Patent Publication Number: US-2019192064-A1

Title: Micro-device and system for determining physiological condition of cervical tissue

Description:
FIELD OF THE INVENTION 
     This invention relates to the treatment of pregnant mammals and more particularly to a device and system useful for determining the physiological condition of cervical tissue. 
     BACKGROUND OF THE INVENTION 
     The birthing process in mammals has a normal or average duration, for example human gestation is normally 266 days while for horses it normally ranges between 335 and 345 days. For cattle gestation averages 283 days while for swine about 113 to 116 days and for sheep 144 to 151 days. The actual period for human gestation is variable but is considered full-term to conclude between 38-42 weeks post-conception. In humans, for example, labor and birth that commences earlier than 36 weeks as a result of a high-risk pregnancy or other complications presents serious if not fatal problems for the newborn infant that can well continue on to adulthood. Delivery at 30-32 weeks normally necessitates considerable time in an NICU and delivery very early at around 23 weeks is considered almost uniformly fatal 
     For most domestic animals entering into labor and the birthing process occurs with little assistance. However, for humans in particular and certain valuable domestic animals, such as thoroughbred horses, the gestation period in the final trimester is normally closely monitored for the beginning of labor and for complications such as preterm labor resulting in preterm birth. 
     For domestic animals a preterm birth will usually produce a still born or a weak and sickly animal requiring expensive attention. Especially in the case of thoroughbred horses where stud fees may run up to six figures a premature foal may not survive or perform to the expectations of the breeder resulting in a substantial financial loss. 
     For humans the societal burden of preterm births in the United States was estimated to be $26 billion in 2005 by the Committee on Understanding Premature Birth and assuring Healthy Outcomes under the auspices of the US Institute of Medicine. These costs include medical care services at $16.9 billion; maternal delivery costs $1.9 billion; early intervention services $611 million; special education services associated with a high incidence of disabling conditions associated with premature infants added $1.1 billion. Finally, the committee estimated that lost household and labor market productivity associated with those disabling conditions contributed $5.7 billion. 
     High-risk pregnancies are not always detected early nor easily determined in advance so that treatment can be provided to alleviate the harmful effects on the infant and mother of a preterm birth. Women pregnant for the first time or who may not have access to medical help can present a high-risk pregnancy without being aware of their condition. Early identification of high-risk pregnancies facilitates monitoring and prompt initiation of therapy. Early initiation of therapy has the potential to decrease the onset of labor, thus reducing the complications endured by the newborn as well as reducing the cost burden. However, monitoring of even normal pregnancies in the last trimester is also recommended if only to avoid unnecessary trips to the hospital because of false labor. 
     The human birthing process is divided into four stages. Stage 1 occurs from the onset of labor to full cervical dilation. Stage 2 is from full cervical dilation to delivery; stage 3 from delivery to expulsion of placenta and stage 4 from expulsion of the placenta to afterbirth recovery. Thus, monitoring the physiological parameters of the cervix in humans and mammals allows the clinician to follow the progress of a pregnancy during stage 1 of the process where complications, particularly preterm labor, can be recognized and possibly treated. In that connection some successful work has been done in this area but the methods employed require the presence of the clinician and usually employ invasive procedures. 
     It is recommended that monitoring of a pregnancy, especially in the last trimester of the pregnancy, be conducted frequently so that the onset of labor and any complications can be identified can be identified in the very early stages. In the case of domestic animals monitoring of the animal&#39;s pregnancy will normally require the on-site presence o f a veterinarian. For both animal and human patients this will be inconvenient. 
     In the case of human patients in the United States and other Western countries where medical services are more readily available, a pregnancy is normally monitored at the doctor&#39;s office as an outpatient or in the hospital. However, this requires a visit to the doctor&#39;s office or the hospital every few days in order to monitor the patient&#39;s progress. In developing countries, it may not be possible for a woman to see a doctor on a regular basis so that intervention to alleviate or treat a condition may be too late. 
