EP4658177A1

EP4658177A1 - Cervical elastography system and methods

Info

Publication number: EP4658177A1
Application number: EP24710916.8A
Authority: EP
Inventors: Peng Hu; Methodius Tuuli; Peinan Zhao; Lihong Wang; Molly Stout
Original assignee: California Institute of Technology; University of Michigan System; Washington University in St Louis WUSTL; Women and Infants Hospital of Rhode Island; University of Michigan Ann Arbor
Current assignee: California Institute of Technology; University of Michigan System; Washington University in St Louis WUSTL; Women and Infants Hospital of Rhode Island; University of Michigan Ann Arbor
Priority date: 2023-01-31
Filing date: 2024-01-30
Publication date: 2025-12-10
Also published as: WO2024163391A1

Abstract

A cervical elastography system includes an ultrasound imaging system including an ultrasound probe having at least one pressure sensor, a stress calibration system coupled to the ultrasound probe, and a computing device communicatively coupled to the ultrasound imaging system and the stress calibration system. The computing device has a memory, at least one processor, and a module stored in the memory of the computing device and executable by the at least one processor of the computing device to: (1) receive continuously acquired B-mode images of cervix tissue from the ultrasound imaging system; (2) calculate strain on the tissue from the continuously acquired B-mode images; and (3) compute an elasticity of the tissue based on a simultaneous assessment of the actual stress applied to the tissue by the ultrasound probe and the calculated strain on the tissue caused by the stress applied.

Description

Cervical Elastography System and Methods

Cross-Reference to Related Applications

[0001] This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63/482,511 , filed January 31 , 2023, which is hereby incorporated by reference in its entirety.

Field of the Disclosure

[0002] This disclosure relates generally to cervical elastography systems and, more specifically, cervical elastography system and methods configured to compute an elasticity of a cervix tissue based on actual stress applied to the cervix tissue via an ultrasound probe and calculated strain on the cervix tissue caused by the stress applied.

Background of the Disclosure

[0003] Two commonly used methods to quantify cervical elasticity are strain elastography and shear wave elastography, yet both methods have drawbacks. Strain elastography is effective in showing tissue elasticity distribution in a single image. However, due to the lack of stress information, strain elastography is inappropriate for longitudinal research, for which values from different imaging sessions need to be compared. Shear wave elastography is effective in measuring shear wave speed (e.g., an intrinsic tissue property correlated with elasticity) in relatively homogeneous tissue, such as in liver. For inhomogeneous tissue in cervix, the shear wave speed measurement is less robust. Moreover, strong ultrasound at shear wave excitation point poses potential risks to fetuses when cervixes of pregnant women are measured.

[0004] Currently, preterm birth (defined as delivery <37 weeks of gestation) is the most significant cause of neonatal morbidity and mortality with significant costs to families and society. One of the biggest challenges in improving clinical management of preterm birth is the lack of clinically useful tools to accurately predict who will, and who will not, deliver preterm. Most patients who deliver preterm do so without antecedent identifiable clinical risk factors. Because the risks of prematurity to a neonate are so significant, maternal hospitalization in patients with preterm labor symptoms accounts for 1/3 of antepartum hospitalizations. Yet, more than half of women hospitalized with threatened preterm labor go on to deliver at term. Thus, there is a significant clinical need to develop novel, clinically useful tools to determine the risk more accurately for premature delivery. In addition, the current understanding of known risk factors for preterm birth miss the majority of patients who are at risk for it and have poor positive predictive value. Because known preventive interventions (such as progesterone supplementation and cervical stitch) are often tested in heterogenous cohorts, they result in conflicting effects and unclear clinical translation, and inhibit new prevention opportunities from being realized. A critical first step in reducing preterm birth is improving detection of those most at risk. To date, exact quantification of cervical remodeling ahead of preterm birth has not been possible.

[0005] Cervical ripening is the process by which the connective tissue of the cervix undergoes changes to soften, shortens, and dilates to allow passage of the fetus. Cervical ripening is a necessary step ahead of cervical dilation and delivery. Although manual palpation (example: the Bishop score) has been used to estimate elasticity of the cervix tissue, its predictive utility for preterm birth is limited. A method to accurately quantify cervical elasticity is required for understanding and monitoring of cervical ripening for preterm birth prediction.

[0006] For a reliable estimation of tissue elasticity, an imaging technique can be utilized. Ultrasound elastography is commonly used to quantify tissue elasticity due to its wide availability at bedside and relatively low cost. Most ultrasound elastography techniques are based on one of two principles. In one principle, a stress is applied to tissue and the tissue strain is quantified from ultrasound images. Then the stress and strain are mathematically related to estimate the tissue’s Young’s modulus. In another principle, shear waves are generated inside tissue and their propagation speeds are measured through ultrafast ultrasound imaging. Both Young’s modulus and shear wave speed are intrinsic properties of tissue that can be used to represent tissue elasticity.

[0007] A strain elastography is commercially available and clinically used to measure tissue elasticity in medical situations such as breast, prostate, liver, and thyroid imaging where identification of regional differences in tissue elasticity are clinically useful. However, this methodology is semi-quantitative, demonstrating relative elasticity in adjacent tissue areas, making it not useful for repeated measurements overtime in the same patient or comparison from patient to patient, thus limiting its utility in cervical ripening evaluation and preterm birth prediction. For longitudinal analysis of cervical elasticity, techniques measuring intrinsic tissue elasticity (such as Young’s modulus or shear wave speed) of cervix are required.

[0008] Shear wave elastography, based on the shear wave principle, has been used to quantify tissue elasticity in breast, prostate, liver, and thyroid. Measuring shear wave speed, an intrinsic tissue property, shear wave elastography allows for longitudinal analysis of tissue elasticity. Although, shear wave elastography has been applied to cervix, the applications have limitations. First, due to acoustic attenuation, the excitation wave must be strong enough so that the generated shear wave can be detected at a point of interest, allowing for shear wave speed estimation. The strong acoustic wave causes strong force and large displacement to tissue at excitation point, which may pose risks to fetuses when cervices are measured during pregnancy. Second, shear wave speed is stress dependent. In shear wave elastography, good contact is necessary for obtaining high quality images to monitor shear wave propagation. To achieve good contact, an initial stress needs to be applied to cervix, which is often operator, patient, and imaging site dependent. Thus, a case dependent variation is introduced to shear wave speed measurement. Third, the shear wave propagation model and its corresponding attenuation model are based on homogeneous medium assumption. This assumption is reliable for liver, but tends to be problematic for more complicated structures, such as cervix, reducing the robustness in measurement of cervical shear wave speed. In addition to these three fundamental issues, data standardization remains a significant technical issue in largescale applications. System settings and parameters can produce biased results if not standardized across patient groups and time points in longitudinal applications. Moreover, results of cervical shear wave elastography are displayed differently as shear wave speed or Young’s modulus (transferred from shear wave speed) in commercialized systems, which may have limitations in accessing the data of interest. Differences in system parameters and data accessibilities impose difficulties in comparing results from different systems.

Summary of the Disclosure

[0009] According to one aspect of the present disclosure, a cervical elastography system comprises a transvaginal ultrasound imaging system including an ultrasound probe having at least one pressure sensor configured to measure real time in vivo pressure applied to tissue and a sleeve configured to be disposed over the at least one pressure sensor. In addition, a stress calibration system is coupled to the ultrasound probe and configured to receive a measured pressure value from the at least one pressure sensor and to determine actual stress applied to the tissue. Further, a computing device is communicatively coupled to the ultrasound imaging system and the stress calibration system. The computing device has a memory, at least one processor, and a module stored in the memory of the computing device and executable by the at least one processor of the computing device to: (1) receive continuously acquired B-mode images of the tissue from the ultrasound imaging system; (2) calculate strain on the tissue from the continuously acquired B-mode images in real time; and (3) compute an elasticity of the tissue based on a simultaneous assessment of the actual stress applied to the tissue by the ultrasound probe and the calculated strain on the tissue caused by the stress applied, such as in real time. [0010] According to another aspect of the present disclosure, a cervical elastography system comprises a transvagina! ultrasound imaging system including an ultrasound probe having at least one pressure sensor configured to measure real time in vivo pressure applied to tissue and a stress calibration system. The stress calibration system is coupled to the ultrasound probe and configured to receive a measured pressure value from the at least one pressure sensor and to determine actual stress applied to the tissue. In addition, the stress calibration system comprises one of: (1 ) a load cell, a load cell amplifier, and a microcontroller board, such that the ultrasound probe is pressed against the load cell for calibration, and a layer of rubber is disposed on the load cell, the ultrasound probe configured to contact the layer of rubber; or (2) a base having a plate holder rotatably coupled to the base, the plate holder configured to receive a weight used to determine a calibration point. Further, a computing device is communicatively coupled to the ultrasound imaging system and the stress calibration system. The computing device has a memory, at least one processor, and a module stored in the memory of the computing device and is executable by the at least one processor of the computing device to: (1 ) receive continuously acquired B-mode images of the tissue from the ultrasound imaging system; (2) calculate strain on the tissue from the continuously acquired B-mode images in real time; and (3) compute an elasticity of the tissue based on a simultaneous assessment of the actual stress applied to the tissue by the ultrasound probe and the calculated strain on the tissue caused by the stress applied.

