Patent Application
20210386300
The present invention relates generally to healthcare, and more particularly to apparatuses and methods for non-invasively measuring physiological parameters of a mammal subject and applications of the same.
The background description provided herein is for the purpose of generally presenting the context of the invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions. Work of the presently named inventors, to the extent it is described in the background of the invention section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the invention.
Current neonatal and pediatric critical care is complicated by involving multiple wired devices, often with an invasive catheter, for measuring health condition continuously. For example, in the United States, over 480,000 critically-ill infants and children are admitted to intensive care units each year, with infants less than one year of age suffering from the highest mortality rate among age groups below 19 years old and requiring more intensive care compared to older children. Furthermore, every year 300,000 neonates are admitted to the NICU in the U.S, with the market is expected to reach $11.86 billion by 2022. These fragile patients include premature infants that may weigh as little as 500 g (1.1 lbs), while the term baby would weigh about seven times more. Continuous monitoring of vital signs is essential for critical care, yet existing technologies require the use of multiple leads and skin-contacting interfaces with hard-wires connected to electronic processing systems that are often tethered to the wall, obstructing the effectiveness of clinical care, making it difficult to perform therapeutic skin-to-skin contact, called kangaroo mother care (KMC), thus impeding psychological bonding between the parent and child. Thus, continuous monitoring of vital signs in the neonatal and pediatric intensive care units generally requires multiple wired devices applied onto the skin and invasive techniques such as arterial line, elevating the risk of complications and impeding the opportunity for skin-to-skin therapy. Thus, new technology is required to meet the unique demands.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.
One of the objectives of the invention is to provide an apparatus for non-invasively measuring physiological parameters of a mammal subject, which may be used as a vital sign monitoring system and/or a pediatric medical device, a method thereof, and applications thereof.
In one aspect, the invention relates to an apparatus for non-invasively measuring physiological parameters of a mammal subject. In certain embodiments, the apparatus includes: a plurality of sensor systems attached to the mammal subject, wherein the sensor systems are time-synchronized and communicate with each other wirelessly and bidirectionally, wherein each of the sensor systems comprises at least one sensor configured to detect a vital sign of the mammal subject and generate a corresponding one of the physiological parameters; and a microcontroller unit (MCU) adapted in wireless communication with the plurality of sensor systems, and configured to receive, from the sensor systems, and to display the physiological parameters of the mammal subject.
In one embodiment, the sensor is configured to detect the vital sign as a signal including one of: an electrical signal related to at least one of electrocardiography (ECG) and electromyography (EMG) technology; a mechanical signal related to movement, respiration and arterial tonometry; an acoustic signal related to vocal cord vocalization, respiratory sound and heart sound; and an optical signal related to blood oxygenation.
In one embodiment, each of the sensor systems is an epidermal electronic system (EES) comprising: a plurality of electronic components, and a plurality of flexible and stretchable interconnects electrically connected to different electronic components; and an elastomeric encapsulation layer at least partially surrounding the electronic components and the flexible and stretchable interconnects to form a tissue-facing surface attached to the mammal subject and an environment-facing surface. In one embodiment, the plurality of flexible and stretchable interconnects comprise at least one of serpentine interconnects and zigzag interconnects. In one embodiment, each of the sensor systems further comprises a foldable electronic board, wherein the plurality of electronic components and the plurality of flexible and stretchable interconnects are disposed on the foldable electronic board.
In one embodiment, the sensor systems comprise: a first EES disposed in a torso region of the mammal subject; and a second EES disposed in a limb region of the mammal subject. In one embodiment, the first EES is an electrocardiography (ECG) EES, and the electronic components of the ECG EES comprise at least two electrodes spatially apart from each other for ECG generation. In one embodiment, the second EES is a photoplethysmography (PPG) EES, and the electronic components of the PPG EES comprise a PPG sensor comprising an optical source and an optical detector located within a sensor footprint. In one embodiment, the electronic components of each of the sensor systems comprise a thermometer.
In one embodiment, each of the sensor systems further comprises a power supply, and the power supply is an embedded power supply or a detachable modular power supply.
In one embodiment, the sensor systems comprise: a first sensor system disposed in a torso region of the mammal subject, wherein the first sensor system is an inertial motion sensor system or an accelerometer system; and a second sensor system disposed in a limb region of the mammal subject, wherein the second sensor system is a photoplethysmography (PPG) epidermal electronic system (EES).
In one embodiment, each of the sensor systems is in wireless communication with the MCU via a near field communication (NFC) protocol, or Bluetooth protocol. In one embodiment, each of the sensor systems comprises a magnetic coil in compliance with the NFC protocol to allow wireless data transmission and wireless power transmission through a single link.
In one embodiment, each of the sensor systems further comprises one or more of: an accelerometer for position or movement monitoring; and a temperature sensor for measuring temperature.
In one embodiment, each of the sensor systems is waterproof.
In one embodiment, the physiological parameters of the mammal subject comprise one or more of: heart rate, heart rate variability, heart sounds, blood pressure, chest wall displacement, electromyography, electrocardiography, blood oxygenation, respiratory rate, respiratory effort, respiratory cadence, tidal volume, coughing, snoring, sneezing, throat clearing, wheezing, apnea, hypoapnea, physical activity, core body position, peripheral limb position, scratching, vocalizations, rubbing, walking, sleep quality, sleep time, wake time upon sleeping, skin temperature, core body temperature, and a combination thereof.
In one embodiment, the blood pressure is measured by: receiving output signals of a first sensor disposed in a first position of the mammal subject and a second sensor disposed in a second position of the mammal subject; processing the output signals to determine a pulse arrival time (PAT) as a time delay Δt between detection of a first signal by the first sensor and detection of a second signal by the second sensor; determining a pulse wave velocity (PWV) based on the PAT and a pulse arrival distance L between the first position and the second position, wherein
and determining the blood pressure P of the mammal subject from the PWV, wherein P=αPWV2+β, and α and β are empirically determined constants depending on artery geometry and artery material properties of the mammal subject. In one embodiment, at a blood pressure range between 5 kPA and 20 kPa,
0.13 kPa×s2/m2≤α≤0.23 kPa×s2/m2; and
2.2 kPa≤β≤3.2 kPa.
In one embodiment, the mammal subject is a human subject or a non-human subject.
In another aspect, the invention relates to a method for developing vaccines for a disease on a mammal subject, including: providing a vaccine agent to the mammal subject not having the disease; monitoring, continuously for a period of time, physiological parameters of the mammal subject using the apparatus as discussed above; and evaluating effects of the vaccine agent on the mammal subject in the period of time based on the physiological parameters.
In yet another aspect, the invention relates to a method for developing therapeutics for a disease on a mammal subject, including: providing a therapeutic agent to the mammal subject having the disease; monitoring, continuously for a period of time, physiological parameters of the mammal subject using the apparatus as discussed above; and evaluating effects of the therapeutic agent on the disease in the period of time based on the physiological parameters.
In a further aspect, the invention relates to a method for diagnosing a disease on a mammal subject, including: monitoring, continuously for a period of time, physiological parameters of the mammal subject using the apparatus as discussed above; and determining whether the mammal subject has the disease based on the physiological parameters.
In one embodiment, the method further includes performing a corresponding treatment of the disease based on the physiological parameters. In one embodiment, the treatment includes providing a respiratory medicine to the mammal subject.
In yet a further aspect, the invention relates to a method of non-invasively measuring physiological parameters of a mammal subject, including: utilizing a plurality of sensor systems on the mammal subject, wherein the sensor systems are time-synchronized and communicate with each other wirelessly and bidirectionally, and each of the sensor systems comprises at least one sensor to monitor one of the physiological parameters; measuring, by the sensor systems, the physiological parameters of the mammal subject; receiving, at a microcontroller remotely communicatively connected to the sensor systems, the physiological parameters of the mammal subject; and displaying, at the microcontroller, the physiological parameters of the mammal subject.
