Patent Application
20240041363
The present invention relates generally to biosensors, and more particularly to wireless, implantable catheter-type oximeters designed for cardiac oxygen saturation and applications of 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.
The cardiovascular system delivers oxygen and nutrients to tissues and cells in the body. Maintaining an adequate balance between oxygen delivery and consumption is essential for cellular physiological function. Accurate and real-time monitoring of specific intracardiac and major vascular oxygen saturations after open-heart surgery is critically important for treating patients, especially those who suffer from cyanotic congenital heart defects. The measurement of these saturations is, in fact, performed during diagnostic cardiac catheterization to calculate cardiac output and derive vascular resistances. In the intensive care unit (ICU) setting, the intravenous fiber optic oximetric catheter is used to monitor continuously blood oxygen saturation, obtained either as mixed venous oxygen saturation (SvO2, a reflection of the global balance between oxygen delivery and consumption as it is measured in the pulmonary artery), or as central venous oxygen saturation (ScvO2, a reflection of regional oxygen extraction from the brain and the upper part of the body as it is measured from a central vein).
Existing fiber optic catheter oximeters use hard glass fiber waveguides to deliver light from an external source to the blood at the tip of the catheter, and to transmit some fraction of the backscattered light back to an external unit for detection. Here, the fiber optic catheter connects to a light source and sensing module and an additional interface joins the system to an apparatus that contains processing and driving circuits, display monitor and controlling software. The complete system provides an effective tool for monitoring venous oxygenation via insertion of the catheter probe through a vein to a desired location, but it tethers the patient to bedside hardware, thereby limiting their freedom of movement and complicating the simultaneous use of other diagnostic or therapeutic tools. Moreover, the rigid properties of the glass fiber can induce adverse events during long-term implantation, e.g. damage to blood vessels, infection, or thrombosis. For all patients who receive catheters, mechanical complications are reported to occur in 5 to 19 percent of patients, infectious complications in 5 to 26 percent, and thrombotic complications in 2 to 26 percent. These complications are particularly frequent and severe in infants and children. An unmet clinical need is in alternative type of oximeter designed to provide real-time, accurate intravascular oxygen saturation yet avoid adverse effects that can occur in these and other high-risk patients.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.
In light of the foregoing, one of the objectives of this invention is to provide a thin, flexible catheter-type optoelectronic probe that connects to a small, wearable electronic module for wireless, real-time, and continuous measurements of intravascular oxygen saturation with clinical-grade accuracy, thereby overcoming the aforementioned challenges in cardiovascular monitoring. The probe tip in some embodiments includes high-performance, miniaturized light-emitting diodes and photodiode, fully encapsulated with medical-grade, soft, transparent silicone elastomer. The electronic module supports rechargeable powering, circuit control, signal processing, and wireless data communication based on Bluetooth protocols. A graphical user interface deployed on a smartphone or tablet computer or ICU monitoring display enables real-time visualization, storage, and analysis of measurement data. The absence of physical tethers, the soft, biocompatible construction of the probe, and the lateral (as opposed to distal) configuration of the measurement represent key defining features. The invention presents potentially important advances in wireless optoelectronic technologies for cardiovascular care.
This invention in one aspect discloses an optoelectronic system. The optoelectronic system comprises an optoelectronic probe operably attached onto a target region of a subject; and an electronic module coupled with the optoelectronic probe for wireless, real-time, and continuous measurements of physiological information of the subject. The target region can be target tissues, a surface of a desired organ, and/or regions in proximity to an organ surface. In one embodiment, the physiological information comprises a tissue oxygenation, a heart rate (HR), a respiration rate (RR), and/or a temperature.
In one embodiment, the optoelectronic probe comprises a low modulus, flexible catheter with a probe tip comprising an optoelectronic sensor mounted onto a flexible printed circuit board (fPCB) in a geometry of a narrow, thin strip that detachably and electrically connects to the electronic module.
In one embodiment, the narrow, thin strip has a width in a range of about 0.5-2 mm, a thickness in a range of about 50-180 μm, and a length in a range of about 5-20 mm.
In one embodiment, the fPCB comprises a flexible substrate and conductive traces, pads and outline defined on the flexible substrate. In one embodiment, the flexible substrate is formed of a flexible material.
In one embodiment, the optoelectronic sensor comprises optical stimulation and sensing components, and optical blocking modules.
In one embodiment, the optical stimulation and sensing components comprise at least two light-emitting diodes (LEDs) and at least one photodiode (PD).
In one embodiment, the at least two LEDs and the at least one PD are surface mount (SMT) electronic components that are placed and attached onto the fPCB using reflow soldering.
In one embodiment, the at least two LEDs comprises a red LED with a peak emission wavelength in a range of about 600-700 nm and an infrared LED with a peak emission wavelength in a range of about 850-1050 nm.
In one embodiment, the optoelectronic probe further comprises one or more LEDs with peak emission wavelengths different from that of the red LED and the IR LED for additional measurement capabilities.
In one embodiment, the optical stimulation and sensing components are arranged in a lateral configuration such that the LEDs have divergent and lateral emission features that maximize light-tissue coupling for a range of implantation sites including blood vessel and cardiac tissue.
In one embodiment, the at least two LEDs are positioned laterally to a long axis of the probe.
In one embodiment, the PD is positioned to be equidistant to the two LEDs at a distance selected to balance sensing depth, probing volume, and signal to noise ratio.
In one embodiment, the probe volume and probe depth are operably adjusted through control over of light intensity of the LEDs and the distance between the LEDs and PD, to allow optimization for measurements of localized tissue oximetry on different sites of interest. In one embodiment, the distance is in a range of about 1-3 mm.
In one embodiment, the optical blocking modules comprise at least two light-blocking structures for eliminating parasitic transmission of light from the LEDs directly to the PD without passing through surrounding tissues of interest.
In one embodiment, at least two light-blocking structures comprise two opaque silicone-based cuboid structures.
In one embodiment, one of the light-blocking structures is positioned between the PD and one side of the LEDs, and the other of the light-blocking structures is positioned at the probe tip close to the other side of the LEDs.