[0011] According to yet another aspect of the present disclosure, a computer-implemented method for automatically extracting strain from continuously acquired B-mode images of an ultrasound system of a cervical elastography system comprises identifying a boundary of a cervix tissue in a B-mode image received from an ultrasound probe of an ultrasound imaging system and tracking at least two subsequent depths of the cervix tissue different from the boundary of the cervix tissue in subsequently obtained B-mode images of the cervix tissue. The method also includes obtaining a variation of a thickness of the cervix tissue, and calculating strain from the thickness variation.

[0012] According to yet another aspect of the present disclosure, a method for automatically computing deformation of cervix tissue due to applied stress comprises applying stress on cervix tissue along a Z-axis only for a period of time T 1 via an ultrasound probe of an ultrasound imaging system, and tracking feature locations of a plurality of layers of the cervix tissue along the Z-axis only for the same period of time T1 in a limited searching range of the cervix tissue. The method also includes calculating one or more of deformation and/or strain of the plurality of layers of the cervix tissue using feature locations of the cervix tissue that were tracked. Brief Description of the Several Views of the Drawings

[0013] FIG. 1 is a block diagram of a cervical elastography system of the present disclosure;

[0014] FIG. 2A is a perspective view of an ultrasound imaging system of the cervical elastography system of the present disclosure;

[0015] FIG. 2B is a block diagram of the ultrasound imaging system of FIG. 2A;

[0016] FIG. 3A is a perspective view of an ultrasound probe of the ultrasound imaging system;

[0017] FIG. 3B is a block diagram of the ultrasound probe of FIG. 3A;

[0018]

[0019] FIG. 4 is a top view of the ultrasound probe of FIG. 3A;FIG. 5 is a side, perspective view of the ultrasound probe of FIG. 3A coupled to a calibration system;

[0020] FIG. 6 is a perspective view of the calibration system;

[0021] FIG. 7 is a block diagram of the microcontroller of the calibration system of FIG. 6;

[0022] FIG. 8 is a perspective view of the ultrasound probe coupled to the calibration system;

[0023] FIG. 9 is a perspective view of another calibration system that may be used with the ultrasound imaging system of the present disclosure;

[0024] FIG. 10 is a block diagram illustrating an exemplary method of operation of the cervical elastography system of the present disclosure;

[0025] FIG. 1 1 is a perspective view of an alternative ultrasound probe of the ultrasound imaging system;

[0026] FIG. 12A is a side view of the ultrasound probe of FIG. 11 in contact with a portion of a cervix;

[0027] FIG. 12B is another side view of the ultrasound probe of FIG. 11 in contact with another portion of the cervix;

[0028] FIG. 12C is a perspective view of a sleeve configured to be coupled to the ultrasound probe of FIGS. 12A and 12B;

[0029] FIG. 13 is a side perspective view of another alternative calibration system that may be used with the ultrasound imaging system of the cervical elastography system of the present disclosure;

[0030] FIG. 14 is a front view of the calibration system of FIG. 13 depicting a first step in the calibration of the calibration system of FIG. 13;

[0031] FIG. 15 is another front view of the calibration system of FIG. 13 depicting another step in the calibration of the calibration system; [0032] FIG. 16 is yet another front view of the calibration system of FIG. 13 depicting another step in the calibration of the calibration system;

[0033] FIG. 17 is a side view of the calibration system of FIG. 13;

[0034] FIG. 18 is a perspective view of the calibration system of FIG. 13 having a large weight disposed thereon for calibration;

[0035] FIG. 19 is a perspective view of the calibration system of FIG. 13 having a small weight disposed thereon for calibration.

[0036] FIG. 20 is a flow chart depicting graphical representations of stress sensor measurement relative to time, stress sensor measurement relative to actual stress, and stress relative to time calibration;

[0037] FIG. 21 is a series of B-mode images from the ultrasound probe of the ultrasound system of the present disclosure;

[0038] FIG. 22 is a graph depicting strains on the cervix extracted from the continuously acquired B-mode images of the ultrasound system of the present disclosure over time;

[0039] FIG. 23 is a close-up B-mode image of a cervix tissue depicting a plurality of layers in the cervix tissue;

[0040] FIG. 24 is a graphical representation of a portion of the cervix tissue of FIG. 23;

[0041] FIG. 25 is a perspective view of a display of the ultrasound imaging system of the present disclosure, depicting real-time measurements and diagnosis according to one example using one or more methods of the present disclosure;

[0042] FIG. 26 is another perspective view of the display of the ultrasound imaging system of the present disclosure, depicting real-time measurements and diagnosis according to another example using one or more methods of the present disclosure;

[0043] FIG. 27 is a graphical representation of cervical length in both preterm birth and term birth patients over a period of time using conventional methods;

[0044] FIG. 28 is a graphical representation of cervical elastography in both preterm birth and term birth patients over a period of time using the cervical elastography system and methods of the present disclosure; and

[0045] FIG. 29 is a graphical representation of cervical elastography in patients with preterm labor symptoms to help predict delivery due date. Detailed Description of the Disclosure

[0046] Generally, a quantitative cervical elastography system of the present disclosure includes a transvaginal ultrasound imaging system, a stress measurement system coupled to the ultrasound imaging system and including a transvaginal probe having at least one pressure sensor, and a stress calibration system. B-mode images of a cervix are obtained from the ultrasound imaging system and from which the cervix deformation can be observed. Using a correlation-based method, such as automatic feature tracking, periodic correction, and strain extraction methods, all of which are explained more below, strains on the cervix are extracted from continuously acquired B-mode images. For stress measurement, at least one stress sensor, such as a pressure sensor, is mounted on a tip of the transvaginal probe. The at least one stress sensor is connected to a microcontroller board for data acquisition, such that a series of measured stress may be collected. For stress calibration, a calibration system is coupled to the stress management system and includes a load cell, a load cell amplifier, and a microcontroller board in one example. After stress measurements are completed and with the stress sensor still mounted, the transvaginal probe is pressed against the load cell of the calibration systems, such as in a direction perpendicular to the load cell, for calibration. To stabilize the contact between the at least one stress sensor and the load cell, a layer of silicone rubber is disposed between the transvaginal probe and the load cell, as explained more below. A calibration curve is formed, based on which the stress sensor measurement can be transferred to true stress. Applying linear regression to the measured stress and strain a line is obtained, and the slope of the line is an estimation of an elasticity, such as Young’s modulus, of the cervix tissue.

[0047] More specifically, and referring now to Fig. 1 , a quantitative cervical elastography system 10 of the present disclosure is depicted. The cervical elastography system 10 includes a transvaginal ultrasound imaging system 12 having a stress management system 13 including an ultrasound probe 14. MA stress calibration system 18 is coupled to the ultrasound probe 14 The cervical elastography system 10 also includes a computing device 20 that is communicatively coupled to the ultrasound imaging system 12 and the stress calibration system 18 by one or more of a wired connection 22 or a wireless connection 24. Specifically, and in one example, the ultrasound imaging system 12 streams images (e.g., video) to a computing device, such as the computing device 20, which is saved to the computing device using a program, such as a Python program. [0048] The computing device 20 also includes at least one processor 26, such as one or more processors, that implement a module 27 stored in a memory 28 to receive and process data corresponding to features of a tissue sample from the ultrasound probe 14 of the ultrasound imaging system 12 and the stress calibration system 18, as explained more below. The computing device 20 may also include a user-input 29 and a network interface 30, which allows the computing device 20 to be communicatively coupled to the wireless network 22 and communicate with both the ultrasound probe 14 and the ultrasound system 16, for example. The computing device 20 may also include a transmitter 31 and a receiver 32. The transmitter 31 may transmit processed data relative to a patient-specific tissue (e.g., from the ultrasound probe 14) back to the ultrasound system 12, allowing a user to view data about the patient- specific tissue being examined in real time on a graphical user interface of the ultrasound system 12, for example. The receiver 32 receives data from the ultrasound system 12 and the calibration system 18, which is processed by one or more processors 26 of the computing device 20 and used to compute an elasticity of tissue, for example and explained more below. The computing device 20 also includes a display 33 (e.g., a graphical user interface), on which data, such as data processed by the computing device 20, may be displayed.