In one embodiment, the sensor is configured to detect a vital sign of the mammal subject as a signal selected from a group consisting of: an electrical signal related to at least one of electrocardiography (ECG) and electromyography (EMG) technology; a mechanical signal related to movement, respiration and arterial tonometry; an acoustic signal related to vocal cord vocalization, respiratory sound and heart sound; and an optical signal related to blood oxygenation.
In one embodiment, each of the plurality of sensor systems is an epidermal electronic system (EES) comprising: a plurality of electronic components, and a plurality of flexible and stretchable interconnects electrically connected to different electronic components; and an elastomeric encapsulation layer at least partially surrounding the electronic components and the flexible and stretchable interconnects to form a tissue-facing surface attached to the mammal subject and an environment-facing surface. In one embodiment, the plurality of flexible and stretchable interconnects comprise at least one of serpentine interconnects and zigzag interconnects. In one embodiment, each of the sensor systems further comprises a foldable electronic board, wherein the plurality of electronic components and the plurality of flexible and stretchable interconnects are disposed on the foldable electronic board.
In one embodiment, the plurality of sensor systems comprise: a first EES disposed in a torso region of the mammal subject; and a second EES disposed in a limb region of the mammal subject. In one embodiment, the first EES is an electrocardiography (ECG) EES and comprises at least two electrodes spatially apart from each other for ECG generation. In one embodiment, the second EES is a photoplethysmography (PPG) EES and comprises a PPG sensor comprising an optical source and an optical detector located within a sensor footprint.
In one embodiment, the sensor systems comprise: a first sensor system disposed in a torso region of the mammal subject, wherein the first sensor system is an inertial motion sensor system or an accelerometer system; and a second sensor system disposed in a limb region of the mammal subject, wherein the second sensor system is a photoplethysmography (PPG) epidermal electronic system (EES).
In one embodiment, the physiological parameters of the mammal subject comprise one or more of: heart rate, heart rate variability, heart sounds, blood pressure, chest wall displacement, electromyography, electrocardiography, blood oxygenation, respiratory rate, respiratory effort, respiratory cadence, tidal volume, coughing, snoring, sneezing, throat clearing, wheezing, apnea, hypoapnea, physical activity, core body position, peripheral limb position, scratching, vocalizations, rubbing, walking, sleep quality, sleep time, wake time upon sleeping, skin temperature, core body temperature, and a combination thereof.
In one embodiment, the blood pressure is measured by: receiving output signals of a first sensor disposed in a first position of the mammal subject and a second sensor disposed in a second position of the mammal subject; processing the output signals to determine a pulse arrival time (PAT) as a time delay Δt between detection of a first signal by the first sensor and detection of a second signal by the second sensor; determining a pulse wave velocity (PWV) based on the PAT and a pulse arrival distance L between the first position and the second position wherein
and determining the blood pressure P of the mammal subject from the PWV, wherein P=αPWV2+β, and α and β are empirically determined constants depending on artery geometry and artery material properties of the mammal subject. In one embodiment, at a blood pressure range between 5 kPA and 20 kPa,
0.13 kPa×s2/m2≤α≤0.23 kPa×s2/m2; and
2.2 kPa≤β≤3.2 kPa.
In one embodiment, each of the plurality of sensor systems further comprises a power supply, and the power supply is an embedded power supply or a detachable modular power supply.
In one embodiment, each of the plurality of sensor systems is in wireless communication with the microcontroller via a near field communication (NFC) protocol, or Bluetooth protocol.
In one embodiment, each of the plurality of sensor systems further comprises one or more of: an accelerometer for position or movement monitoring; and a temperature sensor for measuring temperature. In one embodiment, each of the plurality of sensor systems comprises a magnetic coil in compliance with the NFC protocol to allow wireless data transmission and wireless power transmission through a single link.
In a further aspect, the invention relates to a non-transitory tangible computer-readable medium storing instructions which, when executed by one or more processors, cause the method as discussed above to be performed.
These and other aspects of the invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the invention.
The following drawings form part of the present specification and are included to further demonstrate certain aspects of the invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. The drawings described below are for illustration purposes only. The drawings are not intended to limit the scope of the present teachings in any way.
The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the present invention are shown. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.
The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting and/or capital letters has no influence on the scope and meaning of a term; the scope and meaning of a term are the same, in the same context, whether or not it is highlighted and/or in capital letters. It will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any terms discussed herein, is illustrative only and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.
It will be understood that, although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below can be termed a second element, component, region, layer or section without departing from the teachings of the present invention.
It will be understood that, as used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Also, it will be understood that when an element is referred to as being “on,” “attached” to, “connected” to, “coupled” with, “contacting,” etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on,” “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” to another feature may have portions that overlap or underlie the adjacent feature.
It will be further understood that the terms “comprises” and/or “comprising,” or “includes” and/or “including” or “has” and/or “having” when used in this specification specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.
Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element's relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation shown in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on the “upper” sides of the other elements. The exemplary term “lower” can, therefore, encompass both an orientation of lower and upper, depending on the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used in this disclosure, “around”, “about”, “approximately” or “substantially” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “approximately” or “substantially” can be inferred if not expressly stated.
As used in this disclosure, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
As used in this disclosure, the term “spatially separated” refers to two different locations on skin, where the two sensor systems disposed on those locations are not in physical contact. For example, one sensor system may be on the torso, and another sensor system on the limb.
As used in this disclosure, the term “mammal subject” refers to a living human subject or a living non-human subject. For the purpose of illustration of the invention, the apparatus and method are applied to monitor and/or measure physiological parameters of neonates or infants. It should be appreciated to one skilled in the art that the apparatus can also be applied to monitor and/or measure physiological parameters of children or adults in practice the invention.
The description below is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. The broad teachings of the invention can be implemented in a variety of forms. Therefore, while this invention includes particular examples, the true scope of the invention should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims. For purposes of clarity, the same reference numbers will be used in the drawings to identify similar elements. It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the invention.
The ability to collect multimodal continuous vital signs that is time synced to each other provides deep insights on physiology. This has direct applications in healthcare monitoring. But, more specifically, this technology has direct utility in clinical trials research where physiological vital signs is an important endpoint to determine both the safety and efficacy of a new medication. This is specifically relevant for any medication that leads to a demonstrable change in any of the following physiological vital signs measured by this disclosure. This includes: heart rate, heart rate variability, stroke volume, chest wall displacement, ECG, respiratory rate, respiratory sounds (e.g. wheezing), blood oxygenation, arterial tone, temperature (both central and peripheral), cough count, swallowing, motion, sleep, and vocalization.
In one aspect, the invention relates to an apparatus for non-invasively and continuously measuring physiological parameters of a mammal subject.
Each of the sensor systems 110 and 150 includes one or more sensors that are used to detect a vital sign of the mammal subject, and then to generate one or more corresponding physiological parameters. In certain embodiments, the sensors may be various types of sensors for detecting the vital sign as a signal, and the signal can be, for example, an electrical signal related to at least one of electrocardiography (ECG) and electromyography (EMG) technology; a mechanical signal related to movement, respiration and arterial tonometry; an acoustic signal related to vocal cord vocalization and heart sound; and an optical signal related to blood oxygenation. The MCU 190 is configured to receive, from the sensor systems 110 and 150, output signals representing the physiological parameters, and to display the physiological parameters of the mammal subject. In certain embodiments, the MCU 190 may further process the output signals to obtain a specific vital sign of the mammal subject.