In one embodiment, a small plug-in connector serves as an electrical interface between the optoelectronic probe and the electronic module and allows battery recharge using a wired interface.
In one embodiment, a medical-grade, biocompatible silicone fully encapsulates the optoelectronic probe to define the low modulus, flexible catheter having a cylindrical shape and smooth surface that facilitates surgical manipulation and insertion.
In one embodiment, the low modulus, flexible catheter has a diameter in a range of about 0.5-2 mm.
In one embodiment, the optoelectronic probe is a catheter-type oximetry sensor.
In one embodiment, the optoelectronic probe further comprises sensors for measuring pressure and flow, and/or means for drug delivery.
In one embodiment, the electronic module is a bendable, miniaturized, battery-powered electronic module adapted for rechargeable powering, circuit control, signal processing, and wireless data communication.
In one embodiment, the electronic module comprises a fPCB, electronic components mounted onto the fPCB, and a battery module coupled with the electronic components, which are disposed between a bottom encapsulation layer and a top encapsulation layer.
In one embodiment, the electronic components comprises a wireless controller for performing data sampling, controlling the LEDs in low duty cycle mode, executing data processing and operating wireless communications.
In one embodiment, the wireless communications use at least one communication protocol of near field communication (NFC), Wi-Fi/Internet, Bluetooth, Bluetooth low energy (BLE), and Cellular communication protocols.
In one embodiment, the battery module comprises at least one battery. In one embodiment, the at least one battery is rechargeable.
In one embodiment, the optoelectronic system further comprises a customized app with a graphical user interface deployed on an external device that enables real-time visualization, storage, and analysis of measured data, wherein the graphical user interface provides a control interface to the optoelectronic system.
In one embodiment, the external device is a mobile device, a computer, or an ICU monitoring display.
In one embodiment, the optoelectronic system is mechanically compliant and water resistant.
In one embodiment, the optoelectronic system is devoid of physical tethers.
In one embodiment, the optoelectronic system is configured to measure changes in heart rate, respiration rate, ischemia, and arrhythmias.
In one embodiment, the optoelectronic system is useable for monitoring intravascular or intracardiac oxygen saturation at home or in a surgical operation.
In another aspect, the invention relates to a method of fabricating an optoelectronic system. The method includes forming a low modulus, flexible catheter-type optoelectronic probe; and assembling an electronic module detachably and electrically connected to the optoelectronic probe for wireless, real-time, and continuous measurements of physiological information of the subject.
In one embodiment, said forming the catheter-type optoelectronic probe comprises providing a fPCB comprising a flexible substrate and conductive traces, pads and outline defined on the flexible substrate; attaching an optoelectronic sensor onto the fPCB using reflow soldering with low-temperature solder paste to form a sensing module; connecting the sensing module to a detachable connector through a plurality of conductive wires with a desired length; placing the sensing module and the conductive wires into a flexible tube; injecting a biocompatible silicone prepolymer into the flexible tube, and curing the injected silicone prepolymer in a period of time; and removing the flexible tube to form the comprises the low modulus, flexible catheter-type optoelectronic probe.
In one embodiment, the optoelectronic sensor comprises SMT electronic components comprising a red LED, an infrared LED, and a PD.
In one embodiment, the red and infrared LEDs are positioned laterally to a long axis of the probe, wherein the PD is positioned to be equidistant to the red and infrared LEDs at a distance selected to balance sensing depth, probing volume, and signal to noise ratio.
In one embodiment, the optoelectronic sensor further comprises at least two light-blocking structures, wherein one of the light-blocking structures is positioned between the PD and one side of the red and infrared LEDs, and the other of the light-blocking structures is positioned at the probe tip close to the other side of the red and infrared LEDs.
In one embodiment, the electronic module comprises a fPCB, electronic components mounted onto the fPCB, and a battery module coupled with the electronic components.
In one embodiment, the electronic components comprises a wireless microcontroller.
In one embodiment, said providing the electronic module comprises providing a first layer of a flexible material formed in a mold and a second layer of the flexible material formed on a glass slide, served as a top encapsulation layer and a battom encapsulation layer, respectively; placing the electronic module into the first layer, pouring a solution of soft silicone to fill voids in between electronics and the first layer, and attaching the glass slide with the second layer defined a surface for a skin interface, and clamping them together to form an assembly; curing the assembly to complete encapsulation; and cutting the cured assembly to define a smooth perimeter boundary for the optoelectronic system and openings for detachable and electrical connection to the optoelectronic probe.
These and other aspects of the present 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 disclosure.
The accompanying drawings illustrate one or more embodiments of the invention and together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.
The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This 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 invention 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 has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that 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.
One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.
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. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.
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” another feature may have portions that overlap or underlie the adjacent feature.
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 could be termed a second element, component, region, layer or section without departing from the teachings of the invention.
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 depicted 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 “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending of 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.
It will be further understood that the terms “comprises” and/or “comprising”, or “includes” and/or “including”, or “has” and/or “having”, or “carry” and/or “carrying”, or “contain” and/or “containing”, or “involve” and/or “involving”, “characterized by”, and the like are to be open-ended, i.e., to mean including but not limited to. When used in this disclosure, they 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.
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 this 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 invention, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used in the 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 the 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 the disclosure, the term “bidirectional wireless communication system” refers to onboard components of sensors, wireless controller and other electronic components that provides capability of receiving and sending signals using at least one communication protocol of near field communication (NFC), Wi-Fi/Internet, Bluetooth, Bluetooth low energy (BLE), and Cellular communication protocols for wireless communication. In this manner, an output may be provided to an external device, including a cloud-based device, personal portable device, or a caregiver's computer system. Similarly, a command may be sent to the sensor, such as by an external controller, which may or may not correspond to the external device. Machine learning algorithms may be employed to improve signal analysis and, in turn, command signals sent to the medical sensor, including a stimulator of the medical sensor for providing haptic signal to a user of the medical device useful in a therapy. More generally, these systems may be incorporated into a processor, such as a microprocessor located on-board or physically remote from the electronic device of the medical sensor. An example of the wireless controller is a near field communication (NFC) chip, including NFC chips. NFC is a radio technology enabling bi-directional short range wireless communication between devices. Another example of a wireless controller is a Bluetooth® chip, or a BLE system-on-chip (SoC), which enables devices to communicate via a standard radio frequency instead of through cables, wires or direct user action.