[0049] More specifically, the module 27 in the memory 28 of the computing device 20 is executable by the at least one processor 26 of the computing device 20 to: (1 ) receive continuously acquired B-mode images of the tissue from the ultrasound imaging system 12; (2) calculate strain on the tissue from the continuously acquired B-mode images in real time; and (3) compute an elasticity of the tissue based on a simultaneous assessment of the actual stress applied to the tissue by the ultrasound probe 14 and the actual strain on the tissue calculated by the stress calibration system 18 and caused by the stress applied, as explained more below. [0050] Referring now to FIGS. 2A and 2B, the ultrasound imaging system 12 of the cervical elastography system is disclosed. The ultrasound imaging system 12 includes a display 36, a keyboard 38, and a plurality of control buttons 40 commonly known and used to operate the ultrasound imaging system 12. In FIG. 2A, the transvaginal ultrasound probe 14 is also depicted communicatively coupled to the ultrasound imaging system 12. In one example, a Hitachi Noblus ultrasound system is used for the ultrasound imaging system 12. However, it will be understood that various other ultrasound systems at least having the features described relative to the ultrasound imaging system 12 of the present disclosure may alternatively be used and still fall within the scope of the present disclosure.

[0051] As depicted in FIG. 2B, the ultrasound imaging system 12 may also include at least one processor 42, such as one or more processors, that implement a module 43 stored in a memory 44 to receive and process data corresponding to features of a tissue sample from the ultrasound probe 14 of the ultrasound imaging system 12, as explained more below. The ultrasound imaging system 12 may also include a user-input 45, such as the keyboard 38 and the plurality of control buttons 40, and a network interface 46. The network interface 46 allows the ultrasound imaging system 12 to be communicatively coupled to the wireless network 22 and communicate with both the ultrasound probe 14 and the computing device 20 (FIG. 1 ), for example. The ultrasound imaging system 12 may also include a transmitter 47 and a receiver 48, such that the transmitter 47 may transmit processed data relative to a patient-specific tissue (e.g., from the ultrasound probe 14) to the computing device 20, for example. The receiver 48 may receive data from the ultrasound probe 14 and the computing device 20, which is processed by one or more processors 42 of the ultrasound imaging system 12 and used to implement the operation of the ultrasound system 12. The ultrasound imaging system 12 also includes the display 36 (e.g., a graphical user interface), on which data, such as data processed by the ultrasound imaging system 12 and/or the computing device 20, may be displayed.

[0052] Referring now to FIGS. 3A and 3B, the ultrasound probe 14 of the ultrasound imaging system 12 is depicted. The ultrasound probe 14 includes a body 50, a tip portion 52, and at least one pressure sensor 54 coupled to the tip portion 52, such as offset from a center area of the tip portion 52 in one example. The at least one pressure sensor 54 is configured to measure real time in vivo pressure applied to tissue, such as cervix tissue, during a transvaginal ultrasound examination in which cervix tissue is being examined, for example. The at least one pressure sensor 54 may include any known type of pressure sensor.

[0053] As depicted in FIG. 3B, the ultrasound probe 14 may also include at least one processor 56, such as one or more processors, that implement a module 57 stored in a memory 58 to receive and process data corresponding to features of a tissue sample from the ultrasound probe 14 of the ultrasound imaging system 12, as explained more below. The ultrasound probe 14 may also include a network interface 59. In one example, the network interface 59 allows the ultrasound probe 14 to be communicatively coupled to the wireless network 22 and communicate with both the ultrasound imaging system 12 and the computing device 20 (FIG. 1 ), for example. It will be understood that the ultrasound probe 14 may also be coupled to the ultrasound imaging system 12 via the wired connection 22 (FIG. 1 ), for example. The ultrasound imaging system 12 may also include a transmitter 60 and a receiver 61 , such that the transmitter 60 may transmit processed data relative to a patient-specific tissue to the computing device 20, for example. The receiver 61 may receive data from the ultrasound probe 14 and the computing device 20. It will be further understood that the ultrasound probe 14 includes components typical to well-known ultrasound probes of known ultrasound imaging systems 12.

[0054] Referring now to FIG. 4, the ultrasound probe 14 of the ultrasound imaging system 12 is again depicted. Specifically, FIG. 4 depicts a perspective view of the tip portion 52 of the ultrasound probe 14 with the at least one pressure sensor 54 disposed and/or mounted to the tip portion 52. In addition, a layer of silicone sealant 62 may be disposed on the tip portion 52 of the ultrasound probe 14 for waterproof and better contact. In this example, the at least one pressure sensor 54, such as a stress sensor, is fabricated into the layer of silicone sealant 62 and then mounted to the tip portion 52 of the ultrasound probe 14. In another example, the at least one pressure sensor 54 is sealed with a waterproof material, such as Tegaderm for waterproof feature. The waterproof material, such as Tegaderm, is thin, transparent, waterproof and relatively easy to fabricate and minimally affects the ultrasound image quality due to its thin thickness and transparency. In addition, the thin layer of waterproof material guarantees the best sensitivity of pressure management on the tissue, such as the cervix tissue. Moreover, fabrication of the at least one pressure sensor 54 using Tegaderm or another waterproof material having similar features is easy to standardize and efficient.

[0055] Referring now to FIG. 5, a portion of the ultrasound probe 14 of the ultrasound imaging system 12 is coupled to the stress calibration system 18. The stress calibration system 18 is configured to receive measured pressure values from the at least one pressure sensor 54 of the ultrasound probe 14 and to determine an actual stress applied to the tissue, such as cervix tissue. The calibration system 18 includes a plate or a base 66, a load cell 68 coupled to the plate 66 and having a first end 68a and a second end 68b. The first end 68a is attached to the plate 66, and the second end 68b extends from the plate 66 and is configured to receive and contact the tip portion 52 of the ultrasound probe 14. As further depicted in FIG. 5, a layer of rubber 70 is disposed on the second end 68b of the load cell 68 between the second end 68b of the load cell 68 and the tip portion 52 of the ultrasound probe 14. So configured, the ultrasound probe 14 is configured to contact the layer of rubber 70 to stabilize contact between the at least one pressure sensor 53 of the ultrasound probe 14 and the load cell 68.

[0056] Referring now to FIG. 6, the calibration system 18 further includes a load cell amplifier 72 and a microcontroller 73, both of which are disposed on the plate 66 and communicatively coupled to each other and the load cell 68, such as by a wired connection in this example. The tip portion 52 of the ultrasound probe 14 is configured to be pressed against the load cell 68 for calibration. While the microcontroller 73 and the load cell amplifier 72 are disposed on central areas of the plate 66, it will be understood that each of the microcontroller 73 and the load cell amplifier 72 may alternatively be disposed on another area of the plate 66 and still fall within the scope of the present disclosure.

[0057] As depicted in FIG. 7, the microcontroller 73 may include at least one processor 75, such as one or more processors, that implement a module 76 stored in a memory 77 to receive and process data corresponding to features of a tissue sample from the ultrasound probe 14 of the ultrasound imaging system 12, as explained more below. The microcontroller 73 may also include a network interface 78 that allows the calibration system 18 to be communicatively coupled to the wireless network 22 and communicate with both the ultrasound probe 14 and the computing device 20 (FIG. 1 ), for example. The microcontroller 73 of the calibration system 18 may also include a transmitter 79 and a receiver 80, such that the transmitter 79 may transmit processed data relative to a patient-specific tissue (e.g., from the ultrasound probe 14) to the computing device 20, for example. The receiver 80 may receive data from the ultrasound probe 14, which may be processed by one or more processors 75 of the microcontroller 73 of the stress calibration system 18 and transmitted via the transmitter 79 to the computing device 20 to calculate the elasticity of the tissue in real time.