As discussed above, in certain embodiments, each of the sensor systems can be an EES. In certain embodiments, the first EES 110 can be an electrocardiography (ECG) EES, and the second EES 150 can be a photoplethysmography (PPG) EES. In certain embodiments, the first sensor system 110 is an ECG EES 110 (which is a torso sensor system), and the second sensor system 150 is a PPG EES 150 (which is a limb sensor system or an extremity sensor system).
Referring to
Further referring to
Also referring to
As shown in
Referring to
Still referring to
In addition, each of the plurality of spatially separated sensor systems further includes a plurality of flexible and stretchable interconnects (
In operation, the torso sensor system 110 (ECG EES 110) and the extremity sensor system 150 (PPG EES 150) are in wireless communication with a reader system 190, alternatively, a microcontroller unit (MCU), having an antenna 195. Specifically, the RF loop antennas 125 and 165 in both the torso sensor system 110 (ECG EES 110) and the extremity sensor system 150 (PPG EES 150) are in wireless communication with the antenna 195 and serve dual purposes in power transfer and in data communication, as shown in
In another embodiment as shown in
In certain embodiments, the battery 205 is a rechargeable battery operably recharged with wireless recharging. In one embodiment, the electronic components of each of the first sensor system 210 and the second sensor system 250 further include a failure prevention element that is a short-circuit protection component or a battery circuit (not shown) to avoid battery explosion.
In the embodiments as discussed above, each of the sensor systems can be an EES. However, in certain embodiments, one or more of the sensor systems may be a system other than the EES. For example, in one embodiment, the first sensor system 110 as shown in
As shown in
At procedure 320, the sensor systems 110 and 150 are used to measure or monitor the physiological parameters of the mammal subject. In certain embodiments, the physiological parameters of the mammal subject may include one or more of: heart rate, heart rate variability, heart sounds, blood pressure, chest wall displacement, electromyography, electrocardiography, blood oxygenation, respiratory rate, respiratory effort, respiratory cadence, tidal volume, coughing, snoring, sneezing, throat clearing, wheezing, apnea, hypoapnea, physical activity, core body position, peripheral limb position, scratching, vocalizations, rubbing, walking, sleep quality, sleep time, wake time upon sleeping, skin temperature, core body temperature, and a combination thereof. Once the physiological parameters are obtained, the sensor systems 110 and 150 may respectively generate corresponding output signals, which are then transmitted wirelessly to the MCU 190.
At procedure 330, the MCU 190 receives the physiological parameters from the sensor systems 110 and 150. Specifically, the MCU 190 receives the output signals from the first sensor system 110 and the second sensor system 150, and then processes the output signals to obtain the physiological parameters. At procedure 340, the MCU 190 may display the physiological parameters.
As discussed above, one of the physiological parameters that may be monitored or measured is the blood pressure of the mammal subject.
As shown in
Once the PWV is obtained based on equation 1, at procedure 365, the MCU 190 may further calculate and determine the blood pressure P of the mammal subject from the PWV, where P is a parabolic function of the PWV. In one embodiment, the relation between P and PWV can be represented by:
P=αPWV
2+β, (2)
where α and β are empirically determined constants depending on artery geometry and artery material properties of the mammal subject. In one embodiment, at a blood pressure range between 5 kPA and 20 kPa,
0.13 kPa×s2/m2≤α≤0.23 kPa×s2/m2; and
2.2 kPa≤β≤3.2 kPa.
In one embodiment, each of the sensor systems further includes a power supply, and the power supply is an embedded power supply or a detachable modular power supply.
In one embodiment, each of the sensor systems is in wireless communication with the MCU via a near field communication (NFC) protocol, or Bluetooth protocol. In one embodiment, each of the sensor systems includes a magnetic coil in compliance with the NFC protocol to allow wireless data transmission and wireless power transmission through a single link.
In one embodiment, each of the sensor systems further includes one or more of: an accelerometer for position or movement monitoring; and a temperature sensor for measuring temperature.
In one embodiment, each of the sensor systems is waterproof.
In certain embodiments, the sensor systems, apparatus and method as discussed above are versatile and may be used for a variety healthcare application including clinical applications such as:
In certain embodiments, the sensor systems and apparatus as discussed above may further be used as comprehensive, continuous, and on-body sensor systems in the support and development of therapeutic agents that affect physiological parameters. Clinical trials remain an expensive, high-risk proposition for new medicines. There is a constant need for new outcome measurement tools that detect and measure small, but clinically meaningful changes. These tools serve several purposes:
In certain embodiments, the apparatus and method as discussed above may be used in a variety of different applications. For example, the applicability of the technology is broad across a wide range therapeutic agents. Any agent that affects physiological vital signs characterized as electrical signals (e.g. ECG, EMG), mechanical signals (e.g. chest wall movement, respiration, arterial tonometry), acoustic signals (e.g. vocal cord vocalization, heart sounds), and optical signals (e.g. blood oxygenation) would be applicable to pair with the technology described herein.
In certain embodiments, there are therapeutics to pair with this technology that hold the greatest relevance given the direct impact on measureable physiological parameters that the sensors measure. Specifically, therapeutics that are used in critical care, infectious disease, pulmonology, and cardiology are most relevant.
In certain embodiments, the apparatus and method as discussed above are also applicable to diagnosis, monitoring, management and treatment in the context of applications for infectious diseases:
In certain embodiments, the apparatus and method as discussed above are also applicable to diagnosis, monitoring, management and treatment in the context of sleep medicine:
In certain embodiments, the apparatus and method as discussed above are also applicable to diagnosis, monitoring, management and treatment of applications involving cardiology:
In certain embodiments, the apparatus and method as discussed above are also applicable to diagnosis, monitoring, management and treatment of applications involving respiratory medicine:
In certain embodiments, the apparatus and method as discussed above are also applicable to diagnosis, monitoring, management and treatment of applications involving allergy/immunology:
The apparatus and methods as discussed above may be used in or as a part of a vital sign monitoring system and/or a pediatric medical devices. In certain embodiments, provided herein are battery-powered, wireless (e.g., Bluetooth 5 enabled) vital signs monitoring system that exploits a bi-nodal pair of thin, low-modulus measurement modules, capable of gently and non-invasively interfacing onto the skin of neonates, even at gestational ages that approach the limit of viability. A key distinguishing features of this technology includes low-battery power operation enabling at least 24-hour continuous use between charges while enabling monitoring of a full suite of vital signs. The designs enable measurement of traditional vital signs in addition to advanced physiological parameters not currently measured. The skin interface and electrical/mechanical design of the sensor allows for safe integration with fragile neonatal skin even during life-saving interventions such as cardiac defibrillation. The invention also include systems that are powered using wireless means such as using wireless energy harvesting approaches.
In certain embodiments, the methods as discussed above may use any of the sensor networks, sensor systems and electronic components described herein. In certain embodiments, the invention also relates to any sensor networks for carrying out any of the methods described herein.
In certain embodiments, the invention provides a sensor network for wireless monitoring of physiological parameters comprising: a plurality of time-synchronized sensor systems, wherein each sensor system comprises a sensor to measure or monitor a physiological parameter; a bidirectional wireless communication system for wirelessly transmitting data to and from the plurality of time-synchronized sensor systems; and a remote reader in communication with the bidirectional wireless communication system for real-time display of the monitored physiological parameters, recording of the monitored physiological parameters, and/or alarm for an out of agreement state.
In certain embodiments, the invention provides a wireless sensor system that is modular in nature allowing for a detachable power supply (e.g. battery). In an embodiment, the invention provides a wireless sensor system with waterproof functionality allowing for use in aquatic or highly humid conditions or high sweating. In an embodiment, the invention provides a wireless sensor system for use cases related to clinical trials research, support the approval of new therapeutics, and digital health.