The term “flexibility” or “bendability”, as used in the disclosure, refers to the ability of a material, structure, device or device component to be deformed into a curved or bent shape without undergoing a transformation that introduces significant strain, such as strain characterizing the failure point of a material, structure, device or device component. In an exemplary embodiment, a flexible material, structure, device or device component may be deformed into a curved shape without introducing strain larger than or equal to 5%, for some applications larger than or equal to 1%, and for yet other applications larger than or equal to 0.5% in strain-sensitive regions. A used herein, some, but not necessarily all, flexible structures are also stretchable. A variety of properties provide flexible structures (e.g., device components) of the invention, including materials properties such as a low modulus, bending stiffness and flexural rigidity; physical dimensions such as small average thickness (e.g., less than 100 microns, optionally less than 10 microns and optionally less than 1 micron) and device geometries such as thin film and open or mesh geometries.
The term “bending stiffness” refers to a mechanical property of a material, device or layer describing the resistance of the material, device or layer to an applied bending moment. Generally, bending stiffness is defined as the product of the modulus and area moment of inertia of the material, device or layer. A material having an inhomogeneous bending stiffness may optionally be described in terms of a “bulk” or “average” bending stiffness for the entire layer of material.
The terms “Young's modulus” and “modulus” are used interchangeably and refer to a mechanical property of a material, device or layer which refers to the ratio of stress to strain for a given substance. Young's modulus may be provided by the expression;
where E is Young's modulus, L0 is the equilibrium length, ΔL is the length change under the applied stress, F is the force applied and A is the area over which the force is applied. Young's modulus may also be expressed in terms of Lame constants via the equation:
where λ and μ are Lame constants. High Young's modulus (or “high modulus”) and low Young's modulus (or “low modulus”) are relative descriptors of the magnitude of Young's modulus in a given material, layer or device. In some embodiments, a high Young's modulus is larger than a low Young's modulus, preferably 10 times larger for some applications, more preferably 100 times larger for other applications and even more preferably 1000 times larger for yet other applications. “Inhomogeneous Young's modulus” refers to a material having a Young's modulus that spatially varies (e.g., changes with surface location). A material having an inhomogeneous Young's modulus may optionally be described in terms of a “bulk” or “average” Young's modulus for the entire layer of material.
The term “elastomer”, as used in the disclosure, refers to a polymeric material which can be stretched or deformed and return to its original shape without substantial permanent deformation. Elastomers commonly undergo substantially elastic deformations. Useful elastomers include those comprising polymers, copolymers, composite materials or mixtures of polymers and copolymers. Elastomeric layer refers to a layer comprising at least one elastomer. Elastomeric layers may also include dopants and other non-elastomeric materials. Useful elastomers useful include, but are not limited to, thermoplastic elastomers, styrenic materials, olefenic materials, polyolefin, polyurethane thermoplastic elastomers, polyamides, synthetic rubbers, PDMS, polybutadiene, polyisobutylene, poly(styrene-butadiene-styrene), polyurethanes, polychloroprene and silicones. Exemplary elastomers include, but are not limited to, silicon containing polymers such as polysiloxanes including poly(dimethyl siloxane) (i.e. PDMS and h-PDMS), poly(methyl siloxane), partially alkylated poly(methyl siloxane), poly(alkyl methyl siloxane) and poly(phenyl methyl siloxane), silicon modified elastomers, thermoplastic elastomers, styrenic materials, olefenic materials, polyolefin, polyurethane thermoplastic elastomers, polyamides, synthetic rubbers, polyisobutylene, poly(styrene-butadiene-styrene), polyurethanes, polychloroprene and silicones. In one embodiment, a flexible polymer is a flexible elastomer.
The term “encapsulate” or “encapsulation”, as used in the disclosure, refers to the orientation of one structure such that it is at least partially, and in some cases completely, surrounded by one or more other structures. “Partially encapsulated” refers to the orientation of one structure such that it is partially surrounded by one or more other structures. “Completely encapsulated” refers to the orientation of one structure such that it is completely surrounded by one or more other structures. The invention includes devices having partially or completely encapsulated electronic devices, device components and/or inorganic semiconductor components.
Embodiments of the invention are illustrated in detail hereinafter with reference to accompanying drawings. 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.
Accurate, real-time monitoring of intravascular oxygen levels can be a crucial aspect of tracking the cardiopulmonary health of patients after open-heart surgery. Existing technologies use intravascular placement of glass fiber optic probes which can expose patients to the usual risks of blood vessel damage, thrombosis and infection, associated with indwelling catheters. In addition, the physical tethers that connect currently utilized probes to external light sources, detectors, and data acquisition hardware limit freedom of movement and add clutter to the intensive care unit (ICU) environment.
In view of the foregoing, the invention discloses an alternative oximeter technology that avoids these disadvantages through the application of a miniaturized, implantable optoelectronic catheter that incorporates light emitting and detecting components on the probe itself, encapsulated by soft biocompatible materials. A small, skin-interfaced module serves as a wireless interface to a tablet computer that continuously displays oxygen saturation, as well as cardiac and respiratory activity. In vitro and in vivo testing shows that this platform offers measurement accuracy and precision equivalent to those of clinically used pulse oximeter and clinical fiber optic technologies for pulse oximetry, heart rate and for intravascular oximetry, with results that match values determined with a blood gas analyzer. These findings establish the foundations of advanced wireless technology for monitoring specific intracardiac oxygenation saturation following cardiothoracic surgery.
Referring to
In some embodiments, the optoelectronic probe comprises a low modulus, flexible catheter with a probe tip comprising an optoelectronic sensor mounted onto a flexible printed circuit board (fPCB) in a geometry of a narrow, thin strip that detachably and electrically connects to the electronic module. In one embodiment, the narrow, thin strip has a width in a range of about 0.5-2 mm, a thickness in a range of about 50-180 μm, and a length in a range of about 5-20 mm.