     Various systems have been put forward to monitor the status of a pregnancy. For example, some systems employ small ultrasound reflectors signals transmitted by an ultrasound interface unit located outside of the body detect uterine contractions. For the measurement of uterine electrical activity, electro hysterography, has been proposed as an alternative approach for the detection of labor. For example, WO 94114373 (Garfield) records signals from embedded electrodes, WO 95/31932 and WO 96/39931 (Garfield) disclose a method which stores data and compares activity and U.S. Pat. No. 5,373,852 (Harrison) uses radio-telemetric transmission for sensing pressure, temperature and electrical activity. Rosenberg (WO 97/25922) discloses a further method for analysis of electromyographic data. These techniques relate exclusively to clinical settings, usually intrusive systems for data collection. U.S. Pat. No. 6,823,211 discloses a nonintrusive device including recording electrodes, a digital converter and a display unit that can be worn on the exterior of the abdomen or vaginal area of a body for the analysis of uterine electrical activity to monitor the progress of, and/or diagnose active labor and can be used to obtain an indication of uterine preparedness for labor in the initial phase of parturition before onset of active labor. Another system that relies on the measurement of uterine electrical activity is disclosed in U.S. Pat. No. 6,290,657 that, similar to the &#39;211 patent, uses surface electrodes and a monitor to sense and analyze electrical signals that are transmitted by telephone to the physician&#39;s office. 
     In Patent Application Publication US 2009/0137925 the pregnancy is monitored by attaching a clip carrying a pair of tetra-pole electrodes to the patient&#39;s cervix. The electrodes that are electrically connected to a transducer cable that supplies the signal to an interface unit containing circuitry and a monitor. The transducer cable carries analog to digital conditioning hardware while the interface unit includes an algorithm for comparing typical impedance value with the impedance value of the cervix being measured. The resulting output can be a measure of time of labor vs. cervical stromal impedance (CSI) value or time in labor vs. cervical dilation and/or effacement for plotting a Friedman labor curve. The patient is immobilized during the procedure. US 20100/305406 disclose a gynecological device and mentions measuring impedance. However, this device is hard wired to a monitor or a transmitting device and is not designed for use while the patient is ambulatory. 
     A device suitable to be worn by the patient is shown in Patent Application Publication US2013/0053670. This device measures the potential developed by polarization and depolarization of vaginal and cervical tissue due to tissue contractions. 
     The prior art methods are inconvenient and are not suited for long term, continuous monitoring of the patient. In many cases monitoring involves the intervention of a clinician that requires the patient to visit the hospital or the clinician&#39;s office frequently to undergo the monitoring procedures. Placing sensors externally, as disclosed in several prior art publications, may introduce discrepancies in the data collected. For example, discrepancies due to variations in skin temperature and variations in contact pressure between the skin and the sensor. Other methods require that relatively large devices be placed in the patient that requires frequent removal to avoid odor and possible infection. Several methods require connection by wire to sensors at one end and to burdensome equipment at the output end that requires that the patient be non-ambulatory. In addition, many prior art systems are concerned only with the measurement of vaginal contractions which may be too late in the case of those at risk of premature birth. 
     Electrochemical Impedance Spectroscopy (EIS) is a useful and reliable method for determining the physiological condition of biological tissue. However, EIS employs alternating current to measure tissue potential which is then converted to impedance and plotted. The necessary circuitry is not readily miniaturized because it requires too may components and the power drain is too great for use in applications of the type to which the present invent applies. 
     SUMMARY OF THE INVENTION 
     The present invention relates to a device using low power direct current to simulate alternating current in the manner of EIS. The device includes circuitry that is miniaturized for inclusion in devices that are adapted to be worn by the patient for extended periods of time while permitting the patient to be fully ambulatory during the monitoring procedure. 
     Accordingly, it is an object of the invention to monitor and record the physiological condition of the cervix from sensors immediately adjacent to and in contact with the cervix. 
     An object of the invention is to provide a device for the continuous monitoring of the condition of the cervix while permitting the subject to be completely ambulatory and have complete freedom of action. 
     Another object of the invention is to provide a device that can be employed in a system wherein the monitoring of the cervix can be done remotely. 
     A further object of the invention is to continuously monitor physiological changes in the tissue of the cervix employing electrochemical impedance spectroscopy (EIS). 
     Another object of the invention is to provide a device that can be employed early in pregnancy to detect the early onset of conditions that indicate the likelihood of a preterm birth. 
     It is an object of the invention to provide a device that can be employed in a system that collects and analyses data and distinguishes between normal conditions of the cervix and relevant physiological changes in cervical tissue that may indicate early stages of labor. 
     In one preferred mode digitized data is converted to impedance measurements and is conveniently processed to correlate to cervical stromal impedance (CSI) values stored in the database of the interface device. Typical values may be found in Gandhi, et al., “Comparison of Human Uterine Cervical Electrical Impedance Measurements Derived Using Two Tetrapolar Probes of Different Sizes,” European Journal of Obstetrics &amp; Gynecology and Reproductive Biology, Vol. 129, Issue 2, December 2006, 145-149, which is incorporated herein by reference in its entirety. 