In certain embodiments, features of the invention may include:
In certain embodiments, the apparatus and methods as discussed above provide advantages relevant to a broad range of applications:
In certain embodiments, the apparatus and methods as discussed above provide certain advantages over systems of the related art. Prior groups have developed neonatal vests with embedded sensors and wireless communication capabilities. Others have instrumented neonatal beds. These systems are impractical because they are bulky and cover a significant surface area of the neonate—which further complicates medical care instead of simplifying it. Another previously reported technology is only in the research phase—it still requires multiple wires and lacks the intimate skin connection that enables high fidelity sensing, particularly in the context of a neonate that is moving.
These and other aspects of the present invention are further described below. Without intent to limit the scope of the invention, examples according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.
This example, related to one aspect of the invention, relates to a binodal, wireless, and mechanically soft electronic platform that monitors physiological signals continuously and noninvasively for up to 24 hours on neonatal and pediatric patients. Engineering advancements of this wearable platform include multimodal powering options, soft mechanics, and advanced clinical diagnostic functionalities that aim to enhance neonatal and pediatric patient care: quantification of therapeutic skin-to-skin care or called Kangaroo Mother Care (KMC), cry signal pattern and duration, and non-invasive, continuous blood pressure assessments, along with wireless capturing of clinical vital signs, including heart rate, respiration rate, temperature, and pulse oxygenation. The platform was validated by clinical studies with 40 neonatal patients in the neonatal intensive care unit (NICU) of 23-41 weeks gestational age (GA) and 10 pediatric patients in the pediatric intensive care unit (PICU) of up to 3 years in chronical age (CA). Clinical studies show that this platform demonstrates accurate vital sign measurements continuously for up to 24 hours when compared with clinical standards in the hospital, while reliably providing more advanced functionality beyond measuring vital signs such as tracking of kangaroo mother care and crying activities.
Specifically, this example demonstrates a neonate-friendly, soft and stretchable electronic platform, referred to as the EES, which would allow long-duration wireless monitoring of physiological signals for up to 24 hours. This platform was clinically validated in the neonatal/pediatric intensive care units, demonstrating long duration, accurate, non-invasive measurements of vital signs including heart rate (HR), respiration rate (RR), pulse oxygenation (SpO2), temperature, and blood pressure (BP), when compared with clinical gold standards. Furthermore, the multimodal wireless devices enable exploration of physiological signals outside of conventional clinical standard, such as cry analysis and therapeutic skin-to-skin care tracking for the improvement of neonatal and pediatric care.
KMC is a therapeutic method where a newborn is held against a parent's chest to provide skin-to-skin contact. KMC is known to lower neonatal mortality, stabilizes heart rate, temperature, and respiration rate, and decreases the risk of infection. In low-resource countries, KMC is continuously performed in lieu of high-cost incubators to enhance neonatal health and parental/infant bonding. However, despite the therapeutic benefits of KMC, it remains difficult to quantify KMC compliance, often relying on self-reporting by the parent. In addition, vital sign monitoring during KMC sessions are especially challenging with involvement of wired sensors on neonates. A system having wireless mode of operation and mechanics that is non-obstructive to skin-to-skin contact, that can not only identify KMC event but also measuring vital signs concurrently, would therefore provide means to quantify the benefits of KMC and fruitful information to parents and caregivers consequently.
In this example, a mechanically soft and stretchable wireless electronic platform is provided for neonatal and pediatric vital sign monitoring validated with the continuous operation up to 24 hours. This platform provides multimodal power options that can be operated based on clinical and user preference: (1) embedded battery platform, where an in-sensor, rechargeable battery supports the electrical power required to operate the system, providing the advantage of long-term vital sign monitoring, stable operation, and cost-effectiveness, (2) replaceable battery platform, where power is provided through a battery interface that can be replaced without disturbing the skin/sensor interface, an option especially attractive when providing care for premature neonates with undeveloped skin, (3) wireless power transfer platform, where a modular unit with the RF loop antenna is powered by the primary antenna located underneath a typical incubator, there-in providing complete battery-free operation with the thinnest profile of the overall sensor. In this example, the inventors have validated the platform with 50 patients under 3 years old in the neonatal and pediatric intensive care units, and clinical characteristics of these neonates are listed in a Table as shown in
As shown in
Continuous wireless data transmission to a computer system that supports real-time data analytics yields results that can be graphically displayed in an intuitive manner for nurses, doctors and parents. Wireless and real-time streaming through BLE mode of operation allows to provide a patient-centric and accurate measurement of vital signs. The Chest EES measures ECGs, the chest movement through the accelerometer, and skin temperature each sampled at 504, 100, and 5 Hz, respectively. The Limb EES measure PPGs and skin temperature sampled at 100 and 5 Hz, respectively.
Calculation of SpO2 involves with algorithms known for an effective motion artifact reduction, which is critical to calculate accurate value as babies in NICU and PICU are often fidgeting (
Quantitative comparison in
Beyond to the ability to measure core vital signs as accurate as existing gold standard, EES sensors provide more advanced functionality.
Specifically, panel (a) of
In the developmental period of the neonatal neurological system, early diagnosis of neurological disorders enables intervention and treatment in a timely manner. Cry analysis has been reported as a non-invasive method to analyze the neurophysiological state of the neonate, such as birth trauma, brain injury or pain stress. Capturing crying signal has typically involved audio measurements, where signals may easily be contaminated with non-specific audio signals in the environment. The inventors utilize the accelerometer functionality of the Chest EES to capture the mechanical vibration from the neonatal skin during cry activities.
Neonatal cry is one of the main communication methods for neonates to express distress. The analysis of cry activities and patterns have recently been suggested to reflect the neurodevelopment and physiological states of neonates, including the detection of the Sudden Infant Death Syndrome, asphyxia, congenital heart diseases, and Respiratory Distress Syndrome. The inventors have demonstrated the ability of the Chest EES to capture neonatal cry signals in NICU based on the distinct fundamental frequency of cry activities (
Blood pressure reflects hemodynamics states and cardiovascular health whose disorders are common in neonates and children admitted to the neonatal and pediatric intensive care unit, and thus counts among essential vital signs to monitor. Measurement in current clinical practice involves with invasive catheter to the arterial line, which creates significant barrier to both parents and caregivers. In this example, the inventors present the non-invasive method of calculating blood pressure by the pulse arrival time (PAT) that has been highlighted as a promising surrogate for blood pressure by numerous literatures. PAT is defined as the time required for a pulse pressure wave to travel from the heart to a distal extremity and depends on vascular system geometry and elasticity as well as on blood pressure. Time-synchronization between two physically distant EES sensors is the key to achieve accurate PAT readings. It is achieved with the multi-protocol capability of the BLE SoC, allowed by the timeslot API. Every one second while each EES communicates with the base station (Surface Pro) in BLE mode of operation independently, the Limb EES transmits its local clock information to the Chest EES synchronizes time difference between local clocks of two EES (
The data shown in
Fabrication includes soldering electronics components onto a flexible electronics board obtained through laser process. Embedding the assembled circuit board into a soft silicone elastomer shell then avoids any unwanted exposure of electronics parts. For embedded battery version of the device, a Silbione RTV 4420 (Part A & Part B, mixed with 5% of Silc-Pig silicone opaque dye) layer casted in an aluminium mold provides a top shell. A Silbione 4420RTV bottom layer spin coated at 250 rpm results in a flat bottom layer. Both layers are fully cured in a 100° C. oven for 20 minutes. For ECG device encapsulation, a layer of 3M 96042 double-coated tape laminated onto the flat bottom Silbione RTV 4420 layer allows for good contact of the electronics part with bottom side. For PPG device encapsulation, the flat Silbione RTV 4420 bottom layer stays bare. Using a CO2 Universal laser cutter, openings cut on the bottom layer allow electrical contact of ECG electrodes as well as optical transparency for the LED module of the PPG. For ECG device, the flexible circuit board adheres to the 3M 96042 double-coated tape layer, and Silbione RT GEL 4717 added at left, middle and right part of the device results in a soft cushioning for the folded electronics board parts. Top and bottom layers finally assembled using uncured Silbione RTV 4420 are placed in a 100° C. oven for 50 minutes, resulting in a sealed encapsulation of the device. For PPG device, a thin layer of transparent Silbione RTV 4420 is spin-coated at 250 rpm on the bottom side and cured for 20 min in a 100° C. oven to provide a complete seal of the LED module. Laser-cutting finally provides a clean cut for the outline of both devices.