In some embodiments, the fPCB comprises a flexible substrate and conductive traces, pads and outline defined by, for example, patterned ablation of the copper using a UV laser system, on the flexible substrate. In one embodiment, the flexible substrate is formed of a flexible material. On embodiment of the flexible material includes, is not limited to, a medical-grade, soft, transparent silicone elastomer.
In some embodiments, the optoelectronic sensor comprises optical stimulation and sensing components, and optical blocking modules.
In one embodiment, the optical stimulation and sensing components comprise at least two light-emitting diodes (LEDs) and at least one photodiode (PD). In one embodiment, the at least two LEDs and the at least one PD are surface mount (SMT) electronic components that are placed and attached onto the fPCB using reflow soldering. In one embodiment, the at least two LEDs comprises a red LED with a peak emission wavelength in a range of about 600-700 nm and an infrared LED with a peak emission wavelength in a range of about 850-1050 nm.
In some embodiments, the optical stimulation and sensing components are arranged in a lateral configuration such that the LEDs have divergent and lateral emission features that maximize light-tissue coupling for a range of implantation sites including blood vessel and cardiac tissue. In one embodiment, the at least two LEDs are positioned laterally to a long axis of the probe. In one embodiment, the PD is positioned to be equidistant to the two LEDs at a distance selected to balance sensing depth, probing volume, and signal to noise ratio. In one embodiment, the probe volume and probe depth are operably adjusted through control over of light intensity of the LEDs and the distance between the LEDs and PD, to allow optimization for measurements of localized tissue oximetry on different sites of interest. In one embodiment, the distance is in a range of about 1-3 mm.
In some embodiments, the optical blocking modules comprise at least two light-blocking structures for eliminating parasitic transmission of light from the LEDs directly to the PD without passing through surrounding tissues of interest. In one embodiment, at least two light-blocking structures comprise two opaque silicone-based cuboid structures. In one embodiment, one of the light-blocking structures is positioned between the PD and one side of the LEDs, and the other of the light-blocking structures is positioned at the probe tip close to the other side of the LEDs.
In some embodiments, a small plug-in connector serves as an electrical interface between the optoelectronic probe and the electronic module and allows battery recharge using a wired interface.
In some embodiments, a medical-grade, biocompatible silicone fully encapsulates the optoelectronic probe to define the low modulus, flexible catheter having a cylindrical shape and smooth surface that facilitates surgical manipulation and insertion. In one embodiment, the low modulus, flexible catheter has a diameter in a range of about 0.5-2 mm.
In some embodiments, the optoelectronic probe is a catheter-type oximetry sensor.
In some embodiments, the optoelectronic probe may further comprise one or more LEDs with peak emission wavelengths different from that of the red LED and the IR LED for additional measurement capabilities.
In some embodiments, the optoelectronic probe further comprises sensors for measuring pressure and flow, and/or means for drug delivery.
In some embodiments, the electronic module is a bendable, miniaturized, battery-powered electronic module adapted for rechargeable powering, circuit control, signal processing, and wireless data communication.
In some embodiments, the electronic module comprises a fPCB, electronic components mounted onto the fPCB, and a battery module coupled with the electronic components, which are disposed between a bottom encapsulation layer and a top encapsulation layer.
In some embodiments, the electronic components comprises a wireless controller for performing data sampling, controlling the LEDs in low duty cycle mode, executing data processing and operating wireless communications. In one embodiment, the wireless communications use at least one communication protocol of near field communication (NFC), Wi-Fi/Internet, Bluetooth, Bluetooth low energy (BLE), and Cellular communication protocols.
In some embodiments, the battery module comprises at least one battery. In one embodiment, the at least one battery is rechargeable.
In some embodiments, the optoelectronic system further comprises a customized app with a graphical user interface deployed on an external device that enables real-time visualization, storage, and analysis of measured data. The graphical user interface provides a control interface to the optoelectronic system. The external device can be a mobile device, a computer, or an ICU monitoring display.
In some embodiments, the optoelectronic system is mechanically compliant and water resistant.
In some embodiments, the optoelectronic system is devoid of physical tethers.
In some embodiments, the optoelectronic system is configured to measure changes in heart rate, respiration rate, ischemia, and arrhythmias.
In some embodiments, the optoelectronic system is useable for monitoring intravascular or intracardiac oxygen saturation at home or in a surgical operation.
In one aspect, the invention relates to a method of fabricating an optoelectronic system. The method includes forming a low modulus, flexible catheter-type optoelectronic probe; and assembling an electronic module detachably and electrically connected to the optoelectronic probe for wireless, real-time, and continuous measurements of physiological information of the subject.
In some embodiments, said forming the catheter-type optoelectronic probe comprises providing a fPCB comprising a flexible substrate and conductive traces, pads and outline defined on the flexible substrate; attaching an optoelectronic sensor onto the fPCB using reflow soldering with low-temperature solder paste to form a sensing module; connecting the sensing module to a detachable connector through a plurality of conductive wires with a desired length; placing the sensing module and the conductive wires into a flexible tube; injecting a biocompatible silicone prepolymer into the flexible tube, and curing the injected silicone prepolymer in a period of time; and removing the flexible tube to form the comprises the low modulus, flexible catheter-type optoelectronic probe. The plurality of conductive wires in some embodiments includes four Teflon-coated copper wires.
In some embodiments, the optoelectronic sensor comprises SMT electronic components comprising a red LED, an infrared LED, and a PD.
In some embodiments, the red and infrared LEDs are positioned laterally to a long axis of the probe, wherein the PD is positioned to be equidistant to the red and infrared LEDs at a distance selected to balance sensing depth, probing volume, and signal to noise ratio.
In some embodiments, the optoelectronic sensor further comprises at least two light-blocking structures, wherein one of the light-blocking structures is positioned between the PD and one side of the red and infrared LEDs, and the other of the light-blocking structures is positioned at the probe tip close to the other side of the red and infrared LEDs.