[0058] In one example, and as depicted in FIG. 8, the ultrasound probe 14 is pressed against the load cell 68 in a direction perpendicular to or substantially perpendicular to an axis of the load cell 68. A calibration curve is used, and the pressure sensor 54 measurement can be transferred to actual stress being applied to the tissue based on the calibration curve, for example, and as explained more below. Further, using the linear regression applied to the measured pressure (e.g., stress) and strain extracted from B-mode images acquired from the ultrasound imaging system 12, a line is obtained by the computing device 20, for example. The slope of the line is an estimation of the elasticity (e.g., Young’s modulus) of the tissue (e.g., cervix tissue) via the stress-strain regression in real time.

[0059] Referring now to FIG. 9, the load cell 68 of the calibration system 18 may alternatively be disposed on an extended load cell pad 82 of the calibration system 18. Said another way, the extended load cell pad 82 may be included in the calibration system 18 and is separate from the plate 66 of the calibration system 18. The load cell 68 is not attached to the plate 66, but instead is coupled to the extended load cell pad 82. The extended load cell pad 82 is coupled to each of the amplifier 72 and the microcontroller 73 of the calibration system 18 and includes a base 83, a pad 84 coupled to the base 83, and a pair of posts 84. Each post 84a, 84b is disposed on either side of the pad 84. The load cell 68 is coupled to the pad 84, and the ultrasound probe 14 may likewise be pressed against the load cell 68 in a direction perpendicular to or substantially perpendicular to the axis of the load cell 68.

[0060] So configured, the cervical elastography system 10 described above, including the ultrasound imaging system 12 coupled to the calibration system 18 and the computing device 20, applies the stress-strain principle to cervical imaging to obtain fully quantitative cervical elastography. The sensor reading from the at least one pressure sensor 54 of the ultrasound probe 14 of the ultrasound imaging system 12 is converted to actual stress/pressure via the calibration system 18. In addition, the real time B-mode images continuously acquired by the ultrasound probe 14 is converted to strain applied to the tissue. As depicted in the flow chart of FIG. 10, by affixing the at least one pressure sensor 54 to the transvaginal ultrasound imaging system 12 supporting real time B-mode imaging and streaming, stress is measured by the least one pressure sensor 54 mounted to the ultrasound probe 14 at step 86 as B-mode images of the cervix are simultaneously acquired at step 88. The calibration system 18 transforms the stress/pressure sensor 54 measurements to actual stress in step 90. In addition, using a designed a correlation-based method, which is explained more below, strain is extracted from the B-mode images from the ultrasound imaging system 12 at step 92. The measured stress and extracted strain are then used to estimate and calculate the elasticity of the cervix tissue, e.g., the Young’s modulus of the cervix tissue, by stress-strain regression in step 94. To give real-time feedback to sonographers performing the imaging, a graphical user interfaces (GUI) of the system 10, such as on the display 33 (FIG. 1 ) of the computing device 20 and/or the display 36 of the ultrasound imaging system 12 (FIG. 2A), displays live streaming of B-mode images.

[0061] More specifically, the GUI, such as for the display 36 (FIG. 2A) of the ultrasound imaging system 12, was developed using Python, for example, to provide centralized data acquisition (B-mode video and/or image recording and stress measurement) and to give real-time feedback to sonographers. The GUI is based on real-time streaming of B-mode video and/or images from the ultrasound imaging system 12. During measurements, acquired data are visualized in two windows: one for B-mode video, and the other for stress sensor measurement. After making a proper choice for the ultrasound probe 14 location and orientation yielding high quality images, a sonographer applies press-release cycles to the cervix using the ultrasound probe 14 and observes the tissue deformation and stress sensor response, as explained more below. All stress sensor measurements will be saved. To save memory, only the latest 4 seconds’ B-mode video (120 frames) is cashed in the memory, such as the random-access memory (RAM) 44 of the ultrasound imaging system 12 (FIG. 2B). For example, the n-th frame is stored in the RAM for the (rem(n - 1,120) + 1)-th image. Here rem(p, q) denotes the remainder after division of an integer p by another integer q. Once the “Check Measurements” button is clicked, the stored frames will be automatically organized to their real order and saved to a hard drive. A Matlab script is then used by the sonographer to calculate elasticity (without calibration) and visualize all the intermediate results.

[0062] Referring now to FIGS. 11 -12B, another ultrasound probe 114 is depicted that may alternatively be used with the ultrasound imaging system 12, the calibration system 18 and the computing device (see, e.g., FIG. 1 ) of the cervical elastography system 10 of the present disclosure. The ultrasound probe 1 14 is the same as the ultrasound probe 14 of FIGS. 1-5 except the ultrasound probe 1 14 includes a pair of sensors and a sleeve, as described move below. As a result, parts of the ultrasound probe 114 that are the same as parts of the ultrasound probe 14 are not explained here again for the sake of brevity and/or include reference numbers 100 more than the same parts of the ultrasound probe 14.

[0063] As depicted in FIG. 11 , the ultrasound probe 1 14 includes a body 150, a tip portion 152, and a pair of pressure sensors 154 coupled to a collar 153, such as offset from a center area C of the tip portion 152 and on either side 152a and 152b of the tip portion 152, in one example. The pair of pressure sensors 154 is configured to measure real time in vivo pressure applied to tissue, such as cervix tissue, and during a transvaginal ultrasound examination in which cervix tissue is being examined, for example. The pair of pressure sensors 154 includes a first pressure sensor 154a coupled to a first side 153a of the collar 153 (that is mounted to the tip portion 152 of the ultrasound probe 154, in this example) and a second pressure sensor 154b coupled to a second side 153b of the collar 153. The pair of pressure sensors 154 may include any known type of pressure sensor. A sleeve 196 is disposed over each pressure sensor 154a, 154b of the pair of pressure sensors 154, as depicted in FIG. 1 1 , for example. Moreover, any pressure sliding on the sleeve 196 will push the entire sleeve 196 in a downward direction, creating forces on both the first and second sensors 154a, 154b. The location and direction of the cervix relative to the tip portion 152 of the ultrasound probe 1 14 will determine how much of the total force is measured by each sensor 154a, 154b.

[0064] As further depicted in FIGS. 12A and 12B, the sleeve 196 includes a body 197 having a first side 197a and a second side 197b and a slot 197c disposed in the central area of the body between the first and second sides 197a, 197b. When the sleeve 196 is disposed over each pressure sensor 154a, 154b, the slot 197c enables a portion of the ultrasound probe body 150 to be in an uncovered state to avoid any interference with the operation of the ultrasound probe 1 14. The sleeve 197 may alternatively be a cap and take the form of various other shapes and still fall within the scope of the present disclosure. In addition, the body of the sleeve 197 may be transparent.

[0065] As further depicted in FIGS. 12A and 12B, for example, each pressure sensor 154a, 154b of the pair of pressure sensors 154 is indirectly coupled to the ultrasound probe 114 using the collar 153. The collar 153 includes a shoulders 155a, 155b and an arm 157a, 157b extending downwardly and outwardly from each shoulder 155a, 155b, as depicted. Specifically, each pressure sensor 154a and 154b is coupled to a top portion of the shoulder 155a, 155b, respectively, of the collar 153, and the collar 153 is coupled to a top portion 151 of the body 150 of the ultrasound probe 114, as further depicted. The collar 153 may be coupled to the top portion 151 of the body 150 of the ultrasound probe 114 using any known means. Alternatively, the pressure sensors 154a, 154b may be coupled to the ultrasound probe 1 14 using any other mechanical and/or electrical means and/or structure and still fall within the scope of the present disclosure.

[0066] In FIG. 12A, contact with a cervix 199 is centered to the sleeve 196. In this example, the force measured by each sensor 154a, 154b will be approximately equal. In FIG. 12B, contact with the cervix 199 favors the right sensor, which is the pressure sensor 154b in this example. In this example, the force measured by the second sensor 154b will be greater than the force measured by the first sensor 154a. As explained more below, the force measurement transmitted to the computing device by the ultrasound system 12 will be a combination of the force measured by the first sensor 154a and the force measured by the second sensor 154b.