Modification of the encapsulation process for the sensor part of modular device include the replacement of the top shell by a flat Silbione RTV 4420 coated with 3M 96042 double-coated tape with laser-cut holes to allow exposure of magnets soldered onto the board. In addition, thin profile battery (coin cell and Li-Polymer) or coil encapsulated separately benefit from drop casting technique to achieve thin profile of encapsulation together with soft tapered edges.
To a glass slide coated with Ease Release 200 (Mann Release Technologies) was applied tape masks to generate CB-PDMS 250 μm thick films. To a 200 mL round-bottom flask with a stir bar was weighed out 4.5 g of carbon black and 15.0 g of Sylgard 184 base. Both components were dissolved in n-hexanes (˜100 mL) and stirred vigorously for 10 min at room temperature. To the mixing solution was added 1.5 g Sylgard 184 curing agent diluted 10-fold with hexanes, and the reaction was stirred for 2-3 min. Solvent was rapidly removed and polymer simultaneously degassed with via rotary evaporation at 40° C. until a smooth spreadable paste was achieved. Polymer was spread onto glass molds, ensuring no cracks from excess n-hexanes evaporation with a flat edge. Samples were cured overnight at 70° C. to generate CB-PMDS films.
The top shell was prepared as described above. Briefly, a CB-PDMS sealed bottom layer was prepared by spin coating Silbione 4420RTV and curing as described above. A C02 Universal laser cutter was used to generate sensor openings with the same dimensions. CB-PDMS electrode pads were cut in the same shape with an excess overlap of 2 mm on all edges. Both the Silbione bottom layer and CB-PDMS pads were corona treated with a BD-20A High Frequency Generator (Electro-Technic Products, Inc.) for 40 sec, and pressed together for 15 sec and cured overnight at 70° C. To the cured bottom layer was laminated a layer of 3M 96042 double-coated tape that was cut into the shape of the device with holes for the pads. Double-sided 3M electrical tape adhesive was used to adhere the CB-PDMS to the Au-electrodes. The device components and seal between top and bottom layers was carried out as described above.
Non-functional devices CB-PDMS sealed devices, were prepared by replacing the electronic components with Drierite to monitor water permeability. Nonfunctional devices were submerged at 37° C. in 1× DPBS and weight changes were measured. A functional CB-PDMS sealed device, internally lined with three moisture indicators, was incubated continuously at 70° C. in 1× DPBS. Daily measurements of ECG devices were measured until device failure.
The inventors characterized time synchronization between the two nodes (ECG and PPG) through a bench top validation experiment: a two-channels function generator provided periodic signals (20 ms 3.5V square pulses separated by is) with a controlled time delay between the two channels. By connecting first channel to appropriate ECG layout pins and second channel to a red LED blinking on top of the PPG optical module, the inventors successfully demonstrated that the time delay measured through an oscilloscope connected to the function generator matches the time delay measured by the binodal system with the mean delay less than 1 ms with the average standard deviation of 3.6 ms (
Autoclavability test of sensor modular part (including no battery) and magnets have been performed using a Heidolph Tuttnauer 3545E Autoclave Sterilizer Electronic Model AE-K. Sterilization included a temperature ramp to 121° C. and a subsequent 15 minutes sterilization time, followed by drying. This process resulted in no alteration of devices performances, successfully demonstrating feasibility of autoclave sterilization of the platform.
The accuracy of temperature sensor was determined using reference thermometer (Fisherbrand™ 13202376, Fisher Scientific) measurements as standard. The thermometer of EES and the reference thermometer were both placed in a hot water bath that was heated to 42° C. and cooled to room temperature. During the cooling period, the temperature measurements between EES and the thermometer were recorded to characterize the precision of the temperature sensor in EES on the temperature range of 30° C. to 41° C.
KMC analysis was based on accelerometer measurements with a sampling rate of 100 Hz. The accelerometer was calibrated by aligning the x-, y-, and z-axes with the gravity vector and correlating the accelerometer signals with gravity force. The acceleration signal was processed by a Butterworth low pass filter of a cutoff frequency at 0.1 Hz and the angle of the device axes to the gravitation force was calculated through trigonometry processing. Accelerometer signals of the x-, y-, and z-axes were 3-dimensionally plotted and correlated with clinically recorded body positions.
Cry signal recording was achieved by EES with a sampling rate of 1600 Hz. The accelerometer signal was processed by a Butterworth high pass filter, 20 Hz cutoff frequency. Fast Fourier transform was performed on 200 ms segments. Cry event was identified where local maxima between 350 Hz and 500 Hz were significant, and periodic harmonics from lower frequency signals (such as patting) were excluded.
This example, related to one aspect of the invention, relates to an application of skin-interfaced biosensors and pilot studies for advanced wireless physiological monitoring in neonatal and pediatric intensive care units.
Pilot studies on patients in NICU and PICU demonstrate the feasibility of a pair of soft, skin-interfaced wireless devices to capture HR, SpO2, RR, as well as core and peripheral temperature with high levels of reliability and accuracy as compared with clinical standard monitoring systems that use conventional, hard-wired interfaces. In fact, the data indicate that in many cases the wireless operation and the gentle, mechanically stable measurement interfaces reduce the magnitude and prevalence of noise artifacts associated with motions and other parasitic effects, compared to wired systems. In addition to these basic vital signs, time synchronization techniques yield data that serve as promising surrogates of SBP, thereby offering the potential to bypass the use of cuffs for episodic measurements and arterial lines for continuous tracking48. Predicate results on adults and pediatric populations lend confidence in the findings presented here, as the first measurements that exploit accelerometer-based PTT on patients in the NICU and PICU. The device designs and the simplicity of the user interface suggest opportunities for deployment outside of traditional NICU/PICU facilities, into the developing world and even into the home. The availability of continuous, high quality digital data streams in these and other contexts suggest opportunities for use of advanced analytics to extend the range of utility in clinical and remote care.
Another important outcome of the work is in demonstrated capabilities for capturing advanced and unusual physiological signals such as SCG, body orientation, activity and vocal biomarkers. Cardiac monitoring with SCG yields important data to complement those associated with ECG, with enhanced utility in early detection of cardiac complications. Although SCG measurements are reported on adult populations, their use in routine clinical practice is rare and is absent in neonatal and/or pediatric contexts due, at least partly, to the high degrees of curvature of the chest and the fragility of the skin surface. The same data streams yield, through digital filtering techniques, information on body orientation and activity, which are relevant to identifying and quantifying KMC, feeding, holding, resting, patting, and potentially sleep patterns. Quantifying such measures has potential to provide insight into the role these activities have on physiologic stability, neurodevelopmental, and other short and long term outcomes. The collective suite of measurements may allow optimization and enhancements in care, in which vital signs and other parameters can serve as guiding signatures of efficacy. Here, as well as in traditional vital signs monitoring, advanced analytics, including methods such as machine learning, may be very powerful. Such techniques could offer particular value in the analysis of neonatal cry, as a rich source of information that represents the main method for neonates to communicate distress55. Studies in controlled settings using microphone recordings indicate that cry patterns reflect neurodevelopment and physiological status, with potential relevance to the detection of sudden infant death syndrome, asphyxia, congenital heart diseases, and respiratory distress syndrome57. The platforms introduced here eliminate difficulties associated with ambient sounds in the noisy environments of the NICU and PICU, thereby creating an opportunity to exploit this relatively underexplored, yet rich source of information in settings of practical interest.