In some embodiments, the electronic module comprises a fPCB, electronic components mounted onto the fPCB, and a battery module coupled with the electronic components.
In some embodiments, the electronic components comprises a wireless microcontroller.
In some embodiments, said providing the electronic module comprises providing a first layer of a flexible material formed in a mold and a second layer of the flexible material formed on a glass slide, served as a top encapsulation layer and a battom encapsulation layer, respectively; placing the electronic module into the first layer, pouring a solution of soft silicone to fill voids in between electronics and the first layer, and attaching the glass slide with the second layer defined a surface for a skin interface, and clamping them together to form an assembly; curing the assembly to complete encapsulation; and cutting the cured assembly to define a smooth perimeter boundary for the optoelectronic system and openings for detachable and electrical connection to the optoelectronic probe.
According to the invention, the absence of physical tethers and the flexible, biocompatible construction of the probe represent key defining features, resulting in a high-performance implantable oximeter that can monitor localized tissue oxygenation, heart rate and respiratory activity in a patient-friendly mode with wireless, real-time, continuous operation. In vitro and in vivo testing shows that this platform offers measurement accuracy and precision equivalent to those of existing clinical standards.
These and other aspects of the present invention are further described below. Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results 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.
Accurate, real-time monitoring of intravascular oxygen levels is important in tracking the cardiopulmonary health of patients after cardiothoracic surgery. Existing technologies use intravascular placement of glass fiber-optic catheters that pose risks of blood vessel damage, thrombosis, and infection. In addition, physical tethers to power supply systems and data acquisition hardware limit freedom of movement and add clutter to the intensive care unit.
This exemplary study introduces a wireless, miniaturized, implantable optoelectronic catheter system incorporating optical components on the probe, encapsulated by soft biocompatible materials, as alternative technology that avoids these disadvantages. The absence of physical tethers and the flexible, biocompatible construction of the probe represent key defining features, resulting in a high-performance, patient-friendly implantable oximeter that can monitor localized tissue oxygenation, heart rate, and respiratory activity with wireless, real-time, continuous operation. In vitro and in vivo testing shows that this platform offers measurement accuracy and precision equivalent to those of existing clinical standards.
The platform includes a thin, flexible catheter-type optoelectronic probe that connects to a small, wearable electronic module for wireless, real-time, and continuous measurements of intravascular oxygen saturation with clinical-grade accuracy. The probe tip in this exemplary embodiment includes high-performance, miniaturized light-emitting diodes (LEDs) and photodiode (PD), fully encapsulated with medical-grade, soft, transparent silicone elastomer. The electronic module supports rechargeable powering, circuit control, signal processing, and wireless data communication based on Bluetooth protocols. A graphical user interface deployed on a smartphone or tablet computer or ICU monitoring display enables real-time visualization, storage, and analysis of measurement data. The absence of physical tethers, the soft, biocompatible construction of the probe, and the lateral (as opposed to distal) configuration of the measurement represent key defining features. Systematic studies of these systems inform optimized choices for the materials, the mechanical layouts, the thermal management approaches, the encapsulation strategies, and the optical setups. Tests on healthy human volunteers yield data that are in excellent agreement with clinical standard pulse oximeters for global oxygen saturation and heart rate measurement. Investigations using rat models show that the catheter can be implanted and sutured to the cardiac surface, and that the measured oximetry values match those determined using a clinical blood gas analyzer. These results represent potentially important advances in wireless optoelectronic technologies for cardiovascular care.
Referring to
The wireless electronics module was designed using EAGLE 8.5 (Autodesk Inc.). The schematic and PCB layout are described above. A micropower, zero input crossover distortion amplifier (ADA4505-1, Analog Devices Inc) acts as a transimpedance amplifier. A Bluetooth Low Energy (BLE) microcontroller (NRF52832, Nordic Semiconductor Inc.) with a custom program performs data sampling, controls the LEDs in low duty cycle mode, executes data processing and operates Bluetooth communication. With a feedback resistor of 2 mega ohm, the catheter probe and the wireless electronic module have a dark noise (root mean square, RMS) of 1.9 mV for NIR LED, 1.72 mV for Red, which correspond to a photocurrent sensitivity of 0.95 nA for NIR LED, 0.86 nA for Red.
Fabrication involved procedures similar to those described above, with an fPCB patterned using the laser ablation tool, and SMT components assembled using reflow soldering. A 3-axis milling machine (Roland MDX 540) formed aluminum molds in geometries defined by 3D CAD drawings created using ProE Creo 3.0. Films of a soft silicone material (Silbione RTV 4420; Part A & Part B, mixed with 5% of Silc-Pig silicone opaque dye) created in the mold by drop-casting and other films formed by spin-casting (250 rpm) on glass slides, both thermally cured in an oven (70° C. for 30 min), served as top and bottom layers, respectively, for a soft, encapsulating enclosure. Placing the fully assembled electronic module into the molded layer, pouring a solution of soft silicone to fill the voids in between electronics and the top layer, and attaching the glass slides with silicone films defined the surface for the skin interface. Clamping the parts together and placing the entire assembly into an oven for curing (70° C. for 30 min) completed the encapsulation. A final cutting process with a CO2 laser (ULS) defined a smooth perimeter boundary for the system, and a manual cutting process with a small blade defined openings for the connector and switch.
Spectroscopic measurements (using FOIS-1 Fiber Optic Integrating Sphere, Ocean Optics; FLAME-S-UV-VIS Spectrometer, Ocean Optics) yielded the emission spectra for the red and NIR LEDs. Exposing the photodetector to light passed through a chopper and recording the photocurrent using a data acquisition system (PXI-1031, National Instruments) provided measurements of the response time.
Simulations of light transport in biological tissues used Monte Carlo methods for the devices reported here and for conventional fiber optic systems to define the spatial illumination profiles. The simulations used a three-dimensional computational space with 700×700×700 bins of 2×10−9 cm3 volume, and a total of 11×106 photon packets for each simulation. Commercial light-emitting diodes (LEDs) with peak emission wavelengths at 645 nm (red) and 950 nm (near infrared, NIR) served as light sources, both with active illumination areas of 0.25×0.25 mm2 and emission angles of ±60°. For the optical fiber system, the optical core had a diameter of 0.2 mm a numerical aperture of 0.22, to yield illumination in a ±9.5° emission cone in aqueous solution (naqueous=1.38). The irradiances at the illumination surfaces for both setups were 9.21 mW/mm2 for red and 14.4 mW/mm2 for NIR. Light propagation was simulated in cardiac muscle tissue with the corresponding wavelength dependent scattering anisotropy factor (gRed-m=0.93, gNIR-m=0.93), absorption coefficient (μa-Red-m=0.56 cm−1, μa-NIR-m=0.46 cm−1) and scattering coefficient (μa-Red-m=79 cm−1, μs-NIR-m=64 cm−1). Additional simulations in aqueous solution defined the illumination profiles produced by both systems at the red wavelength. The scattering anisotropy factor (gRed-a=0.95), scattering coefficient (μs-Red-a=1 cm−1) and absorption coefficient (μa-Red-a=0.43 cm−1) were used for a solution with 1.6 μM concentration of fluorescent dye (Alexa Fluor 647) as a local illumination reporter (MW=1.25 kDa and i=270×103 cm−1M−1). The illumination profile was extracted from the simulation volume given by the photon fluence (Φ) which represents the phenomenological optical irradiance.
An NTC component (ERTJZEG103FA, with dimensions of 600 μm×300 μm×300 μm, Panasonic Co.) attached to the outer encapsulation layer, at a position directly above the LEDs, yielded measurements of temperature for the case of insertion inside a piece of pork belly. The thermistor connected to the input of a digital multimeter (PXIE-4065, National Instrument) through Teflon-coated copper wires (40 AWG enameled coppwer, Remington Industries), for continuous resistance measurements. The oximeter probe was activated at 1 min and de-activated at 4 min, for a total recording of 6 min. Converting the resistances into temperatures using manufacturers specifications yielded changes in temperature as a function of time during this simple on-and-off cycle, as shown in
Heat transfer analysis shown in
where T is temperature, t is time; k, ρ, and Cp are the thermal conductivity, mass density and heat capacity of the heart, respectively; Qthe is the heat generated from thermal power of the LEDs. The heat associated with light emission was calculated as the product of the light fluence rate Φ obtained in the optical simulation and the absorption coefficient j a of the cardiac muscle tissue. The optical and thermal properties appear in Tables 1 and 2. The cardiac tissue, probe geometry, and the LEDs were modeled using 4-node tetrahedral elements. Convergence tests of the mesh size were performed to ensure accuracy. The total number of elements in the models was approximately 650,000.
The Young's moduli of different coating materials were measured by indentation testing (Hysitron BioSoft Indenter, Bruker) with an indenter radius of r=200 μm. Tests on films of different materials (˜1 mm in thickness) generated force-displacement curves upon contact of the indenter and the film surface. The Young's modulus was calculated by fitting the force-displacement data within an indentation depth (δ=20 μm using a Hertzian contact model.
Catheter tubes with different coating materials and conductive copper wire diameters exhibit different bending stiffness, as measured by cantilever bending tests using a dynamic mechanical analyzer (RSA-G2, TA Instruments). A wire sample (L=19 mm) with one end clamped and the other end under a point load applied by an indenter served as a cantilever for bending stiffness measurement (
The bending stiffness EI can then be calculated as
For each measurement, the force-displacement data from the initial deflection of 6=0.2 mm upon contact between the indenter and the wire was used for the calculation of bending stiffness. Four measurements at different sections of the wire were taken for each sample.
The finite element analysis (FEA) commercial software ABAQUS (Analysis User's Manual 2010, V6.10) was utilized to study the mechanics and to optimize the design layouts and materials selections. The objective was to decrease the strains in the Cu wire interconnects and the Cu layers in the sensor probe during mechanical deformations. The silicone, Cu wires (80 μm diameter), and PI films (75 μm thick) were modeled by hexahedron elements (C3D8R) while the thin Cu layer (18 μm thick) of the flexible printed circuit board were modeled by shell elements (S4R). The minimal element size was 115 th of the width of the narrowest interconnects (15 μm), to ensure the convergence of the mesh, and the accuracy of the simulation results. The values of the elastic modulus (E) and Poisson's ratio (v) used in the analysis were ECu=119 GPa, vCu=0.34, EPI=2.5 GPa, vPI=0.34, ESlicone=1 MPa, and vslicone=0.49.
The two ends of a device were clamped (distance between the two clamped ends is 4 cm) to two translational stages. Repeatedly moving one translational stage towards the other back and forth by a distance of 3 cm led to bending of the probe to minimum bending radius of −5 mm. After every 2000 bending cycles, the probe was removed from the apparatus, inserted into an integrating sphere (Fiber Optic Spectrometer FOIS-1 Integrating Sphere, Ocean Optics), connected to the electronic module, and activated to yield measurements of photovoltages corresponding to emission from the two LEDs. Gripping the tip of the probe between the thumb and index finger, connecting the probe to the electronic module, and operating the system yielded photoplethysmograms. Such tests were performed up to 10,000 bending cycles. The soak tests began with immersion of the probe into a chamber filled with phosphate-buffered saline (PBS) and mounting in an oven at 37° C. Evaluations of the devices occurred once per week, according to procedures described above, for a total of 8 weeks.
A medical-grade autoclave system (Tuttnauer EZ10 Fully Automatic Autoclave) was used to sterilize the optical sensing probe, with LEDs, PD and light blocking elements on the fPCB and fully encapsulated with a medical-grade silicone material (MED-1000) in a cylinder (diameter: 1.5 mm, length: 16 mm) just prior to implantation. The procedures involved anaesthetizing a female CD-1 mouse (Charles River Laboratories) with isoflurane gas (˜2%), opening a 2-cm-length pocket at the subcutaneous region on the back near the spine, inserting the device into the pocket, and suturing to close the surgical opening. The procedures were approved by the Institutional Animal Care and Use Committee of Northwestern University (protocol IS00005877). The health status of each animal was checked daily. Euthanizing the mice at 1 month after device implantation preceded the extraction of blood. Charles River Laboratories conducted complete blood counts and blood chemistry tests on samples collected in K-EDTA tubes and gel tubes, respectively.