[0067] In addition, and referring now to FIG. 12C , a force concentrator 159, such as a puck, may be disposed on the sleeve 196 to ensure all forces from the sleeve 196 are directed to the pressure sensors 154a, 154b and fixes the measurement portion of the sensor 154a, 154b in place. In this example, two force concentrators 159 are disposed on separate underside portions of the sleeve 196, such that each force concentrator 159 is disposed on a separate side of the sleeve 196. It will be understood that one force concentrator 159 may alternatively be disposed on the underside of the sleeve 196 and still fall within the scope of the present disclosure. Including the force concentrators 159 on the sleeve 196 prevents uncontrolled sensor movements or bending that create erroneous force measurements, for example. Like the ultrasound probe 14, the ultrasound probe 114 includes all of the same internal components of the ultrasound probe 14 depicted in FIG. 3B, for example. Specifically, the ultrasound probe 1 14 includes the at least one processor 56, such as one or more processors, that implement the module 57 stored in the memory 58 to receive and process data corresponding to features of a tissue sample from the ultrasound probe 114 of the ultrasound imaging system 12, as explained more below. The ultrasound probe 114 may also include the network interface 59. In one example, the network interface 59 allows the ultrasound probe 1 14 to be communicatively coupled to the wireless network 22 and communicate with both the ultrasound imaging system 12 and the computing device 20 (FIG. 1 ), for example. It will be understood that the ultrasound probe 114 may also be coupled to the ultrasound imaging system 12 via the wired connection 22 (FIG. 1 ), for example. The ultrasound imaging system 12 may also include a transmitter 60 and a receiver 61 , such that the transmitter 60 may transmit processed data relative to a patient-specific tissue to the computing device 20, for example. The receiver 61 may receive data from the ultrasound probe 114 and the computing device 20. It will be further understood that the ultrasound probe 1 14 includes components typical to well-known ultrasound probes of known ultrasound imaging systems 12.

[0068] Referring now to FIGS. 13-16, as an alternative to the stress calibration system 18 described above and depicted in FIGS. 5, 6, and 7, for example, another stress calibration system 1 18 depicted in FIGS. 13-16 may be used. The calibration system 118 includes a plate or a base 166, a plate holder 167 rotatably coupled to the base 166 and configured to receive a weight used to determine a calibration point, as explained more below. The plate holder 167 includes a semi-circular shape and a projection 167a extending upwardly from a central portion of the plate holder 167. The plate holder 167 and/or the projection 167a are configured to receive a weight used to determine a calibration point of the stress calibration system 118, as also described more below.

[0069] The stress calibration system 118 is calibrated by first rotating the plate holder 167 in a upward direction, such that it is in the position A depicted in FIG. 14. Next, a clip 169 is flipped in a first direction to allow a load sensor 168 to be secured to a central portion 166a of the base 166, such that the load sensor 168 is disposed beneath plate holder 167 when the plate holder is rotated back into an initial position depicted in Fig. 15. As depicted in FIG. 16, the clip 169 is then rotated in a second direction, opposite to the first direction, to secure the load sensor 168 in place on the base 166.

[0070] Referring now to FIGS. 17-20, the load sensor 169 is preconditioned using large and small weights. More specifically, the calibration system 118 is placed back into its initial position of FIG. 13, but with the load sensor 169 secured to the base 166, as depicted in FIG. 17. A high calibration point (HOP) is obtained by placing a large weight 170 on the plate holder 167, as depicted in FIG. 18, and saving an FSR reading. A low calibration point (LCP) is obtained by placing a small weight 172 onto the plate holder 167, as depicted in FIG. 19, and saving the FSR reading. A transfer function is then calculated using the low and high calibration points to create linear regression for calibration.

[0071] Referring now to FIG. 20, a flow chart depicting graphs of measured stress and calibrated stress is illustrated. In part e, a graph showing a series of measured stress from the ultrasound probe 14, 1 14 is depicted, with stress sensor measurement (y-axis) graphed as a function of time (x-axis). In part g, a graph showing a calibration curve describing the relationship between the stress sensor measurement and true stress is depicted. In part h, a series of true stress obtained by calibrating the stress sensor measurement of part e using the calibration curve in part g is depicted.

[0072] It will be understood that the cervical elastography system 10 described above may operate according to one or more the following methods. For example, and in one example, a method for automatically extracting strain from the continuously acquired B-mode images of the ultrasound system 12 of the cervical elastography system 10 comprises identifying a boundary of the cervix tissue in a B-mode image. Extracting strain from continuously acquired B-mode images is critical for the quantitative cervical elastography system 10. As depicted in FIG. 21 , a posterior lip boundary of the cervix is identified in the first B-mode image B1 , and the boundary has a first depth D1 . The method also includes tracking at least two subsequent depths in the cervix tissue that are different from the boundary of the cervix tissue, such as the boundary having the first depth D1 in subsequently obtained B-mode images of the cervix tissue, as depicted in images B2 and B3 of FIG. 21 . In addition, variation in the thickness of the cervix tissue can then be obtained, such as by subtracting the depths of the posterior lip boundary and the ultrasound probe 14, 1 14 surface. Lastly, strain is calculated from the thickness variations, as explained more below. To automatically compute the deformation of cervix tissue due to applied stress, a correlation-based feature tracking algorithm is applied, as also explained more below. Strains of the cervix extracted from the continuously acquired B-mode images over time are depicted in FIG. 22, for example.

[0073] In one example, tracking at least two subsequent depths of the cervix tissue different from the boundary of the cervix tissue comprises tracking at least two subsequent depths D2 and D3 of the cervix tissue in at least two subsequently obtained images of the cervix tissue, such as in images B2 and B3 of FIG. 21 . In another example, obtaining a variation of a thickness of the cervix tissue comprises obtaining a variation of the thickness of the cervix tissue by subtracting the depth D1 of the boundary of the cervix tissue from a depth Dp of a surface of the ultrasound probe 14, 114.

[0074] In addition, and in another example, a method for automatically computing a deformation of the cervix tissue due to applied stress comprises applying stress using the ultrasound probe 14, 114 on cervix tissue along a Z-axis only for a period of time T 1 . The method also includes tracking feature locations of a plurality of layers 202 of the cervix tissue 199 along the Z-axis only for the same period of time T1 in a limited searching range 204 of the cervix tissue 199, as depicted in FIG. 23. The method also includes calculating one or more of deformation and/or strain of the plurality of layers 202 of the cervix tissue 199 using tracked feature locations of the cervix tissue 199, for example, and as explained more below.

[0075] More specifically, before stress is applied to the cervix tissue along the Z-axis only for the period of time T1 , the method may also include constructing a coordinate system 206 using a tip of the ultrasound probe 14 ,1 14, as also depicted in FIG. 23. The coordinate system 206 includes the vertical direction along the Z-axis and the horizontal direction along an X-axis, such as a downward vertical direction along the Z-axis and a rightward horizontal direction along the X-axis in one example.

[0076] In addition, the B-mode video or images are then expressed as with L denoting the number of frames. The B-mode video is a sequence of B-mode images, so the video is expressed as where x denotes the X-axis, z denotes the Z-axis, and / denotes the number of frames in the video, from 1 , 2, ... to L, the maximum frames. In this example, stress on the cervix tissue 199 was applied along z-axis by the tip portion of the ultrasound probe 14, 114, causing cervical deformation along the same direction. Therefore, a tracking algorithm was only performed along z-axis. For convenience, is denoted. The denotes the tracking function of B-mode images At each specific depth there will be the imaging feature as a function of z. The n= 1 ,2,3,..., N denotes the number of layers that is aimed to track. The algorithm tracks multiples layers of tissue in the

[0077] In the first image, and in one example, features of length L, such as and centered at are chosen. The depths of the centers of these features in the Z-th image are denoted as Due to spatiotemporal continuity of cervical deformation, a feature has similar values in different frames, which can be mathematically expressed as: [0078]

[0079] Based on Equation (1), the correlation-based algorithm for feature tracking is:

[0080]

[0081] In this equation, is an estimation of from . Letting and solving the optimization problems described by Equation (2) directly, one may obtain for all I = 2, ... , L and n = 1,2, ... .N. However, this direct method is not robust in practice, at least due to accumulative deformation, which may be large. As a result, needs to be searched in a long range, which is not robust due to similarity between different features and large deformations of a single feature. To increase the robustness in the searching of Equation (2) is reduced to:

[0082] (3)

[0083] Here z_s denotes the half searching length. is iteratively obtained from , based on Equation (3). Due to small deformation between adjacent frames, the deformation of a single feature is negligible; and a small value can be assigned to effectively removing the issue caused by similarity between different features.

[0084] More generally, and in one example, tracking feature locations of the plurality of layers 202 of the cervix tissue 199 along the Z-axis only for the same period of time T 1 in the limited searching range 204 may include the length L and depths D of the plurality of layers of the cervix tissue 199, as depicted in FIG. 24, for example.

[0085] In another example, another correlation-based algorithm to track the n-th feature’s movement from the Z-th frame to the Z'-th frame includes:

In this example, the n-th feature’s depth in the is estimated based on the feature’s depth in the frame using the Pearson correlation coefficient (PCC) of two functions in an interval:

One may directly obtain for all I' = 2, ...,L and n = 1,2, ... N by letting I = 1 and solving the optimization problems described by Equation (3A). However, this direct algorithm is not robust in practice. Due to accumulative deformation, can be large, meaning needs to be searched in a large range, which is not robust due to similarities between different features and large deformations of a single feature. To increase the robustness in the search of one reduces Equation (3A) to

Here, z_s denotes the half search length, and one recursively obtains (defined as z_{1 , n}) based on Equation (3B). Due to small deformation between adjacent frames (30- Hz frame rate), the deformation of a single feature is negligible and a small value is assigned to z_s, which means that the recursive search of based on Equation (3B) is more robust than the direct search based on Equation (3A). In practice, to reduce the error caused by tissue movement along the x-axis, one applies spatial lowpass filtering along the x-axis to all images 1,2, ... , L before the feature tracking. Because one only analyzes the strain along the probe axis in this research, the strain estimation (the most time-consuming part of data processing) takes only a few seconds and is negligible in practice.

[0086] In another example, the method may further comprise periodically correcting the tracking by pressing and releasing the cervix tissue 199 with the ultrasound probe 14, 1 14 and acquiring B-mode videos and/or images with durations longer than the time T1 . This occurs before calculating one or more of deformation and/or strain of the plurality of layers 202 of the cervix tissue 199. For example, and for participant comfort, the number of press-release cycles should be as few as possible. In one example, three videos were obtained for each participant, for example.

[0087] More specifically, the application of Equation (3) generates accumulative error. To reduce accumulative error, a sonographer may periodically press and release the cervix 199 with the ultrasound probe 14, 114 and acquire B-mode videos with durations longer than one period. After feature tracking based on Equation (3), a period starting with the first frame and ending with the L'-th frame can be identified. Due to periodicity, deformation between the first frame and the L'-th frame is small. Thus, using Equation (2) for I' = 1 and I = L', a corrected version of denoted as can be found robustly in the small searching range 204 (e.g., FIG. 23). Based on the correction to the L'-th, other frames in this period can be corrected through linear interpolation:

[0088] (4)

[0089] Frames out of this period (L' < l < L) can be corrected using frames (with the same phases) in this period based on Equation (2) with the small searching range 204. This correction process is the periodic correction.

[0090] Given the tracked feature locations the strain of the cervix tissue 199 between the n- th and n'-th (n' < n) features can be defined as:

[0091 ] (5)

[0092] In this research, the general strain of the cervix cross section (n' = l, n = n_p) was analyzed:

[0093] (6)

[0094] Here n_p denotes the index of the feature indicating the posterior boundary of the cervix.

[0095] Deformation simulation

[0096] Given a B-mode image f(x,z), its vertical deformation by strain is defined as:

[0097] (7)

[0098] Here, z = 0 means zero depth. Based on Equation (7), given a series of strains 1,2, ... , L, a series of B-mode images can be obtained.

[0099] Stress measurement

[0100] The currently used the pressure sensor 54, 154a, 154b, such as the stress sensor FlexiForce A101 , may be damaged if directly used in an aqueous environment. To make it waterproof, a layer of silicone sealant may be fabricated onto the pressure sensor 54, 154a, 154b. Before each measurement, both the ultrasound probe 14, 114 and the pressure, such as stress, sensor 54, 154a, 154b are disinfected and then dried for stable contacting. Next, the ultrasound probe 14, 1 14 is connected to the ultrasound imaging system 12, and wires, such as the two wires, soldered to the at least one pressure sensor 54, 154a, 154b are connected to a microcontroller board, such as an Arduino Uno, of the calibration system 18, for example. The pressure sensor 54, 154a, 154b sampling rate is set as 80 Hz, higher than the frame rate (30 Hz) of the B-mode videos from the ultrasound imaging system 12, such as a Hitachi Noblus ultrasound system. Then the pressure sensor 54, 154a, 154b is mounted onto the tip portion of the ultrasound probe 14, 1 14. After the pressure sensor 54, 154a, 154b is mounted, a syringe may be used to inject ultrasound gel to an ultrasonic transparent area. In one example, the whole fabricated sensor component may cover an area of the detection surface of the ultrasound probe 14, 1 14. In part of this area, the ultrasound is blocked by the pressure sensor 54, 154a, 154b. In the remaining part of this area covered only by silicone sealant, the ultrasound is transmitted, allowing for imaging in areas otherwise blocked by the pressure sensor 54, 154a, 154b.

[0101] Stress calibration

[0102] Referring back to FIGS. 5-8, the load cell amplifier 72 of the calibration system 18 may be a SparkFun HX711 model and may further support two sampling frequencies: 10 Hz and 80 Hz. The higher one (same as the sampling frequency for stress sensor) is chosen for faster calibration. Each load cell 68, which includes a 780g maximum weight in one example, is calibrated with standard weights after initial setup and weekly maintenances. Load cell calibration is not required after a stress sensor calibration. During stress sensor calibration, to stabilize the contacting, the layer of rubber 70 may be placed between the load cell 68 and the stress sensor 54 mounted on the ultrasound probe 14, as previously described and depicted in FIG. 5, for example. Multiple press-release cycles are applied to the ultrasound probe 14 so that the stress sensor 54 responses cover the whole range of measurements for cervix tissue. Measurements from stress/pressure sensor 54 and the load cell 68 during these cycles are used for calibration.

[0103] Assuming that the load cell measurements are and the stress sensor measurements are Here L denotes the number of sampling points in the calibration. Then the true stress may be expressed as

[0104] [ [0105] [where g = 9.81 m • s^-2 is the gravitational acceleration constant and A is the contacting area. Load cell measurements are relatively accurate. To reduce noises in the pressure sensor measurements, a median filtering of kernel size three (with duration 0.1 s) is applied to A press-release cycle has duration from 2 s to 4 s, thus the median filter has negligible effects on the general trend of stress variation while reducing noise locally. Then are sorted in the ascending order of resulting in respectively. Here is a permute of {1,2, ..., L }. To further reduce noises in the pressure sensor measurements, a median filtering of size three was applied to Applying a nonparametric regression⁴⁵ to the calibration curve, such as in FIG. 20, was obtained.

[0106] (9)

[0107] The accuracy of this calibration system 18 may be estimated from the confidence curves in this nonparametric regression. From pressure sensor measurements the true stress is obtained through the inversion of Equation

[0108] Stress-strain regression

[0109] Applying linear regression to stress and strain (Equation (6)), the following equation is obtained:

[0110] (10)

[0111] Here E and b denote the estimated Young’s modulus and the system bias, respectively.

[0112] In some cases, while the stress varies, the strain is constant at some time. This discrepancy is caused by a relatively high resolution in stress measurement and a relatively low resolution in strain measurement (limited by B-mode image quality). Tissue nonlinear response also contributes to this discrepancy. To mitigate error caused by this discrepancy, time durations with constant strains are rejected. This rejection is achieved by calculating the first derivative of the strain variation and identifying large clusters of zeros (with number of zeros ≥ 6 for this research).

[0113] [At least in view of the foregoing, one will understand that the systems and methods described above include several advantages. Real-time feedback is given to the sonographers as an estimation of the general data quality, and they can acquire more videos only if the data quality is poor. As a result, the general data quality is improved with minimal increase of measurements. Furthermore, visualization of all the intermediate results helps sonographers identify issues in measurements and adjust accordingly to improve accuracy.

[0114] In addition, the ultrasound probe 114 having the pair of pressure sensors 154 includes several further advantages. First, the full force applied to the cervix 199 is captured, the axial force applied independent of cervix positioning is measured, and the sensor use and processing is improved. While the ultrasound probe 14 with the single pressure sensor 54 advantageously measures the force applied to the cervix 199 at the one point of contact, the ultrasound probe 1 14 with the sleeve 196 (e.g., which covers the entire probe tip) further ensures that all axial forces applied to the cervix 199 are measured. The sliding sleeve 196 also allows the operator to apply the necessary force to the cervix 199 regardless of its position relative to the cervix 199. Previously, the operator was forced to compromise between desired image and maintaining contact between the single sensor point measurement and the cervix 199. Moreover, the addition of the force concentrator helps ensure all forces from the sleeve 196 are directed to the sensor 154a, 154b and fixes the measurement portion of the sensor 154a, 154b in place to prevent uncontrolled sensor movements. Lastly, the ultrasound probe 114 having the pair of pressure sensors 154 implements an op-amp circuit for signal processing to create a linear relationship between the sensor signal and the force applied. The linear signal provides for easier calibration and improved resolution across the entire measurement range.

[0115] Further, the fabrication of the new ultrasound probe 14, 114 is more sensitive, standardized and efficient. The modification of the strain tracking algorithm, including extracting the strain on the cervix tissue 199 via the B-mode images, for example, guarantees better robustness and accuracy in computation. Moreover, the new calibration algorithm, including methods of calibrating true stress from the sensor reading of one of more of the pressure sensors 54, 154a, 154b can obtain more accurate force-pressure association and is robust against operation variation. In addition, the automatic strain extraction described above including extracting strain from the B-mode images during the transvaginal ultrasound examination based on the correlation-based imaging feature tracking algorithm, providing significantly more accurate assessment of the elasticity of the cervix 199 than other methods (e.g., comparing relative strain). This enables a more accurate diagnosis of the condition of one’s cervix and ultimately predicting both potential pre-term labor and delivery due dates. In addition, applying the strain tracking with dynamic searching of a fixed window size and searching range, as explained above, provides a more robust in clinical ultrasound examination acquisition. [0116] Moreover, the foregoing new system 10 and ultrasound probes 14, 114 and related methods may be used with any application where cervical hardness/softness is altered. This may include: (1 ) term birth onset/prediction; (2) preterm birth onset/prediction; (3) surveillance after preterm birth therapies are applied; (4) indication of labor (including therapeutic decisions, procedural monitoring; (5) cesarean birth prediction; and (6) cervical cancer screening (potential non-obstetric use).

[0117] Referring now to FIGS. 25 and 26, perspective views of the display 36 (see, e.g., Fig. 2A) of the ultrasound imaging system 12 depicting real-time measurements and diagnosis according to two separate examples using one or more of the foregoing methods and/or algorithms described above are provided. More specifically, the display 36 of the ultrasound imaging system 12 provides central data acquisition (B-mode video and/or image recording and stress management) and gives real-time feedback to users, as described above relative to Fig. 2A, for example. During measurements and after each time of checking measurement, the software will automatically call a real-time diagnosis and analysis algorithm, such as those described above relative to the various methods of the present disclosure. A figure will then appear on the display 36 to visualize the measurement quality, for example. In this example, the figure includes a left panel including a graph depicting a pressure curve and another graph depicting strain tracking. The figure also includes a right panel having pressure-strain regression graph. It will be appreciated that the pressure-strain regression graph may be disposed on another area of the figure depicted on the display 36, and the pressure curve graph along with the strain tracking graph may likewise be disposed on another area of the figure different from the left panel and still fall within the scope of the present disclosure. In other words, the location of the graphs within the figure displayed is not critical to the feature of providing the real-time measurement quality of the methods of the present disclosure.

[0118] Generally, the pressure curve and strain tracking curve should show smooth wave form shape according to a press-release cycle to the cervix, such as using the ultrasound probe 14, 1 14 during examination and as explained above. If the pressure curve is noisy, the sensor 54, 154 of the ultrasound probe 14, 114 may be loose, for example, and the operator can consider repeat the examination. If the noise is not resolved, the operator can consider removing the sensor 54, 154 and re-applying the sensor 54, 154. If the strain curve is noisy, the ultrasound image depicted may be too dark, or the cervix may not be adequately under the ultrasound probe 14, 114. [0119] Referring now to FIG. 25, the display 36 of the ultrasound imaging system 12 is depicted, including the figure with a top left panel including a graph (ST) with a strain tracking curve. The strain is derived from the ultrasound image data stored in the computing device 20, for example. The figure also includes a bottom left panel having a graph (PC) with the pressure curve derived from the stress reading from the sensor 54, 154 of the ultrasound probe 14, 114, for example. The two profiles of the strain tracking graph ST and the pressure curve graph (PC) showed nice synchronization; thus, the tissue deformation corresponded well to the pressure applied. The stress-strain regression is depicted in a right panel of the figure and includes a graph (PSR) showing the pressure-strain regression. In this example, the Pearson correlation coefficient referred to above was calculated and marked in a center area of the PSR graph as Cor: 0.96 in this example.. The higher Pearson correlation coefficient (range from -1 to 1 ) indicates better correlation between the strain and stress. The Cor>=0.8 is general guideline and cutoff for a successful elastography exam using the quantitative cervical elastography system 10 of the present disclosure, for example.

[0120] Referring now to FIG. 26, the display 36 of the ultrasound imaging system 12 is again depicted, including the figure with a top left panel including the strain tracking graph (ST), the bottom left panel including the pressure curve graph (PC), and the right panel including the pressure-strain regression (PSR) graph. The strain shows a nice wave form in the strain tracking graph (ST), indicating nice ultrasound image quality. However, the pressure curve graph (PC) indicating the stress shows a noisy and deviated pattern compared to the strain profile in the strain tracking graph (ST). This observation suggests that the sensor 54, 154 might be loose in the examination. Also, Pearson correlation coefficient of Cor=0.56 shown the center area of the pressure-strain regression graph (PSR) on the right panel, suggests that the user needs to adjust the sensor 54, 154 and repeat the examination, for example.

[0121] Clinical Data Results from Prospective Study

[0122] In a cohort study, asymptomatic patients presenting for routine prenatal care visits were imaged, performing the methods described above related to the ultrasound probe 14 of the cervical elastography system 10 at three time points across pregnancy. The cervical elastography system 10 detects statistically significant cervical softening over pregnancy, as depicted in FIG. 28 compared to the current standard of monitoring cervical length in FIG. 27. In addition, the cervical elastography system 10 using the ultrasound probe 14 demonstrated a statistically softer (e.g., more remodeled) cervix detectable in early pregnancy in patients with subsequent preterm birth (PTB) compared to those with term birth (TB). [0123] The study also included individuals presenting with symptoms of preterm labor to assess whether the cervical elastography system 10 can predict delivery within 7 and within 14 days (clinically important windows for interventions to optimize neonatal outcomes). The cervical elastography system 10 can detect statistically significant differences is cervical stiffness in people who will deliver in 1 -2 weeks, as depicted in FIG. 29. Clinical data indicates that the ultrasound probe 14 of the cervical elastography system 10 has successfully overcome prior limitations and can achieve fully-quantitative operator-independent cervical stiffness measurements. This technology provides the opportunity to apply known prevention strategies, effectively test novel prevention strategies, and apply life-saving therapies for neonatal survival in those at risk for imminent preterm birth.

[0124] Future Integration into Clinic Systems

[0125] Future clinical integration of the cervical elastography system 10 and related methods described above can be envisioned as a new, and more predictive, version of the currently available cervical length. Transvaginal ultrasound cervical length is performed routinely in early pregnancy as a PTB risk stratification process and is an independently reimbursable procedure covered by payers as a standard part of obstetric care. As evidenced at least by the above data, the cervical elastography system 10 captures cervical remodeling more powerfully than cervical length.

[0126] There is currently no standard method for fully quantifying cervical stiffness in a standardized, reproducible, operator-independent method. Achieving this with the cervical elastography system 10 of the present disclosure provides three key innovative benefits directly appliable to preterm birth progress: 1) the first system to quantitatively measure cervical stiffness in a reproducible and operator-independent fashion, facilitating comparisons across time and between patients; this allows development of normative values and diagnostic cut-offs to describe and quantify normal and abnormal obstetric physiology; 2) the first opportunity for establishing diagnostic cut-offs of cervical stiffness across early pregnancy to identify those at risk for preterm birth; and 3) the first opportunity for improved targeted enrollment for clinical trials to test individualized treatment and surveillance practices to decrease preterm birth risk.

[0127] The following additional considerations apply to the foregoing discussion. Throughout this specification, plural instances may implement components, operations, or structures described as a single instance. Although individual operations of one or more methods are illustrated and described as separate operations, one or more of the individual operations may be performed concurrently, and nothing requires that the operations be performed in the order illustrated. Structures and functionality presented as separate components in example configurations may be implemented as a combined structure or component. Similarly, structures and functionality presented as a single component may be implemented as separate components. These and other variations, modifications, additions, and improvements fall within the scope of the subject matter herein.