The robustness of the platforms, the options in power supply, the sealed/waterproof construction, the soft mechanics, the skin-safe adhesive interfaces with no instances of skin tearing or dermatitis associated with the devices, the compatibility with established sterilization techniques, the re-usability of the devices, and the alignment of the constituent components, materials and designs with advanced manufacturing practice suggest broad deployability. The outcomes have the potential to enhance the quality and breadth of information for physicians, nurses and parents responsible for the care of neonatal/pediatric patients. A growing base of multilateral physiological data, most notably continuous heart activity, respiration, temperature, blood pressure, motion, body orientation, and vocal biomarkers, coupled with advanced learning algorithms, may facilitate early diagnosis of many common complications in these populations, including seizures, and apnea, upon extensive collection and analysis of data from relevant clinical studies. The core technology, beyond neonatal and pediatric critical care, has clear applications in post-acute monitoring, outpatient or home settings, trauma situations, and low-resource environments.
In certain embodiments, a soft, skin-like electronic system is provided to address these unmet clinical needs. Evaluation studies in the NICU confirm capabilities for clinically accurate measurements of heart rate (HR), blood oxygenation (SpO2), temperature, respiration rate (RR) and pulse wave velocity (PWV) in the NICU. However, this system is limited by (1) the modest maximum operating distances (˜30 cm) supported by NFC protocols used for power transfer and data communication, (2) the mechanically fragile nature of the ultrathin, compliant mechanics designs, (3) the sufficient, but constrained range of measurement capabilities, and (4) the demand for highly advanced device configurations, capable of fabrication only in specialized facilities with customized tools. The results reported below adopt and extend similar principles in soft electronics design, but in mechanically robust, manufacturable systems that rely on Bluetooth technology to circumvent these limitations. These systems include a range of options in operation and power supply that address a broad spectrum of clinical use cases and provider preferences, ranging from modular primary batteries to integrated secondary batteries to wireless power harvesting schemes. These platforms additionally support important modalities in monitoring that lie beyond both the standard of care and the capabilities of the previously reported systems. These include the ability to: (1) monitor movements and changes in body orientation, (2) track and assess the therapeutic effects of KMC and other forms of hands-on care, (3) capture acoustic signatures associated with cardiac activity by capturing mechanical vibrations generated through the skin on the chest wall reflective of valvular function (4), record vocal biomarkers associated with tonality and temporal characteristics of crying, and (5) quantify pulse wave dynamics through multiple measurements, as a reliable surrogate for systolic blood pressure.
The ability for this system to provide addition quantitative information on hemodynamic and cardiovascular health states beyond the core vital signs of heart rate, respiratory rate and blood oximetry holds direct relevance to the management of patients in the NICU/PICU. Visualization of heart vibrations, referred to as a seismocardiogram (SCG), is rarely performed in general clinical practice, especially in the NICU/PICU, yet it provides essential information on the mechanical outcomes of myocardial activity, valve motions and other features that are absent from ECG data. Episodic measurements of BP in current clinical practice on neonates and pediatric patients involve miniaturized, but otherwise conventional, BP cuffs that wrap around the limbs, while continuous tracking requires catheter-based pressure sensors (arterial lines) that insert into peripheral arteries. Both procedures, particularly the latter, are invasive and involve multiple risk factors, to an extent that they are used only in limited cases despite the essential utility of the information. The capabilities of the system enable the ability to address aspects of neurological, respiratory, and pathological disorders that are common in premature neonates and can lead to abnormalities in vocalization, range of motion, and posture control. Quantitative, continuous tracking of such behavior offers the potential for early detection of complications associated with birth trauma, brain injury or pain stress. Measurements of movement and physical activity specifically can provide insights into sensorimotor development. These same data can also inform effective methods for neonatal care such as KMC, a therapeutic skin-to-skin “treatment”, in which a pediatric patient is held against a parent's chest in a manner that lowers mortality, stabilizes heart rate, temperature, and respiration rate, and decreases the risks for infection.
The device and system design of this example is similar to those as used in Example 1. The technology platforms, measurement capabilities, clinical effectiveness, and safety through pilot studies on the same 50 patients in
This example uses a modular battery unit for power supply in a design that allows for gentle placement on the curved skin of the chest (chest unit) via a thin hydrogel coupling layer to record electrocardiograms (ECGs), acoustic signals of vocalization and cardiac/respiratory activity, body orientation and movements, and skin temperature, all enabled by a BLE SoC and associated collection of sensors. The overall layout includes a thin, flexible printed circuit board (PCB) and mounted components, configured in an open design with serpentine interconnect traces. The construction involves folding of distinct, but connected, platforms as a key step in assembly and packaging. Quantitative insights from three-dimensional finite element analysis (FEA) of the system-level mechanics helped to define an optimal distribution of the active components to reduce the lateral dimensions of the device by ˜250%. A pre-compression process in the assembly forms buckled layouts in a serpentine configuration to enhance flexibility and stretchability. An elastomeric enclosure with an inner silicone gel liner (˜300 μm thick, ˜4 kPa) enhances the device softness ensuring compatibility with the fragile skin and highly curved anatomical features of neonates born at the lowest gestational ages. A pair of thin, conductive elements formed using a doped silicone material (carbon black in polydimethylsiloxane, abbreviated as ‘CB PDMS’; bulk resistivity of 4.2 Ω·cm) serve as soft electrical connections to corresponding gold electrodes on the flexible printed circuit board and to conductive hydrogel skin interfaces for ECG measurements. The result is a soft and completely sealed, waterproof system with applicability across a wide range of settings, focused on but not limited to the NICU and PICU.
The modular battery unit couples to the device mechanically and electrically through pairs of matching sets of embedded magnets, thereby: (1) allowing replacement of the battery without removing the device from the patient with the aim to minimize disruptions in clinical care, decrease the burden on clinical staff, and consequently reduce risks of skin injury; (2) enabling removal of the battery to allow autoclave sterilization of device; and (3) mechanically decoupling the battery from the device to improve the bendability and, therefore, the compliance at the skin interface. The magnetic scheme also allows for other options for power supply, not only in choices of battery sizes, shapes and storage capacities (and therefore operational lifetimes), but also in alternative modalities, including battery-free schemes that rely on wireless power transfer. As an example of this latter possibility, a magnetically coupled harvesting unit can be configured to receive power from a transmission antenna placed under the bed and designed to operate at a radio frequency of 13.56 MHz with a negligible absorption in biological tissue.
Modular batteries are encapsulated with various shapes, showing the possible compatibility with choking hazard prevention requirements. Given that a removable battery can act as a swallowing and choking hazard in older infants, the battery can be designed with geometries that are larger than the minimum size requirements for consumer products used by children under the age of three (see
This limb unit features a layout that facilitates wrapping around the foot, palm or toe—this accommodates neonates and pediatric patients of varying ages and anatomies. The overall design of the limb unit is with umbilical interconnects that can bend to radii as small as ˜3.9 mm twist through angles as large as 180° and elastically stretch to uniaxial strains as high as 17% (see
The chest unit includes a wide-bandwidth 3-axial accelerometer (BMI160, Bosch Sensortec), a clinical-grade temperature sensor (MAX30205, Maxim Integrated), and an ECG system that consists of two gold-plated electrodes. The limb unit includes an integrated pulse oximetry module (MAX30101, Maxim Integrated) for measuring dual wavelength PPGs and a temperature sensor (MAX30205, Maxim Integrated). The power management circuit for battery operation uses a voltage regulator to provide supply voltages required for the various components (3.3V or 1.8V). The modular battery-free platform includes an inductive coil tuned to 13.56 MHz, a full-wave rectifier, and a two-stage cascaded voltage regulating unit.
The soft mechanical properties and the wireless modes of operation are critically important to effective use on neonatal and pediatric ICU patients, particularly when located at highly curved regions of anatomy on a limited surface area. Wrapping around the ankle-to-base of the foot is effective for premature neonates, as commonly encountered in the NICU. Other options include mounting around the foot-to-toe or the wrist-to-hand, typically most suitable for babies with chronological ages greater than 12 months. These mounting options enhance nearly all aspects of routine and specialized procedures in clinical care, ranging from intimate contact during KMC and parental holding to feed, change diapers, and bathe the infant.
Continuous wireless data transmission to a computer system that supports real-time data analytics yields results that can be graphically displayed in an intuitive manner for nurses, doctors and parents. The chest unit measures ECGs and skin temperature, together with a rich range of information that can be inferred from data collected with the high-bandwidth, 3-axis accelerometer, including SCGs, respiration rate and others, with sampling frequencies of 504 Hz (ECG), 0.2 Hz (temperature) and 100 Hz (SCG). The SCG provides information not only on HR, but also on the systolic interval, the pre-ejection period (PEP), and left ventricular ejection time. The limb unit measures PPGs at red (660 nm) and infrared (IR, 880 nm) wavelengths, and skin temperature, sampled at 100 and 0.2 Hz, respectively.
The streaming raw data from the devices undergoes real-time signal processing on the mobile tablet allowing for dynamic, adaptive vital signs display with negligible time delays. In many cases, relevant information can be extracted from different, independent data streams.
Calculation of peripheral capillary oxygen saturation (SpO2) exploits dual color PPGs with algorithms designed to minimize the effects of motion artifacts commonly encountered in the NICU and PICU due to naturally occurring movements (panel (c) of
The results for HR and SpO2 are within the regulatory guidelines set by the US Food and Drug Administration (FDA), which require errors less than +10% or +5 bpm for HR and less than 3.5% for Arms for reflectance mode SpO2. FDA guidelines for RR monitors under 21 CFR 870.2375 does not specify requirements in terms of accuracy, but a 510(k) cleared bedside monitoring system (Siemens SC 6000) delivers a target accuracy of ±3 breath per minute. Further safety testing on additional neonates (n=50) was conducted to evaluate skin tolerability and ensure negligible heat generation from the sensors operating concomitantly with standard monitoring systems. These results included a diverse range of age groups (23-40 wks gestational age and 1 week-4 yrs chronical age), and ethnicities (16 Caucasian, 24 Hispanic/Latino, and 10 Black/African American) (
Pulse arrival time (PAT) and pulse transit time (PTT) are two related but distinct measures with established correlations to systolic BP (SBP). The PAT, calculated from the time difference between the R-peak of ECGs on the chest unit and valley regions of the PPGs on the limb unit, represents the time delay of the pulse pressure wave to travel from the aorta to peripheral limb location at each cardiac cycle. Some studies suggest that the exclusion of the PEP from the PAT may improve correlation with SBP. PTT, calculated from the peak-to-foot time delay between the SCG and PPG waveforms, achieves this exclusion by capturing the residual peak when the aorta valve opens. Ultimately, both PAT and PTT depend on vascular system geometry, elasticity, SBP, and other factors. Extensive studies on adult subjects establish calibrated correlations between PAT, PTT and SBP using both empirical and theoretical models, some of which are clinically approved for monitoring in certain scenarios (e.g. Sotera ViSi Mobile® System). Few studies report the correlation of PAT with SBP in infants, mainly in the context of sleep studies and as screening method rather than a core clinical tool. None report measurements of PTT in this critical care population.
This design integrates synchronous operation of the chest and limb devices, enabling measurements of PAT and PTT for each cardiac cycle. To ensure timing accuracy, once every second the chest unit transmits its 16 MHz local clock information to the limb unit. The result eliminates timing drift to enable a synchronization accuracy of greater than 1 ms, on average, and a standard deviation of 3.6 ms over a continuous, 24 hour period of operation (see
SBP=−a(PT)+b (3)
Calculation of coefficients in the equation involves the linear regression of PAT and PTT data to 5 min of SBP data measured using an A-line, which serves as an initial calibration. The demonstration here of exclusion of PEP in the form of PTT is the first reported in NICU/PICU. Accelerometry data of a chest unit (
In addition to SCG and PTT, several additional important modes of operation follow from further use of data from the high-bandwidth 3-axis accelerometer. Examples include motion/movement (including tracking KMC and infant holding), and measuring vocal biomarkers such as tonality, dynamics and frequency of crying. According to guidelines from the World Health Organization (WHO), KMC involves holding the neonate in an upright position on the parent's chest, with the neonate's abdomen placed at the level of the parent's epigastrium, and the neonate's head turned to one side to allow eye contact with the parent. This body position, which can be precisely and continuously monitored using low pass filtered (0-0.1 Hz) data from the accelerometer of the chest unit, is distinct from those that occur during most other activities and forms of care.
Panel (a) of
Based on the results of HR, SpO2, central and peripheral skin temperature, along with a measurement of activity derived from the accelerometry data before, during, and after the KMC study, including removal and return of the neonate to the crib, activity corresponds to the root mean square value of 3-axis accelerometry data after bandpass filtering between 1 and 10 Hz. The data show that skin-to-skin contact during KMC produced a pronounced, gradual increase in the peripheral skin temperature, consistent with expectation and as demonstrated in previous studies. The mean activity levels during rest and KMC events are 0.07±0.02 g/s, while during hands-on care these values are 0.24±0.05 g/s (data are mean±std for 3 neonates, total 8 hours of KMC/rest and 75 min of hands-on care). These data have potential to provide a quantitative indicator to help minimize the disturbance of neonates during various forms of care, and, therefore, risks of hypopnea, apnea, and oxygen desaturation. Current work seeks to explore this opportunity and to establish methods to use the full set of measurement results to provide feedback on the timing and techniques of KMC, particularly in sessions extending beyond 4 hours, in which the impact on physiological parameters are expected to be enhanced.
In addition to activity, orientation and SCG, the accelerometer also yields information on vocal biomarkers generally, and crying in particular, via analysis of the high frequency components of the data. Cry analysis can serve as a non-invasive method to analyze the neurophysiological state, often influenced by birth trauma, brain injury or pain stress. Crying captured by measurements with microphones are easily confounded by ambient sounds in the environment, a particular challenge in NICU and PICU settings. The accelerometer, by contrast, responds only to mechanical vibratory motions of the chest, and is nearly completely unaffected by ambient noise. Panel (b) of
Fabrication involved soldering electronic components onto flexible printed circuit boards patterned using a laser ablation process. Embedding the assembled and folded system into a soft silicone enclosure completed the process. For the chest unit with modular options in power supply, films of a soft silicone material (Silbione RTV 4420; Part A & Part B, mixed with 5% of Silc-Pig silicone opaque dye) formed by spin-cast at 250 rpm and thermally curing (100° C. in an oven for 20 min) on glass slides served as top and a bottom layers for the encapsulation process. Curing of both layers involved heating to 100° C. in an oven for 20 minutes. A cutting process with a CO2 laser (ULS) defined openings for the ECG electrodes on the bottom layer and for magnets on the top layer. A silicone-based adhesive (3M 96042) bonded the electronics to the bottom layer. Pre-compression of the serpentines during this step ensured high levels of stretchability, with associated enhancements in the bendability. A silicone gel (Ecoflex, Smooth-On) cured at 100° C. for 20 min provided a soft, strain-isolating interface layer both below (center part) and above (whole coverage) the electronics. Bonding an overlayer of Silbione finalized the encapsulation process. A drop-casting technique formed coatings of Silbione on top of the various modules for power supply.