     Alternatively, in another embodiment the processed data is accumulated to generate baseline data for the individual being monitored. The baseline data can be displayed as a curve or displayed in textual form. In either case a significant change in the slope of the curve or an increase or decrease in data values is an indication that a significant change in the physiological condition of the cervix and that labor may be imminent. 
     In accordance with the invention these techniques can be employed early on in the pregnancy with no discomfort to the individual and without the necessity of restraining or otherwise preventing the free movement of the individual during the monitoring process. 
     To maintain freedom of movement for the individual being monitored all transmissions of data from the device is wireless, i.e. direct transmission from the device to an external module, such as a computer, which for computation of impedance or indirect to an external device, such as a cell phone, for more robust retransmission to a remote computer for calculating impedance. 
     These and other objects and advantages will become apparent from the following description of the invention taken in conjunction with the drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a block diagram of steps using the micro-device of the invention; 
         FIG. 2  is an isometric view of one embodiment of a device i n accordance with the invention; 
         FIG. 3  is a cross sectional view of the device o f  FIG. 2  positioned adjacent the cervix; 
         FIG. 4  is an isometric view of an embodiment of the device that is adapted for suturing onto the cervix; 
         FIG. 5  is an isometric view of another embodiment of the device of the invention illustrating the power supply extending from the body of the device; 
         FIG. 6  is a cross sectional view of the device o f  FIG. 5  positioned adjacent the cervix; 
         FIG. 7  is an isometric view of an embodiment of the invention in which the device also functions as a constricting pessary; 
         FIG. 8  is a block diagram of the microcircuit for simulating EIS; 
         FIG. 9  is an isometric view of the device of  FIG. 1  illustrating location of the circuitry, electrodes and antenna; and 
         FIG. 10  illustrates radiation from the antenna of the device of  FIG. 8 ; 
     
    
    
     DESCRIPTION OF THE INVENTION 
     The system of the invention is suited for monitoring the pregnancy of mammals, however for ease of description the invention will be described in connection with monitoring the pregnancy of a human female. The device of the invention includes circuitry that simulates EIS using low power direct currant. 
       FIG. 1  illustrates the basic steps for utilization of the device of the invention to determine the physiological condition of cervical tissue. The first step shown at  10  is to secure electrodes in intimate contact with cervical tissue. Circuitry is provided to create binary pulses of direct current and to convert the pulses to alternating current. The potential of the pulses passing through the cervical tissue is sensed and digitized at  12  to create digital data points. At  14  the digital data points are wirelessly transmitted to an external module for conversion to impedance data points. The impedance data points may be displayed at the external module or transmitted to a remote display module. The final step  16  is to record and analyze the impedance data to determine a data trend and to treat the patient if necessary, baseline data for the respective parameter. A significant change in received data from the baseline data will cause the software program to transmit a warning to the clinician that some action is required. 
     As illustrated in  FIG. 2  and  FIG. 3 , in one embodiment a device  18  for sensing potential through cervical tissue  22  comprises a flexible annulus  20  for positioning around a cervix  22 . The annulus  20  is formed of a resilient, electrically non-conductive, biocompatible material, such a s polyurethane, silicone or silicone rubber that exhibits the desired properties of resiliency, flexibility, biocompatibility and non-conductivity. In one embodiment the annulus  20  is transparent or translucent for activation of the device  12  circuitry by a light sensitive on/off switch as will be more fully described in connection with  FIG. 8 . The inner radial surface of the annulus  20  is provided with one or more Kelvin configured sensing electrodes  34 ′ and one or more current injection electrode electrodes  34 ″ that are in electrical communication with signal converting electronics for converting potential measurements to digital data. The annulus  20  being flexible and resilient can be slightly stretched between the fingers of a clinician for placement around the cervix  22 . When the clinician&#39;s fingers are removed the annulus  20  will return to its original diameter to provide intimate contact between the electrodes  34  and the cervix  22 . 
     In view of the fact that the patient is ambulatory during the monitoring process there exists the danger of a shift in the position of the annulus  20  on the cervix  22  which will result in the change of the position of the electrodes  34 ′ and  34 ″. Any such change can affect the applied pressure on the electrodes. Either or both events will change the resulting data which can give a false indication of a change of impedance in the cervix tissue or could hide an impedance change in cervix tissue. Notice of any such shift the annular body  22  can be indicated from an unusual change in the total electrode potential which is the sum of the potential measured between the injecting electrodes  34 ′ and the pair of electrodes  34 ″ that are measuring cervix tissue potential. Such an unusual change in the total potential correlates to an unusual change in total impedance and will clearly show in the displayed data trend. Such a change in the data trend may also be an indication of a system malfunction. As a precaution, however, depending on the predicted activity of the patient, the device  18  can be adapted for stitching on to the cervix  21  to prevent any shifting. 
