG. 8 is schematic view of the probe of FIG. 1 wirelessly coupled with a three-dimensional holographic visual display device according to an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is of the best currently contemplated modes of carrying out exemplary embodiments of the invention. The description is not to be taken in a limiting sense but is made merely for the purpose of illustrating the general principles of the invention, since the scope of the invention is best defined by the appended claims.

Broadly, an embodiment of the present invention is a hand-held breast cancer sensor probe.

The probe provides a local/focal benefit by early alerting those, typically those under age 40 with dense breasts, of a potential for breast tumors. Its small, low-power, simple use negates the need for large, complex electronics/tables/gantries and technician support needed by electronic impedance topography (EIT), electronic impedance spectroscopy (EIS), or other clinical mammography methods. The present invention detects a suspected presence of calcium hydroxyapatite (CHA) by way of emitting magnetic fields and measuring a conductivity of the breast. A breast tumor with CHA has a larger electrical conductivity than normal breast tissue without CHA. Hence, measuring the electrical conductivity of the breast indicates a presence or absence of a breast tumor. Since skin contact is not necessary (as it is in bioelectric methods such as EIT) the inventive noninvasive, biomagnetic device may be used with a thin blouse or shirt for modesty.

The present noninvasive invention does not require skin penetration nor skin contact by electric voltage probes. Therefore, the probe may freely move from site-to-site without adjustment and problems with skin potentials.

The probe comprises one or more ferrite coil sensors and an oscillator. The ferrite coil sensors may be a ferrite core wrapped in a multi turn coil. The ferrite core squeezes and concentrates magnetic field lines generated by the device into a stronger, deeper pattern. The probe may use a large number of miniature ferrite core coils in its array.

As the breast cancer sensor probe is manually moved across the breast, it may just barely touch the skin. In some embodiments, two ferrite coil sensors may be alternately sampled while electronically connected to a Colpitts-type oscillator. This activity may be directed by a microprocessor embedded in the hand probe. The “sampling” process includes energizing a sensor while the other sensor is dormant. The sampling projects a focused alternating current (AC) magnetic field from the energized sensor into breast tissue. In some cases, the two sensor outputs are simultaneously entered into a differential op-amp circuit and the dormant sensor receives the magnetic field. In other cases, the two sensors are alternatively switched and chosen as separately energized. Each signal is entered into an onboard microprocessor that performs differencing. In both cases, this gradiometer technique is well known in treasure hunting instruments using dual coils in a “double- D” configuration.

Without being bound by theory, electromagnetic eddy currents, induced in a biological sample in proportion to the sample’s electrical conductivity, manufacture a secondary magnetic field by Lenz’s law that affects the mutual impedance between the projected and secondary magnetic fields (i.e., a virtual electrical transformer). This change may be sensed by Colpitts coil oscillator electronics to provide a measure of the sample’s electrical conductivity. More sophisticated electronics, such as an impedance analyzer, may provide the phase angle and permittivity of the sample at each impressed frequency. [See Ko, H. W., Hansen, J. S., Hart, L. W. (1986). “The APL Bioelectromagnetics Laboratory.” Johns Hopkins Applied Physics Laboratory Technical Digest, 7, 300-307. Hart, L. W., Ko, H. W., Meyer, J. Vasholtz, D., Joseph, R (1998). “A noninvasive electromagnetic conductivity sensor for biomedical applications.” IEEE Transactions on Biomedical Engineering, 35; Guo, Y., Ko, H. W. (1998). “3D Localization of Buried Objects by Nearfield Electromagnetic Holography.” Geophysics, 63, 880-889.]

Simultaneous to the projection of the magnetic field by the energized sensor, a change in the Colpitts oscillator voltage occurs due to a change in mutual inductance between the transmitted magnetic field and the received induced or secondary magnetic field. This resultant voltage change is directly proportional to the electrical conductivity of the breast tissue eradiated. A measurement of the change in this voltage may alert a user of a cancerous tumor.

The probe may operate at frequencies between about 10 kHz (kiloHertz) and about 10MHz (MegaHertz), a region of the electromagnetic spectrum which is deemed safe (e.g., radiofrequencies). This safe frequency range has been chosen as consistent with applicant’s published experience (a) with electromagnetic field induction detection in biological tissue such as prostate tumor, and (b) the low electromagnetic background interference during actual in-vivo magnetic bioimpedance tests.

Since background signals from adjacent healthy tissue can mask the higher conductivity tumor signal, two coils relatively close to each other in a single sensor head may be used with dual input amplification, e.g., of the differential operational amplifier variety. As the sensor head is moved around in a search pattern, the second coil provides similar information to the first coil at a small spatial distance away. In other words, when one coil senses the tumor signal T, in the presence of background tissue and electronics noise, N, (i.e., T+N), simultaneously the other coil, not in the presence of the tumor, measures just N. Then the difference of the two sensor readings gives (T+N) - N = T. This configuration is called a gradiometer, and the method is called gradiometry. [See Ko, H. W., Hansen, J. S., Hart, L. W. (1986). “The APL Bioelectromagnetics Laboratory.” Johns Hopkins Applied Physics Laboratory Technical Digest, 7, 300-307, incorporated herein by reference.] Gradiometry enables the device to subtract the “noise” due to the intrinsic Colpitts oscillator signal and conductivity presented by adjacent (but not cancerous) breast tissue. This gradiometer differencing may be accomplished with the use of differential op-amp circuitry, or alternatively, by an algorithm embedded in an onboard microprocessor. The two gradiometer coils may be separated or may be positioned next to each other in the well-known “double D” configuration to save sensor space.

In some embodiments, an electromagnetic field may be projected into a biological sample with the use of a simple Colpitts oscillator and a single coil which serves as both the transmitter and receiver of the electromagnetic field. An oscilloscope voltage and signal spectrum measurement result of just the Colpitts oscillator without a target may be considered a background electronics signal. This background signal may be compared to a target signal to increase accuracy of the system.

As the probe is moved in a search pattern, an audible tone may sound, responsive to the voltage/conductivity gradient provided by the two adjacent coils. When a larger than “normal” (i.e., approximately 0.2 mS/cm) conductivity is detected, a light-emitting diode (LED) lamp may flash, the alarmed location may be marked or noted, and medical professionals may be notified.

Metastatic breast cancer (also called Stage IV) may be rapidly detected by the present invention if the electrical conductivity of metastatic sites (e.g., lymph nodes, organs) is larger than normal and distinguishable from the large electrical conductivity of nearby normal tissue (e.g., with large blood volumes).

The inventive probe has been demonstrated by applicant in tumor phantom testing to detect a silicon-based calibrated wafer of 6 to 8 mS/cm as a calibrated stand in for tumors. Similarly, over-the-counter pharmaceutical CHA samples of several concentrations with butter fat has been used by applicant to organically stand in for tumors in testing the system. In addition, the invention may be shown effective by measurements on breast tumor tissue excised from women and sold commercially for research (i.e., ex-vivo.) (Silicon wafers provided by NOVA Semiconductor Wafers, 1 189 Porter Rd., Flower Mound, TX 76022.)

In some embodiments, a sensor system connected to a computer may provide a three-dimensional (3D) display of the breast tumor detected using the inventive probe. [See Guo, Y., Ko, H. W. (1998). “3D Localization of Buried Objects by Nearfield Electromagnetic Holography.” Geophysics, 63, 880-889 and Smith, D., Ko, H. W. (1998). “Electromagnetic Holographic Imaging of Bioimpedance”; SPIE, 3253, 188-190 for the math-physics explanation with experimental proof, and US Patent No. 7,283,868 to Ko for an experimental protocol.]

Referring to Figures 1 through 8, Figure 1 illustrates a breast cancer probe 10 according to an embodiment of the present invention, comprising a handheld housing 12, a sensor end 14, an indicator light 16 such as an LED, and a conductivity display screen 18. The sensor may be used for self-examination or examination by a health-care provider as shown in Figure 1 , with a user 11 A holding the handheld housing 12 such that the sensor end 14 of a ferrite core sensor unit 20 is juxtaposed with a breast 11 B. The indicator light 16 notifies the user 11 A when a change in voltage indicates an invasive tumor 11C. An audible tone may be emitted simultaneously. A display screen 18 displays the conductivity value.

Figures 2 and 3 illustrate different embodiments of a ferrite core sensor unit 20 core 22. The core 22 may have a flat end 26A or a tapered end 26B. The core 22 is wrapped in a multi-turn coil 24. When excited by an alternating current from an oscillator-based driver circuit (see Figure 7), the coil 24 generates a nonionizing alternating magnetic field concentrated around the core 22 that induces electrical eddy currents in the breast 11 B. The eddy currents then produce a secondary magnetic field that has the effect of changing the mutual inductance between the tissue and the coil that applied the initial magnetic field. The amplitude of the secondary magnetic field is proportional to the conductivity of the tissue. The change in mutual inductance causes a change in voltage across the oscillator circuit.

Figures 4 and 5 depict alternate core configurations 22, 32 of a gradiometer according to an embodiment of the present invention, with two ferrite core sensor units 20 or a single core 30 with two sensor ends 36 relatively close to each other in a sensor head 13, as shown in Figure 6. The core or cores 22, 32 are wrapped in multi-turn coils 24, 34 proximate to the core ends 26B, 36. In Figure 5, each end 36 of the core 32 acts as a separate core sensor unit 15.

Figure 6 is a side elevation view of the probe housing 12 with two core sensor units 14A in the sensor head 13 according to an embodiment of the present invention. Microelectronics 42, shown in Figure 7, are housed within the housing 12. The probe also features an on/off switch 38 and a USB power charging port 40. The indicator light 16 flashes when the core sensor units 14A detect an invasive tumor 11C within surrounding tissue 11 D, i.e., when the core sensor units 14A detect a difference in tissue conductivity.

Figure 7 is a schematic illustrating the microelectronics housed within the housing 12, including a sensor coil selection switch 44, a Colpitts Oscillator complex 46, and a microprocessor 48 which calibrates the coil(s), analyzes the data, stores and retrieves data, and operates the digital display 18, an audible tone generator 17, and the LED 16. The coil selection switch 44 enables the sensor to function in a number of modes, including using a single coil, alternating use of two coils, and using two coils simultaneously.

Figure 8 illustrates use of a device 50, such as a tablet computer, to render a visual 3D image of an invasive tumor 11C detected by the probe 12 on a display 52. The device 50 may be a television, a desktop or laptop computer, or any other device with a display 52.

It should be understood, of course, that the foregoing relates to exemplary embodiments of the invention and that modifications may be made without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

What is claimed is:

1 . A noninvasive handheld probe for breast cancer detection, comprising: an elongated housing having a sensor head at a first end; a ferrite coil sensor mounted within the sensor head, said ferrite coil sensor comprising a ferrite core wrapped in a multi-turn coil; and microelectronics mounted within the elongated housing including a Colpitts oscillator module electrically communicating with the multi-turn coil; wherein the ferrite coil sensor is operative to generate a primary magnetic field and to receive a secondary magnetic field generated by electrical conductivity of biological tissue, and the Colpitts oscillator module is operative to detect a voltage change due to the secondary magnetic field.

2. The noninvasive handheld probe of claim 1 , further comprising an indicator light operative to flash when the voltage change is consistent with the electrical conductivity of a tumor in the biological tissue.

3. The noninvasive handheld probe of claim 1 , wherein the ferrite core is characterized by a flat sensor end, a round sensor end, or a tapered sensor end.

4. The noninvasive handheld probe of claim 1 , wherein the microelectronics further comprises an impedance analyzer electrically communicating with an imbedded microprocessor with memory operative to catalogue historical bioimpedance values and to display bioimpedance images for medical diagnosis.

5. The noninvasive handheld probe of claim 1 , further comprising a speaker mounted within the housing, electrically communicating with the microelectronics, and operative to emit an audible alarm.

6. The noninvasive handheld probe of claim 1 , further comprising a digital display screen mounted in a sidewall of the elongated housing and electrically communicating with the microelectronics.

7. The noninvasive handheld probe of claim 1 , further comprising a monitor wirelessly coupled with the noninvasive handheld probe and operative to generate a three-dimensional display of conductivity variations.

8. The noninvasive handheld probe of claim 1 , wherein the ferrite core sensor operates at a frequency between about 10 kilohertz and about 10 Megahertz.

9. The noninvasive handheld probe of claim 1 , wherein the ferrite coil sensor comprises at least two gradiometer coils.

10. The noninvasive handheld probe of claim 9, further comprising a sensor coil selection switch.

1 1 .The noninvasive handheld probe of claim 9, wherein the ferrite coil sensor comprises two ferrite cores, each wrapped with one of the two gradiometer coils.

12. The noninvasive handheld probe of claim 9, wherein the ferrite coil sensor comprises one C-shaped ferrite core with adjacent ends. The noninvasive handheld probe of claim 9, wherein the microelectronics further comprise a differential operational amplifier. The noninvasive handheld probe of claim 9, wherein the microelectronics further comprise a microprocessor with an embedded algorithm operative to evaluate voltage differences between the two gradiometer coils. A method of detecting breast cancer, comprising: providing a noninvasive handheld probe comprising a ferrite coil sensor and microelectronics mounted within a housing, having a conductivity indicator; projecting an electromagnetic field from the noninvasive handheld probe at a frequency between about 10 kilohertz and about 10 Megahertz through a subject’s skin and into the subject’s breast tissue; moving the noninvasive handheld probe in a search pattern across the subject’s skin while observing the conductivity indicator; and documenting a location of the subject’s breast tissue where the conductivity indicator indicates a conductivity consistent with hydroxyapatite. The method of claim 15, further comprising a step of determining a background signal by projecting an electromagnetic field into an ambient environment or into a calibrated semiconductor wafer prior to projecting the electromagnetic field into the breast tissue. The method of claim 15, wherein the ferrite coil sensor comprises two coils, the microelectronics comprises dual input amplification, and the conductivity indicator further indicates variation in conductivity of the breast tissue by calculating a difference in voltage change between the two coils. The method of claim 17, wherein the microelectronics further comprise a Colpitts oscillator and a microprocessor operative to alternately energize the two coils.