Fabrication of the integrated secondary battery version of the device exploited a related encapsulation process, but designed to yield an enclosed air-pocket design as a strain insulation layer to minimize the mechanical load associated with the battery. Here, Silbione cast in a machined aluminum mold served as a top capping layer. A film of this same material, formed as previously described, served as the bottom seal against the perimeter region of the shell to complete the enclosure.
An analogous process defined the encapsulating enclosure for the limb unit, with transparent regions at the location of the LED module for PPG measurements. For all devices, a final laser cutting step yielded a smooth, clean perimeter.
Preparation of Soft, Integrated Electrodes of PDMS Doped with Carbon Black (CB-PDMS)
The formulation involved the addition of 4.5 g of carbon black to 15.0 g of a silicone prepolymer (Sylgard 184 base) in a 200 mL round-bottom flask containing n-hexanes (100 mL) and stirred vigorously with a stir bar for 10 min at room temperature. Addition of 1.5 g of silicone curing agent (Sylgard 184 curing agent) pre-diluted in 1 mL hexane with continuous stirring for 2-3 min induced polymerization. Rotary evaporation at 40° C. led to simultaneous rapid removal of solvent and degassing of the polymer to yield a smooth paste. Uncured CB-PDMS, spread with a flat edge onto glass slides containing level guides coated with mold release spray (Ease Release 200, Mann Release Technologies), yielded thin solid films of CB-PDMS (250 μm thickness) after curing overnight in an oven at 70° C. Electrode pads, cut with a CO2 laser to lateral geometries larger by 2 mm along all edges of the openings for the ECG electrodes on the bottom surfaces of the chest unit, provided overlapping regions for bonding. Treatment of both elastomeric surfaces with a corona gun (BD-20A High Frequency Generator, Electro-Technic Products, Inc.) for 40 s, immediately followed by pressure induced lamination (15 s) and overnight curing at 70° C. in an oven yielded excellent adhesion. A double-sided conductive tape (3M 9719) bonded the CB-PDMS pads to the Au electrodes on the flexible printed circuit board.
Tests of permeation used platforms with the electronic components replaced with a dessicant (Drierite) (n=4). Studies involved daily gravimetric measurements following continuous immersion in 1× DPBS (Dulbecco's Phosphate Buffered Saline) at 37° C. A rapid increase in device weight (>1000 mg in 24 h) at ˜19-28 days followed from partial delamination of the perimeter seal between the top and bottom Silbione layers, as opposed to the seal between the CB-PDMS and Silbione. Additional tests with a functional chest unit continuously immersed in 1× DPBS at 70° C., demonstrated stable operation, evaluated daily, for 18 days.
Characterization of time synchronization used a two-channel function generator to provide a pair of periodic signals (20 ms 3.5V square pulses separated by is) with a controlled time delay between the two. Connecting one channel to the ECG module and the other to a red LED placed on top of the PPG module, yielded data that validated synchronization to a mean delay of less than 1 ms and a standard deviation of 3.6 ms.
Testing of Compatibility with Autoclave Sterilization
The tests focused on a chest unit with a modular primary battery and a Heidolph Tuttnauer 3545E Autoclave Sterilizer (Electronic Model AE-K). The process involved a temperature ramp to 121° C., a sterilization time of 15 min, and a drying time of 60 min, performed using a device with the battery removed. Functional tests before and after sterilization revealed no change in performance.
Measurements of the accuracy of the temperature sensor involved immersion in a water bath, heated to 42° C. and then cooled to room temperature, with simultaneous measurements using a reference thermometer (Fisherbrand™ 13202376, Fisher Scientific) as a standard.
The research protocol was approved by the Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University's Institutional Review Board (STU00202449) and registered on ClinicalTrials.gov (NCT02865070). After informed consent from at least one parent for all participants, the experimental sensors were placed on the chest and limb (foot or hand) by trained research staff. The sensors were placed in a way as to not disrupt any of the existing gold-standard monitoring equipment. No skin preparation was conducted prior to sensor placement or with sensor removal. The protocol enabled collection times of up to 24 hours. However, medical procedures (e.g. surgery) or imaging required removal of the sensors. Upon removal of the sensors, a board-certified dermatologist evaluated the underlying skin for evidence of irritation, redness, or erosions. Data were transmitted, collected, and stored for further data analysis on a tablet PC (Surface Pro 4, Microsoft) placed out of view from parents and clinical staff. All subjects in the Northwestern Prentice Women's Hospital and Lurie Children's Hospital admitted to the neonatal intensive care unit and pediatric intensive care unit were eligible regardless of gestational age.
KMC analysis relied on accelerometer measurements captured at a sampling rate of 100 Hz. Calibration involved aligning the x-, y-, and z-axes of the device with the gravity vector. Signal processing used a Butterworth low pass filter (3rd order) with a cutoff frequency at 0.1 Hz. Simple trigonometry defined the orientation angle from the acceleration values. Results plotted in three dimensions were correlated to manually recorded body positions. Processing the acceleration signal through a Butterworth bandpass filter (3rd order) between 1-10 Hz, followed by computation of the root-mean-square of the acceleration values along the x-, y-, and z-axes yielded a metric for neonatal activity level, determined each second.
Recording vibratory signatures of vocalization, including crying, involved operation of the accelerometer at a sampling rate of 1600 Hz. Signal processing used a Butterworth high pass filter (3rd order) with a 20 Hz cutoff frequency. Fast Fourier transforms yielded power spectra on time segments with durations of 200 ms. Cry events correspond to spectra with significant peaks between 350 Hz and 500 Hz, with exclusion of harmonics from lower frequency signals (such as those due to patting).
Statistical analysis used a one-way Multivariate Analysis of Variance (MANOVA) via MATLAB, with an assumption that data points for each group are normally distributed. P-value <0.05 was considered significant.
In certain embodiments, any of the systems and devices described herein may be used to practice any of the methods of the invention.
In a further aspect, the invention relates to a non-transitory tangible computer-readable medium storing instructions which, when executed by one or more processors, cause the methods as discussed above to be performed.
The foregoing description of the exemplary embodiments of the present invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to explain the principles of the invention and their practical application so as to activate others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the present invention pertains without departing from its spirit and scope. Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein.
This PCT application claims priority to and the benefit of U.S. Provisional Patent Application Ser. Nos. 62/753,303, 62/753,453 and 62/753,625, each of which was filed Oct. 31, 2018, and U.S. Provisional Patent Application Ser. No. 62/857,179, which was filed Jun. 4, 2019. The contents of the applications are incorporated herein by reference in their entireties. This PCT application is related to a co-pending PCT patent application entitled “APPARATUS AND METHOD FOR MEASURING PHYSIOLOGICAL PARAMETERS OF MAMMAL SUBJECT AND APPLICATIONS OF SAME”, by John A. Rogers et al., with Attorney Docket No. 0116936.213WO2, a co-pending PCT patent application entitled “SENSOR NETWORK FOR MEASURING PHYSIOLOGICAL PARAMETERS OF MAMMAL SUBJECT AND APPLICATIONS OF SAME”, by John A. Rogers et al., with Attorney Docket No. 0116936.214WO2, and a co-pending U.S. patent application entitled “APPARATUS AND METHOD FOR NON-INVASIVELY MEASURING BLOOD PRESSURE OF MAMMAL SUBJECT”, by John A. Rogers et al., with Attorney Docket No. 0116936.215US2, each of which is filed on the same day that this PCT application is filed, and with the same assignee as that of this application, and is incorporated herein by reference in its entirety. Some references, which may include patents, patent applications and various publications, are cited and discussed in the description of this invention. The citation and/or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2019/059190 | 10/31/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62753303 | Oct 2018 | US | |
| 62753453 | Oct 2018 | US | |
| 62753625 | Oct 2018 | US | |
| 62857179 | Jun 2019 | US |