[0128] As used herein any reference to “one implementation,” “one embodiment,” “one example,” “an implementation,” “an embodiment,” or “an example” means that a particular element, feature, structure, or characteristic described in connection with the implementation is included in at least one implementation. The appearances of the phrase “in one implementation” or “in one embodiment” or “in one example” in various places in the specification are not necessarily all referring to the same implementation.

[0129] Some implementations may be described using the expression “coupled” along with its derivatives. For example, some implementations may be described using the term “coupled” to indicate that two or more elements are in direct physical or electrical contact. The term “coupled,” however, may also mean that two or more elements are not in direct contact with each other, but yet still co-operate or interact with each other. The implementations are not limited in this context.

[0130] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0131] In addition, use of the “a” or “an” are employed to describe elements and components of the implementations herein. This is done merely for convenience and to give a general sense of the invention. This description should be read to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.

[0132] Upon reading this disclosure, those of skill in the art will appreciate still additional alternative structural and functional designs for the system and method disclosed herein. Thus, while particular implementations and applications have been illustrated and described, it is to be understood that the disclosed implementations are not limited to the precise construction and components disclosed herein. Various modifications, changes and variations, which will be apparent to those skilled in the art, may be made in the arrangement, operation and details of the method and apparatus disclosed herein without departing from the spirit and scope defined in the appended claims.

Claims

CLAIMS What is claimed is:

1 . A cervical elastography system comprising: a transvaginal ultrasound imaging system including an ultrasound probe having at least one pressure sensor configured to measure real time in vivo pressure applied to tissue and a sleeve configured to be disposed over the at least one pressure sensor; a stress calibration system coupled to the ultrasound probe and configured to receive a measured pressure value from the at least one pressure sensor and to determine actual stress applied to the tissue; and a computing device communicatively coupled to the ultrasound imaging system and the stress calibration system, the computing device having a memory, at least one processor, and a module stored in the memory of the computing device and executable by the at least one processor of the computing device to:

(1) receive continuously acquired B-mode images of the tissue from the ultrasound imaging system;

(2) calculate strain on the tissue from the continuously acquired B-mode images in real time; and

(3) compute an elasticity of the tissue based on a simultaneous assessment of the actual stress applied to the tissue by the ultrasound probe and the calculated strain on the tissue caused by the stress applied in real time.

2. The system of claim 1 , wherein the ultrasound probe further comprises a tip portion and a single stress sensor mounted offset from a center area of the tip portion.

3. The system of claim 1 , wherein the ultrasound probe further includes a pair of pressure sensors mounted on either side of a collar disposed on the probe, the sleeve disposed over each pressure sensor of the pair of pressure sensors.

4. The system of any one of claims 1 -3, wherein the at least one pressure sensor is sealed with a waterproof material.

5. The system of claim any one of claims 1 -4, wherein the stress calibration system coupled to the ultrasound probe comprises a load cell, a load cell amplifier, and a microcontroller board, such that the probe is configured to be pressed against the load cell for calibration, and a layer of rubber is disposed on the load cell between the load cell and the tip portion of the ultrasound probe, such that the ultrasound probe is configured to contact the layer of rubber to stabilize contact between the at least one pressure sensor of the ultrasound probe and the load cell.

6. The system of any one of claims 1 -4, wherein the stress calibration system coupled to the ultrasound probe comprises a base having a plate holder rotatably coupled to the base, the plate holder adapted to receive a weight used to determine a calibration point.

7. A cervical elastography system comprising: a transvaginal ultrasound imaging system including an ultrasound probe having at least one pressure sensor configured to measure real time in vivo pressure applied to tissue; a stress calibration system coupled to the ultrasound probe and configured to receive a measured pressure value from the at least one pressure sensor and to determine actual stress applied to the tissue, the stress calibration system comprising one of: (1 ) a load cell, a load cell amplifier, and a microcontroller board, such that the ultrasound probe is pressed against the load cell for calibration, and a layer of rubber is disposed on the load cell, the ultrasound probe configured to contact the layer of rubber; or (2) a base having a plate holder rotatably coupled to the base, the plate holder configured to receive a weight used to determine a calibration point; and a computing device communicatively coupled to the ultrasound imaging system and the stress calibration system, the computing device having a memory, at least one processor, and a module stored in the memory of the computing device and executable by the at least one processor of the computing device to:

(3) compute an elasticity of the tissue based on a simultaneous assessment of the actual stress applied to the tissue by the ultrasound probe and the calculated strain on the tissue caused by the stress applied.

8. The system of claim 7, wherein the ultrasound probe further comprises a tip portion and a single stress sensor mounted offset from a center area of the tip portion.

9. The system of claim 7, wherein the ultrasound probe further includes a pair of pressure sensors mounted on either side of a collar disposed on the probe, and a sleeve disposed over each pressure sensor of the pair of pressure sensors.

10. The system of claim 7, wherein the ultrasound imaging system further comprises a sleeve configured to be disposed over the at least one pressure sensor.

11 . The system of any one of claims 7-10, wherein the stress calibration system comprises the load cell, the load cell amplifier, and the microcontroller board, and further comprises a plate on which each of the load cell, the load cell amplifier, and the microcontroller board are disposed, the load cell amplifier coupled to the microcontroller board.

12. The system of any one of claims 7-10, wherein the stress calibration system comprises the base having the plate holder rotatably coupled to the base, the plate holder having a semi-circular shape and a projection extending from a central portion and configured to receive a weight used to determine the calibration point.

13. The system of claim 12, wherein the stress calibration system is calibrated by: rotating the plate holder in an upward direction; securing a load sensor to a central portion of the base; rotating the plate holder back in a downward direction, such that the load sensor is disposed beneath the plate holder; obtaining a low calibration point by loading a small weight onto the plate holder; obtaining a high calibration point by loading a large weight onto the plate holder; and calculating a transfer function using the low and high calibration points to create linear regression for calibration.

14. A computer-implemented method for automatically extracting strain from continuously acquired B-mode images of an ultrasound system of a cervical elastography system, the method comprising: identifying a boundary of a cervix tissue in a B-mode image received from an ultrasound probe of an ultrasound imaging system; tracking at least two subsequent depths of the cervix tissue different from the boundary of the cervix tissue in subsequently obtained B-mode images of the cervix tissue; obtaining a variation of a thickness of the cervix tissue; and calculating strain from the thickness variation.

15. The method of claim 14, wherein identifying a boundary of a cervix tissue in a B- mode image comprises identifying a boundary of a cervix tissue in a first image of the B-mode images, the boundary having a first depth D1 .

16. The method of either one of claims 14 and 15, wherein tracking at least two subsequent depths of the cervix tissue different from the boundary of cervix tissue comprises tracking at least two subsequent depths D2 and D3 of the cervix tissue in at least two subsequently obtained images of the cervix tissue.

17. The method of any one of claims 14-16, wherein obtaining a variation of a thickness of the cervix tissue comprises obtaining a variation of the thickness of the cervix tissue by subtracting the depth D1 of boundary of the cervix tissue from a depth Dp of a surface of the ultrasound probe.

18. A method for automatically computing deformation of cervix tissue due to applied stress, the method comprising: applying stress on cervix tissue along a Z-axis only for a period of time T1 via an ultrasound probe of an ultrasound imaging system; tracking feature locations of a plurality of layers of the cervix tissue along the Z-axis only for the same period of time T1 in a limited searching range of the cervix tissue; and calculating one or more of deformation and/or strain of the plurality of layers of the cervix tissue using tracked feature locations of the cervix tissue.

19. The method of claim 18, further comprising, before applying stress on the cervix tissue along the Z-axis only, constructing a coordinate system using a tip of the ultrasound probe, the coordinate system including a vertical direction along a Z-axis and a horizontal direction along an x-axis.

20. The method of claim 18, wherein tracking feature locations of a plurality of layers of the cervix tissue along the Y-axis only for the same period of time T1 in a limited searching range of the cervix tissue comprises tracking feature locations, including one or more of a length and a depth, of the plurality of layers of the cervix tissue along the Z-axis or vertical direction only for the same period of time T 1 in the limited searching range of the cervix tissue.

21 . The method of any one of claims 18-20, the method further comprising periodically correcting the tracking by pressing and releasing the cervix tissue with the ultrasound probe and acquiring B-mode videos with durations longer that the time T1 before calculating one or more of deformation and/or strain of the plurality of layers of the cervix tissue.