       FIG. 4  illustrates an embodiment of the device  18  comprising the annulus  20 , electrodes  34 ′ and  34 ″ and circuitry as described in  FIG. 1 . To further secure the device  18 , a plurality of eyes  44  are formed on a circumference of the annulus  20 , as shown, for suturing the annulus to the patient&#39;s cervix. 
     Yet another embodiment of the device, shown generally as  18 , is illustrated in  FIG. 5  and  FIG. 6  in which the annular body  20  is interrupted to define free ends  42  and  43 . Free end  42  extends away from the annular body  22  and is elongated to define a compartment  36  for battery and associated electronics. A single pair of electrodes  34  serves both as the injecting electrodes and the measuring electrodes. The device functions as described above in measuring impedance. However, as shown in  FIG. 6  when the annulus  20  is disposed on the cervix  22  the compartment  36  is urged against the uterine wall  38  as an aid in maintaining the annulus in position on the cervix. 
     In another embodiment shown in  FIG. 7  the device  18  is configured as a constricting pessary to maintain closure of the cervix  21 . In this embodiment the device  18  comprises the annular body  22  on which is formed enlarged compartments  40   a  and  40   b  in which are respectively disposed the battery and the associated electronics. The annular body  22  is interrupted to define a pair of resilient, flexible U-shaped arms  42 . In this embodiment electrodes  44 ′,  44 ″ and  44 ′″ are disposed in the arms  42 . The electrodes  44 ′ and  44 ′″ comprises the injecting electrodes and electrode pair  44 ″ comprise the impedance measuring electrodes. 
     The device  18  is positioned around the cervix by spreading the U-shaped arms  42 . 
     Once positioned, the arms  42  are allowed to return to their original configuration so that each arm securely contacts the cervix to provide constrictive support of the cervix as a pessary and to maintain the electrodes  44 ′,  44 ″ and  44 ′″ securely positioned in intimate contact with the cervix. 
     The circuitry utilized in the device of the invention must be able to supply alternating currant to the injection electrodes in order to simulate EIS. In addition, the circuitry power requirements must be low for the device to function for relatively long periods. Finally, the circuit must be miniaturized in order to fit in a small body such as a pessary. Conventional EIS circuitry cannot be used in the present invention as it requires too many components and cannot be miniaturized to fit in a pessary. Also, EIS requires a constant current source and too much power to apply a constant source of alternating current to the biological load. In accordance with the invention, Kelvin configured circuitry is described that can be miniaturized to about size of a quarter to fit in a pessary. The micro-circuit operates on low power direct current which it converts to sinusoidal binary pulses so that the device of the invention operates as though it were measuring tissue impedance by EIS. 
       FIG. 8  a block diagram of a micro-circuit  116  that simulates EIS and which miniaturized to fit in a small body such as pessary. A low power battery  118  electrically communicates through line  119  to a microcontroller  120 . An on/off switch  121  is disposed in the line  119  for activating and deactivating the circuit. Because the micro-circuit is embedded in a body such as a pessary it is preferred that the body be composed of a material that is at least translucent and switch  121  be light activated so the circuitry can be activated just prior to application of the micro-device. Other means for activating the on/off switch  121  may be employed, such as sound, if a translucent or transparent pessary is undesirable. 
     A microinverter  122  communicates with positive analog switches  125  through line  123  and with negative analog switches  126  through negative line  124 . Switches  125  communicate with positive injection electrode  128  and switches  126  with negative injection electrode  130 . As illustrated, common is at negative electrode  130  so that the polarity is positive and the positive injection electrode injects a positive current pulse into tissue  132 . The microcontroller  120  changes common to the positive electrode  128  reversing polarity and closing switch  126  for injection of a negative current pulse through electrode  130 . The microcontroller  120  controls switch  125  and  126  to rapidly open and close to inject alternate positive and negative pulses of current in to tissue  132 . In this manner alternating current is produced and EIS is simulated. Present day micro-controllers such as the Texas Instruments MSP430 series have become quite competent with peripheral resources and can handle the rapid multiple switching operations. 