Analysis of complete blood count (
Defibrinated horse blood (100 ml, from Fisher Scientific) contained in a cylindrical reservoir (diameter: 4 cm, height: 30 cm) was maintained at 37.0±0.1° C. by a temperature controller (Fisher Scientific). Inserting both the catheter probe of the wireless sensing system and a commercial fiber optic catheter oximeter (Swan Ganz 777F8, recorded by HemoSphere monitoring platform, Edwards Life Science Inc) into the reservoir with the sensing tips 3 cm below the surface of the horse blood and in the center of the reservoir to eliminate effects of the reservoir sidewalls enabled comparative measurements of oxygenation. Adding reducing agents (ranging from 0.01 to 0.1 mg. sodium dithionite, purchased from Millipore Sigma) into the reservoir converted some of the oxygenated hemoglobin into deoxygenated hemoglobin, to define, in a controlled manner, the oxygenation level across a relevant range from 35% to 73%.
Testing on human subjects involved placing the wireless catheter probe on the index figure. A standard transmissive oximeter (GE DASH 3000) was clasped on the index finger of the other hand, as shown in
Male Sprague Dawley rats (weight: 400-500 g; age: 14-16 weeks) were purchased from Charles River Laboratories International. Inc. (Wilmington, MA). The animals were kept on a 12-h light-dark cycle in a temperature-controlled room. The experimental procedures were approved by the Animal Care and Use Committee of the Northwestern University and conformed to the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research, National Academy of Sciences, USA, 8th edition, 2011).
Sprague Dawley rats were initially anesthetized in a chamber with isoflurane gas (5% isoflurane, 100% oxygen). Once consciousness was lost, the animals were intubated with a 16-gauge flexible catheter, and endotracheal tube was connected to a mechanical ventilator (Braintree VentStar ventilator) that provided positive-pressure ventilation with oxygen/isoflurane. The ventilator was set based on animal weight: tidal volume (Vt, mL)=6.2×M1.01 and respiratory rate (RR, min−1)=53.5×M−0.26, M=animal weight in kilograms. Each rat was connected to a vaporizer that delivers approximately 2.0% isoflurane driven by 100% oxygen. Rats were placed in the dorsal decubitus position on a warming platform. Intradermal bupivicaine was infiltrated at the incision sites approximately 10 min prior to incisions. Rats were maintained at approximately 37° C. on a heating pad, with body temperature monitored throughout the experiment using a rectal temperature probe. The animal's hair was removed from the surgical site with hair removal cream NAIR post shaving. The surgical areas were scrubbed and disinfected with a povidone iodine prep pad and the area was then wiping with an alcohol prep pad. Peripheral blood oxygen saturation was monitored throughout the experiment using a commercial pulse oximetry system (MouseSTAT Jr., Kent Scientific Co.).
Details of thoracotomy in rats appear elsewhere. Briefly, isoflurane-anesthetized rats were ventilated with room air supplemented with 100% oxygen. A left thoracotomy was performed at the fourth intercostal space, and the heart was suspended in a pericardial cradle. The left lung will be gently pushed away from the pericardium with a small sponge. The oximeter probe was sutured to the anterior wall of the left ventricle close to the left anterior descending coronary artery with a nylon 6-0 suture, avoiding injuring coronary vessels. The oximeter wire went through a subcutaneous tunnel to the head. After instrumentation was completed, all rats were stabilized for 30 min and subjected to hypoxia by adjusting ventilation rate and tidal volume of the ventilator. The blood was withdrawn from the chamber of the left ventricle using a 27 G needle with 1.0 ml syringe, as shown in
Analysis of pulse oximeter data relied on a commercial software package (MATLAB® R2016b, The MathWorks Inc.). Data acquired from the two LEDs (Red: R, 640 nm, InfraRed: IR, 950 nm) were provided by the system at a sampling frequency of 100 Hz. The signal at each wavelength was bandpass filtered (0.5-3 Hz for human data, 3.5-6 Hz for animal data, 4th order, zero-lag Butterworth digital filter) to extract the main frequency of the pulsating component, AC(t), and low-pass filtered (0.5Hz, 4th order, zero-lag Butterworth digital filter) to estimate the slow fluctuating signal unrelated to pulsation, DC(t), e.g. induced by respiration. The relative pulsatile signal intensity S(t) was computed as the ratio of the two signals for both the red and the infrared wavelengths:
A local minima (m) and maxima (M) identification algorithm in the signal S(t) identified the peaks of each pulse cycle and yielded an interpolated modulation amplitude, A(t), as:
A(t)=M(t)−m(t). (2)
The ratio R(t) between the red and infrared pulsatile components at every sample was evaluated in a moving integration window of 5 s as:
From photon-diffusion theory and the modified Lambert-Beer equation, the following equation can be derived to express the relationship between the percent of arterial blood saturation, SpO2(t), and the R(t):
where εHbO
BPM(t)=60 f(t)IR,5s. (5)
Evaluation of blood saturation in in-vitro experiments used averages of red and IR values converted into optical densities (ODs) according to the equation:
OD(i)=−ln(I(i)/I0), (6)
where I(i) is the recorded signal intensity in each experimental phase and Io is its value in the first phase. In the absence of pulsating signals, assumptions on the baseline hemoglobin concentration and its oxygen saturation are required to infer changes in the saturation. We assumed a concentration of 15 g/dl for hemoglobin in the blood solution and, based on the commercial catheter oximeter, an oxygen saturation of 39% in the first experimental phase. When considering that the molar mass of hemoglobin is 65 kg/Mol, these assumptions yielded a baseline HbO2 and Hb concentration in blood of HbO20=0.90 mM and Hb0=1.41 mM, respectively. Calculation of changes in HbO2, ΔHbO2, and Hb, ΔHb, were evaluated employing the modified Lambert-Beer law.
where ρeff is the effective photon path in the backreflection recording geometry and are the extinction coefficients for the two chromophores.
The saturation of blood for each phase was estimated as:
The effective photon path of the probe was estimated experimentally by fitting to SO2(i) the commercial catheter oximeter saturation values, as shown in
The exploded view schematic illustration of this module shown in
Oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb) correspond to hemoglobin with and without bound oxygen, respectively. Well-known optical approaches provide effective estimates of blood oxygen saturation, defined as the fraction of HbO2 relative to total hemoglobin (HbO2+Hb), by comparing the distinct absorption spectra of HbO2 and Hb in the visible and NIR spectral range.
The optical sensing probe uses a single high-speed photodiode (TEMD7000X01, Vishay Semiconductors Inc.) with relative spectral sensitivities S(Z) at 950 nm and 640 nm of 99% and 54%, respectively, as shown in
The physics of light transport in biological tissues can be captured numerically using the Monte Carlo method. The results provide quantitative insights into the illumination distributions around the LEDs and into aspects of light detection by the PD, as shown in
Thermal images shown in
Minimizing the duty cycle also reduces the power consumption of the system and thereby extends the battery life. The system reported here uses a 45 mAh rechargeable lithium battery. For operational parameters described previously, this battery supports continuous operation and wireless data streaming at 200 Sa/s for more than 22 h using a 10% duty cycle (
The compliant mechanical properties of the device minimize mechanical forces on adjacent biological tissues, for improved biocompatibility. Human skin has Young's modulus between ˜400 to ˜800 kPa, while human cardiac muscles have Young's moduli of ˜100 kPa. The BLE module uses a biocompatible silicone (Silbione RTV 4420) for encapsulation, with a modulus in the range of human skin. The catheter oximeter probe uses three different biocompatible silicones (MED-1040, MED-1000, MED-1037, Avantor Inc), with Young's modulus values of 797, 1022 to 1667 kPa as in
Results of FEA in
Mixed venous oxygen saturation (SvO2) and central venous oxygen saturation (ScvO2) are two essential diagnostic indicators. The former, measured in the pulmonary artery, reflects the global balance between oxygen delivery and consumption. The latter, measured via a central venous catheter, reflects principally the degree of oxygen extraction from the brain and the upper part of the body. Major surgeries, especially cardiac surgeries, rely on monitoring of SvO2 and ScvO2 with fiber optic oximeters (e.g. Swan Ganz series catheter and HemoSphere monitoring platform, Edwards LifeScience), to guide care. Such devices are implanted transvenously, where the fiber optics support the optical transmission from external sources and sensing of backscattered light using external detectors, thereby tethering the patient to bedside apparatus.
In vitro tests of the device with horse blood (Fisher Scientific) at various oxygenation levels yield results that agree well with those measured with the commercial system (
A simple demonstration involves measurements of pulse oxygen saturation by pressing the device onto an index finger (
The primary envisioned application of the technology introduced here is in the context of pediatric cardiac surgery and recovery, where sutures hold the probe against the surface of major cardiac vessels for real-time monitoring of oxygen saturation within that vessel during the early and critical postoperative period of several days. Experiments on rat models, as illustrated in
The results presented here include design features, feasibility testing, and validation data for an implantable optoelectronic system tailored for use in cardiovascular monitoring, specifically in the context of surgical operations. The designs yield devices that are mechanically compliant and water resistant. This millimeter-scale, wireless optoelectronic platform enables chronic, continuous, precision sensing of intravascular or intracardiac oxygen saturation, free from the entanglement by conventional catheter oximeters. The advancement in mechanical compliance and material softness, compared with fiber-optic catheter, suggests opportunities in mitigating the complications seen by old technology. Moreover, the lateral mode of illumination maximizes light-tissue coupling, allowing a range of implantation sites including blood vessel and cardiac tissue. Comparison test and validation studies on blood samples, on human fingertips, and on cardiac surfaces in live animal models indicate measurement performance comparable to that of clinical standard oximeters and with values that match those determined with a blood gas analyzer.
The values of cardiac oxygenation saturation detected using the platforms described here correlate with the oxygenation of left ventricular blood measured using a blood gas analyzer in experiments on anesthetized rats. The wall thickness of the left ventricle in rats is 1.5 to 2.8 mm. With a penetration depth of 4 to 5 mm in muscular tissues, light can pass through the entire transmural extent of left ventricular wall to detect the oxygen saturation of the blood inside. As mentioned previously, the penetration depth can be changed by adjusting the optical power. Future studies will examine the efficacy and reliability of the catheter-type oximeter in quantifying the oxygen saturation of the heart, superior vena cava, and main pulmonary artery in larger animals and patients undergoing open-heart surgery.
These in vivo results must, however, be interpreted within the constraints of a few potential limitations. In addition to intracardiac oxygen saturation, oxygenation levels of the superior vena cava or main pulmonary artery are important in open-heart surgery. The small-animal studies here prevent evaluations of capabilities in such anatomic locations. Additional work is necessary to test the accuracy and efficacy of the device in these major vascular locations acutely, and after the chest is closed in larger animals. The small-animal studies also prevent in vivo chronic demonstration of the reported device. Systematic examination of the inflammatory responses associated with subdermal implantation of the optical probes reveals no observable increases in leukocytes, indicating negligible inflammatory response (
In conclusion, the present study indicates that a flexible, thin, catheter-type oximeter can accurately monitor venous and cardiac oxygenation levels in real time. Specifically, results demonstrate that this millimeter-scale, wireless optoelectronic platform can detect cardiac oxygenation saturation in rats during open-heart surgery. To explore the potential of the device to monitor oxygenation levels in main vessels, further studies will focus on the efficacy and reliability for detecting the oxygenation saturation in the superior vena cava and main pulmonary artery of large animals, mimicking open-heart surgery of patients.
The foregoing description of the exemplary embodiments of the 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 enable 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. 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.
This application claims priority to and the benefit of U.S. Provisional Application Ser. No. 63/112,011, filed Nov. 10, 2020, which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/058705 | 11/10/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63112011 | Nov 2020 | US |