     The potential of the alternating current through tissue  132  is sensed by electrodes  134  and  136  and transmitted through lines to amplifiers  142  and multiplexor  144  and analog to digital converter  146 . The digitized potential signal is transmitted to microcontroller  120  and is wirelessly transmitted by R/F circuitry  148  including a circular antenna  150  to an external module  152 . The R/F transmitter circuitry uses as low a frequency and power level as practical to minimize any possibility of fetal harm. The R/F circuitry may operate in the range of about 300 MHz to about 900 MHz without the danger of harming the patient or the fetus. A frequency in the 400 MHz band and a power level of about −30 dBm provides a connectivity range of greater than three meters which is sufficient and which ensures the safety of the fetus. The circuits are maintained at a very low power level until awakened by the micro-controller-based firmware. The unprocessed data is uploaded at regular intervals to the external module  152 . 
     The external module  152  may be an external interface device, such as a cell phone, which is carried by or in close proximity to the patient for more robust transmission to a remote computer or may be directly transmitted to a computer if it is within the transmission range of the RF transmission from the micro-device  18 . At the computer impedance is calculated from the digitized data, the positive and negative impedances are averaged and read out or displayed to produce an impedance trend line for the patient. By averaging a “positively driven” impedance and a “negatively driven” impedance and taking the average, an unbiased impedance value may be derived. 
       FIG. 9  illustrates a preferred embodiment of the device  18  in which like numbers represent like parts and like functions. The device  18  comprises a pessary  154  in which is embedded the circuitry  116  of  FIG. 8 . Preferably the pessary  154  is composed of a bio-compatible translucent material and includes the on/off switch  121  that is light activated after the circuitry  116  is embedded in the pessary. The low power battery source consists of a pair of 1.5 v batteries  118 . Injection electrodes  128  and  130  and sensing electrodes  134  and  136  are in electrical communication with the circuitry  116  and are disposed on the inner wall of the pessary  154  for contact with the cervical tissue. 
     As discussed above the digitized unprocessed data is transmitted by R/F to an external module for calculation of impedance or to an external interface module for retransmission to a more remote module, such as a computer, for calculating and displaying the impedance measurements. The R/F circuitry includes the circular antenna  150 , comprising an antenna wire, extending around the circumference of the pessary  154   
     There is evidence that electromagnetic radiation from sources such as high tension power lines, television sets, appliances, R/F transmission systems and the like can be harmful to biological organisms. A fetus may be highly susceptible to injury from electromagnetic radiation from R/F transmission. Thus, radiation due to the R/F transmission of data must be taken into account to avoid possible injury to the fetus particularly since the device  18  is designed to be worn for extended periods of time while the patient&#39;s cervix is being monitored. 
       FIG. 10  illustrates a fetus  156  disposed within the uterus  158  of a female patient  160 . The uterus  158  is defined by a uterine wall  162  which is located in the abdomen  164  of the patient  158 . Extending ventrally from the uterus  158  is the cervix  164  which normally closes the uterus  158  but the tissue of which under goes changes such as effacement and ripeness during the birthing process. These changes are conventionally detected by manual examination as the patient is starting into labor. The micro-device of the invention utilizes EIS simulating micro-circuitry as described in  FIG. 8  to monitor the cervical tissue and detect physiological changes to the cervix as an early indicator of impending labor before such changes can be detected by examination of the patient. The micro-device  18  is placed about the cervix  164  of the patient  158  and does not interfere with the normal activities of the patient. In addition, the clinician can monitor the physiological condition of the cervical tissue without the need of patient&#39;s presence at the clinic or office. 
     As illustrated the micro-device  18  in the form of a pessary  154  as described in  FIG. 9  fits snugly about the cervix  164  and holds the positive and negative injection electrodes  126  and  128  and the sensing electrodes  134  and  136  in intimate contact with the tissue of the cervix  164 . Two 1.5v batteries  118  embedded in the micro-device  18  provide low power direct current to the circuitry  116  that converts the current into positive and negative sine waves to simulate alternating current as required by EIS. The potentials of the positive and negative sine waves are detected by the sensing electrodes  134  and  136  and digitized as described in connection with  FIG. 8 . The digitized data are wirelessly transmitted for calculation of the impedance of the cervical tissue. During transmission an electromagnetic radiation field is created around the antenna wire comprising the circular antenna  150 . Due to the configuration of the circular antenna  150  the electromagnetic radiation field is created around the antenna wire and is directed away from the fetus  156 . 
     While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of a preferred embodiment should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims.