Infection detection medical systems and methods

Abstract

An infection detection medical system may include an indwelling medical device and a dedicated computing device. The indwelling medical device may include an internal conduit configured to be inserted percutaneously into the patient's blood vessels and a microcontroller integrated into part of the indwelling medical device. The microcontroller may include a chemical sensor module and one or more chemical sensors configured to generate electrical signals in response to interaction with one or more volatile organic compounds (VOCs) associated with the patient. The microcontroller may also include a microcontroller processor configured to generate chemical sensor data from the electrical signals. In addition, the dedicated computing device may include a computing device processor configured to generate one or more observed chemical signatures from the chemical sensor data and to determine whether the patient has a microbial infection by comparing one or more observed chemical signatures for a microbial infection with known chemical signatures.

Description

Background Art

[0001] Catheter-related bloodstream infection (CRBSI) is one of the most frequent infections in hospitals. Current estimates suggest that 15% - 30% of all nosocomial bacteremias are catheter-related. The incidence of catheter-related infections varies widely depending on the type and intended use of the catheter, the insertion site, the experience and training of the clinician placing the catheter, the frequency with which the catheter is accessed, the duration of catheter placement, patient characteristics, and the use of proven preventive strategies. In particular, patients requiring medical intervention typically also have a high risk of severe infections (sepsis) involving the blood and the entire body. In recent years, the inventors' knowledge of the epidemiology of CRBSI, as well as the most appropriate methodologies for diagnosis, management, and prevention, has increased significantly. However, CRBSI still has a significant associated morbidity, leading to an increase in hospital costs estimated at nearly $2000 per episode and an increase in length of hospital stay. The attributable mortality rate ranges from 12% - 25%.

[0002] This specification discloses an infection sensing medical system and method for addressing the above.

Summary of the Invention

[0003] This specification discloses infection-sensing medical systems, in some embodiments, that include an indwelling medical device and a dedicated computing device. The indwelling medical device includes an internal conduit, one or more external conduits fluidly connected to the internal conduit, a hub between the proximal portion of the internal conduit and one or more distal portions of the one or more external conduits, and a microcontroller integrated into a portion of the indwelling medical device. The internal conduit is configured to be inserted percutaneously into the patient's blood vessels. One or more external conduits are configured to remain outside the patient's body. The microcontroller includes a chemical sensor module and a microcontroller processor. The chemical sensor module includes one or more chemical sensors configured to generate electrical signals in response to interaction with one or more volatile organic chemicals ("VOCs") associated with the patient. The microcontroller processor is configured to generate chemical sensor data from the electrical signals. The dedicated computing device includes a computing device processor configured to generate one or more observed chemical signatures from the chemical sensor data. In addition, the computing device processor is configured to determine whether a patient has a microbial infection by comparing one or more observed chemical signatures with known chemical signatures for microbial infections.

[0004] In some embodiments, the indwelling medical device further includes one or more connectors for one or more extracorporeal conduits. The portion of the indwelling medical device in which a microcontroller is integrated is one of the connectors.

[0005] In some embodiments, the part of the implantable medical device that integrates the microcontroller is the hub. In some embodiments, the microcontroller further includes a microcontroller communication module configured for wireless communication with a computing device communication module of a dedicated computing device. The wireless communication includes at least chemical sensor data.

[0006] In some embodiments, the microcontroller further includes a memory configured to store chemical sensor data over time. One or more observed chemical signatures generated by the computing device processor include multiple time-dependent observed chemical signatures based on the chemical sensor data stored in memory over time.

[0007] In some embodiments, one or more observed chemical signatures are at least semi-quantitative with respect to one or more constituent VOCs. Multiple time-dependent observed chemical signatures thereby indicate semi-quantitative changes in one or more constituent VOCs over time, and consequently, any changes in the patient's condition over time.

[0008] In some embodiments, the implantable medical device further includes a VOC permeable membrane on top of the chemical sensor module. The VOC permeable membrane is configured to selectively allow one or more VOCs to pass through it rather than water vapor.

[0009] In some embodiments, one or more VOCs are selected from indole, methanol, 1-undecene, ethyl acetate, 2,4-dimethyl-1-heptane, 2-butanone, benzaldehyde, dimethylcyclohexanol, isovaleric acid, 2-pentanol, 4-methylquinazoline, and 2-methylbutanal.

[0010] In some embodiments, known chemical signatures for microbial infections are selected from the following: a Staphylococcus aureus chemical signature containing several combinations of benzaldehyde, isovaleric acid, and 2-methylbutanal; a Pseudomonas aeruginosa chemical signature containing several combinations of 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 2-pentanol, and 4-methylquinazoline; an Escherichia coli chemical signature containing several combinations of indole, methanol, ethyl acetate, and 2-pentanol; a Clostridium sporogenes chemical signature containing several combinations of indole, methanol, ethyl acetate, and 2-pentanol; and a Candida albicans chemical signature containing several combinations of methanol and dimethylcyclohexanol.

[0011] In some embodiments, the medical system further includes an insertion site, any portion of the internal conduit of the implanted medical device extending from the insertion site, and a wound dressing sized to cover the hub of the implanted medical device. The wound dressing includes a water vapor permeable membrane configured to selectively allow water vapor to pass through it more than one or more VOCs.

[0012] In some embodiments, the indwelling medical device is a central venous catheter ("CVC"), a peripherally inserted central catheter ("PICC"), a midline catheter, a peripheral intravenous catheter ("PIVC"), or an acute dialysis catheter.

[0013] This specification also discloses methods for infection detection medical systems. In some embodiments, the methods include electrical signal generation operations, data generation operations, chemical signature generation operations, and microbial infection determination operations. The electrical signal generation operation includes generating electrical signals by one or more chemical sensors of a chemical sensor module in response to interaction with one or more VOCs associated with a patient. The data generation operation includes generating chemical sensor data from the electrical signals by a microcontroller processor. Both the chemical sensor module and the microcontroller processor are part of a microcontroller integrated into a part of an indwelling medical device. The indwelling medical device includes an internal conduit inserted percutaneously into a patient's blood vessel, one or more extracorporeal conduits that remain outside the patient's body and are fluidly connected to the internal conduit, and a hub between the proximal portion of the internal conduit and one or more distal portions of the one or more extracorporeal conduits. The chemical signature generation operation includes generating one or more observed chemical signatures from the chemical sensor data by a computing device processor of a dedicated computing device. The microbial infection determination operation includes determining whether a patient has a microbial infection by using a computing device processor to compare one or more observed chemical signatures with known chemical signatures for microbial infections.

[0014] In some embodiments, the part of the implantable medical device that integrates the microcontroller is the hub. In some embodiments, the method further includes a communication operation. The communication operation includes wirelessly transmitting chemical sensor data from a microcontroller communication module of a microcontroller to a computing device communication module of a dedicated computing device.

[0015] In some embodiments, the communication operation includes wirelessly transmitting chemical sensor data from a microcontroller communication module to a computing device communication module via any communication protocol selected from wireless fidelity ("WiFi"), Bluetooth®, near-field communication ("NFC"), and Zigbee® communication protocols.

[0016] In some embodiments, the method further includes a data storage operation. The data storage operation includes storing chemical sensor data in the memory of a microcontroller over time. One or more observed chemical signatures generated by the computing device processor in the chemical signature generation operation include multiple time-dependent observed chemical signatures based on the chemical sensor data stored in memory over time during the data storage operation.

[0017] In some embodiments, the method further includes a patient status determination operation. The patient status determination operation includes determining any changes in the patient's status over time. One or more observed chemical signatures are at least semi-quantitative with respect to one or more constituent VOCs. Multiple time-dependent observed chemical signatures thereby indicate the semi-quantitative changes in one or more constituent VOCs over time for the patient status determination operation.

[0018] In some embodiments, the method further includes a VOC permeation operation. The VOC permeation operation involves selectively allowing one or more VOCs to permeate through the VOC permeable membrane rather than water vapor. The implantable medical device further includes a VOC permeable membrane on top of a chemical sensor module.

[0019] In some embodiments, one or more VOCs are selected from indole, methanol, 1-undecene, ethyl acetate, 2,4-dimethyl-1-heptane, 2-butanone, benzaldehyde, dimethylcyclohexanol, isovaleric acid, 2-pentanol, 4-methylquinazoline, and 2-methylbutanal.

[0020] In some embodiments, known chemical signatures for microbial infections are selected from: Staphylococcus aureus chemical signatures comprising several combinations of benzaldehyde, isovaleric acid, and 2-methylbutanal; Pseudomonas aeruginosa chemical signatures comprising several combinations of 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 2-pentanol, and 4-methylquinazoline; Escherichia coli chemical signatures comprising several combinations of indole, methanol, ethyl acetate, and 2-pentanol; Clostridium sporogenes chemical signatures comprising several combinations of indole, methanol, ethyl acetate, and 2-pentanol; and Candida albicans chemical signatures comprising several combinations of methanol and dimethylcyclohexanol.

[0021] In some embodiments, the method further includes a water permeability operation. The water permeability operation includes selectively allowing water vapor to permeate through the water vapor permeable membrane more than one or more VOCs. The medical system further includes an insertion site, any portion of the internal conduit of the implanted medical device extending from the insertion site, and a wound dressing sized to cover the hub of the implanted medical device. The wound dressing includes a water vapor permeable membrane.

[0022] In some embodiments, the indwelling medical device is a CVC, PICC, midline catheter, PIVC, or acute dialysis catheter. This specification discloses disease-sensing medical systems, in some embodiments, that include a breath analyzer and a dedicated computing device. The breath analyzer includes a breath receiving tube configured to receive the patient's exhaled breath and a microcontroller integrated into a portion of the breath analyzer. The microcontroller includes a chemical sensor module and a microcontroller processor. The chemical sensor module includes one or more chemical sensors configured to generate electrical signals in response to interaction with one or more volatile organic compounds ("VOCs") associated with the patient. The microcontroller processor is configured to generate chemical sensor data from the electrical signals. The dedicated computing device includes a computing device processor configured to generate one or more observed chemical signatures from the chemical sensor data. In addition, the computing device processor is configured to determine whether the patient has a disease by comparing one or more observed chemical signatures with chemical signatures known for the disease.

[0023] In some embodiments, one or more VOCs are selected from acetic acid, ethyl cyclopropane, 2-ethyl-1-hexanol, acetone, and isopropanol. In some embodiments, known chemical signatures for diseases are selected from chemical signatures for tuberculosis, which include several combinations of acetic acid, ethyl cyclopropane, and 2-ethyl-1-hexanol, and chemical signatures for diabetic ketoacidosis, which include several combinations of acetone and isopropanol.

[0024] In some embodiments, the breath analyzer and dedicated computing device are integrated into a single disease-sensing medical device that falls within the same scope as the disease-sensing medical system. These and other features of the concepts provided herein will become more apparent to those skilled in the art by reading the accompanying drawings and the following description, which describe in more detail specific embodiments of such concepts. [Brief explanation of the drawing]

[0025] [Figure 1] An infection-sensing medical system is shown that includes an indwelling medical device being used on a patient and a dedicated computing device, according to some embodiments. [Figure 2] A detailed view of an indwelling medical device disposed within a patient, including a wound dressing material thereon, is shown, according to some embodiments. [Figure 3] An indwelling medical device is shown, according to some embodiments. [Figure 4] A detailed view of an indwelling medical device including a microcontroller integrated into a portion of the indwelling medical device is shown, according to some embodiments. [Figure 5] A schematic diagram is provided showing a VOC permeable membrane over a sensor module of a microcontroller, and a water vapor permeable membrane of a wound dressing material over the VOC permeable membrane, according to some embodiments. [Figure 6] A block diagram is provided showing a microcontroller of an indwelling medical device, according to some embodiments. [Figure 7] A block diagram is provided showing a dedicated computing device, according to some embodiments. [Figure 8] An observed chemical signature overlaid on a known chemical signature is provided, according to some embodiments. [Figure 9] A principal component analysis ("PCA") of a sample of a fluid containing Candida albicans and a control fluid not containing Candida albicans is provided. [Figure 10A] A PCA of a sample of a fluid containing Escherichia coli at a relatively low level and a control fluid not containing Escherichia coli is provided. [Figure 10B] A PCA of a sample of a fluid containing Escherichia coli at a relatively high level and a control fluid not containing Escherichia coli is provided. [Figure 11] A disease-sensing medical system is shown, according to some embodiments. [Modes for carrying out the invention]

[0026] Before certain specific embodiments are disclosed in more detail, it should be understood that certain embodiments disclosed herein do not limit the scope of the concepts provided herein. It should also be understood that certain embodiments disclosed herein may have features that are easily separable from a particular embodiment and which, at their discretion, can be combined with or substituted for features of any of the many other embodiments disclosed herein.

[0027] With regard to the terminology used herein, it should be understood that the terms are for the purpose of describing certain specific embodiments and do not limit the scope of the concepts provided herein. Ordinal numbers (e.g., 1st, 2nd, 3rd, etc.) are generally used to distinguish or identify different features or steps within a group of multiple features or processes and do not provide a sequential or numerical limitation. For example, the "1st," "2nd," and "3rd" features or steps do not necessarily have to appear in that order, and a particular embodiment containing such features or steps does not necessarily have to be limited to three features or steps. In addition, unless otherwise specified, any of the aforementioned features or steps may further include one or more features or steps. Labels such as "left," "right," "up," "down," "front," and "back" are used for convenience and do not, for example, imply a specific fixed position, orientation, or direction. Instead, such notations are used to reflect, for example, a relative position, orientation, or direction. The singular forms "one," "one," and "the said" also include plural references unless explicitly indicated in the context.

[0028] The term "proximal" is used to indicate a part, section, piece, element, etc., of a medical device that is intended to be near or relatively near the clinician when the medical device is used on a patient. For example, the "proximal portion" or "proximal section" of a medical device includes the portion or section of the medical device that is intended to be near the clinician when the medical device is used on a patient. Similarly, the "proximal length" of a medical device includes the length of the medical device that is intended to be near the clinician when the medical device is used on a patient. The "proximal end" of a medical device includes the end of the medical device that is intended to be near the clinician when the medical device is used on a patient. The proximal portion, proximal section, or proximal length of a medical device does not necessarily include the proximal end of the medical device. In practice, the proximal portion, proximal section, or proximal length of a medical device may be shorter than the proximal end of the medical device. However, the proximal portion, proximal section, or proximal length of a medical device may include the proximal end of the medical device. Where the context does not suggest that the proximal portion, proximal section, or proximal length of a medical device includes the proximal end of the medical device, or where it is deemed convenient in the following detailed description, “proximal portion,” “proximal section,” or “proximal length” may be modified, respectively, to indicate the portion, section, or length including the end portion, end section, or end length of the medical device, in relation to the “proximal end portion,” “proximal end section,” or “proximal end length” of the medical device.

[0029] The term "distal" is used to indicate a part, section, piece, element, etc., of a medical device that is intended to be near, relatively near, or within the patient when the medical device is used on a patient. For example, the "distal portion" or "distal section" of a medical device includes the part or section of the medical device that is intended to be near, relatively near, or within the patient when the medical device is used on a patient. Similarly, the "distal length" of a medical device includes the length of the medical device that is intended to be near, relatively near, or within the patient when the medical device is used on a patient. The "distal end" of a medical device includes the end of the medical device that is intended to be near, relatively near, or within the patient when the medical device is used on a patient. The distal portion, distal section, or distal length of a medical device does not necessarily include the distal end of the medical device. In practice, the distal portion, distal section, or distal length of a medical device may be shorter than the distal end of the medical device. However, the distal portion, distal section, or distal length of a medical device may include the distal end of the medical device. Where the context does not suggest that the distal portion, distal section, or distal length of a medical device includes the distal end of the medical device, or where it is deemed convenient in the following detailed description, “distal portion,” “distal section,” or “distal length” may be modified to refer to the “distal end portion,” “distal end section,” or “distal end length” of the medical device, respectively, to include the end portion, end section, or end length of the medical device.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Healthcare system Figure 1 shows an infection detection medical system 100, including an indwelling medical device 102 and a dedicated computing device 104 used in a patient, according to several embodiments. As shown, the infection detection medical system 100 may include an indwelling medical device 102 and a dedicated computing device 104. However, it should be understood that the infection detection medical system 100 is not limited to the indwelling medical device 102 and the dedicated computing device 104. The indwelling medical device 102 may alternatively be any medical device configured to interface with a patient and collect one or more VOCs from there. For example, the indwelling medical device 102 could alternatively be an exhalation analyzer 170 as shown in Figure 11, which may be similarly configured with a microcontroller 118, a VOC permeable membrane 120, etc., but may be modified to collect one or more VOCs from exhaled breath blown into an exhalation receiving tube 172 to determine whether the patient has tuberculosis, coronavirus disease 2019 ("COVID-19"), lung cancer, diabetic ketoacidosis, etc.

[0031] The dedicated computing device 104 may, alternatively, be any general-purpose computing device (e.g., a desktop computer, a smartphone, etc.) configured as described below with respect to the dedicated computing device 104, in order to generate one or more observed chemical signatures and determine whether a patient has a microbial infection or the aforementioned tuberculosis, COVID-19, lung cancer, or diabetic ketoacidosis resulting therefrom. Furthermore, the medical devices including the indwelling medical device 102 and the computing devices including the dedicated computing device 104 may be separate as shown in Figure 1, or may be integrated into a single infection-sensing medical device substantially identical in scope to the infection-sensing medical system 100, or more broadly, into a single disease-sensing medical device substantially identical in scope to a disease-sensing medical system such as the breath analyzer 170 shown in Figure 11. In particular, in such embodiments, the microcontroller 118 and the dedicated computing device 104 may be integrated into a single unit such as a single printed circuit board assembly ("PCBA") configured to function as described below.

[0032] Figure 2 shows a detail view of an indwelling medical device 102 placed in a patient, including a wound dressing 106, according to several embodiments. As shown, the infection-sensing medical system 100 may further include a wound dressing 106 sized to cover the insertion site, any portion of the internal conduit 110 of the indwelling medical device 102 extending from the insertion site, and the hub 114 of the indwelling medical device 102.

[0033] In particular, the wound dressing 106 may include a water vapor permeable membrane 108 configured to selectively allow water vapor to pass through it rather than one or more VOCs. In fact, the water vapor permeable membrane 108 may include a reverse osmosis membrane or a porous membrane such as a two-dimensional ("2D") or three-dimensional ("3D") covalent-organic-framework ("COF") membrane configured to selectively allow water vapor to pass through it rather than one or more VOCs. Furthermore, instead of the indwelling medical device 102 being configured as described herein, the wound dressing 106 may similarly be configured with a microcontroller 118, a VOC permeable membrane 120, etc., for use with existing indwelling medical devices such as CVCs, PICCs, midline catheters, PIVCs, or acute dialysis catheters to collect one or more VOCs. That said, such a wound dressing 106 may also be used with the indwelling medical device 102 for fail-proof redundancy or confirmation of one or the other. Furthermore, it should be understood that catheter stabilization devices, hospital bags, wearable drug delivery patches, wristbands, smartwatches, etc., can similarly be configured together with a microcontroller 118, a VOC permeable membrane 120, etc., to collect one or more VOCs.

[0034] Figure 3 shows an indwelling medical device 102 according to several embodiments. As shown, the indwelling medical device 102 may include an internal conduit 110, one or more external conduits 112 fluidly connected to the internal conduit 110, a hub 114 between the proximal portion of the internal conduit 110 and one or more respective distal portions of the one or more external conduits 112, and one or more respective connectors 116 of the one or more external conduits 112. In particular, the internal conduit 110 is configured to be inserted percutaneously into the patient's blood vessels, and the one or more external conduits 112 are configured to remain outside the patient's body. Such an indwelling medical device 102 may include, but is not limited to, a catheter such as a CVC, PICC, midline catheter, PIVC, or acute dialysis catheter, the internal conduit 110 is the catheter tube of the catheter, and the one or more external conduits 112 are extension legs of the catheter.

[0035] Figure 4 shows a detailed view of an indwelling medical device 102 including a microcontroller 118 integrated into a portion of the indwelling medical device 102, according to several embodiments. Figure 6 provides a block diagram showing the microcontroller 118 of the indwelling medical device 102, according to several embodiments. As shown, the microcontroller 118 can be integrated into a portion of the indwelling medical device 102. As shown, the portion of the indwelling medical device into which the microcontroller 118 is integrated may be the hub 114, such as the top of the hub 114, the side of the hub 114, or both the top and side of the hub 114.

[0036] In at least the latter embodiment, the components of the microcontroller 118 may be divided between the top and side of the hub 114, with, for example, the chemical sensor module 122 on the side of the hub 114 closest to the insertion site being operably coupled to the rest of the microcontroller 118 on the top of the hub 114, which has a power supply 132 (e.g., an internal power supply). Although not shown, the portion of the indwelling medical device into which the microcontroller 118 is integrated may alternatively be one of the connectors 116. Alternatively, instead of the indwelling medical device 102 being configured as described herein, the unnecessary connector, similarly configured with the microcontroller 118, VOC permeable membrane 120, etc., may be connected to one or more connectors of an existing indwelling medical device such as a CVC, PICC, midline catheter, PIVC, or acute dialysis catheter to collect one or more VOCs. The advantage of the microcontroller 118 being integrated into one or more connectors 116 or the aforementioned unnecessary connector, although further away from the insertion site, includes the convenience of coupling to a dedicated computing device 104 in a wired embodiment.

[0037] Figure 5 provides a schematic diagram showing, according to several embodiments, a VOC permeable membrane 120 on the sensor module of a microcontroller 118 and a water vapor permeable membrane 108 of a wound dressing 106 on the VOC permeable membrane 120. As shown, the implantable medical device 102 may include at least the VOC permeable membrane 120 on the chemical sensor module 122. In fact, the VOC permeable membrane 120 may further be on the entire microcontroller 118, as shown in Figure 4, thereby advantageously increasing the volume of VOC collection headspace on the chemical sensor module 122. The VOC permeable membrane 120 may be configured to selectively permeate one or more VOCs rather than water vapor, any water condensates, any sensor contaminants of wound exudate, etc. Additionally or alternatively, the VOC permeable membrane 120 may be hydrophobic, which limits the interaction of water vapor or condensates with it. As described above, together with the water vapor permeable membrane 108 of the wound dressing 106, which can be configured to selectively allow water vapor to permeate through it more than one or more VOCs, the VOC permeable membrane 120 can facilitate the separation and concentration of one or more VOCs in the VOC collection headspace above the chemical sensor module.

[0038] The VOC permeable membrane 120 may be configured to selectively permeate through it for interaction with one or more chemical sensors 134 of the chemical sensor module 122. One or more VOCs may be selected from at least indole, methanol, 1-undecene, ethyl acetate, 2,4-dimethyl-1-heptane, 2-butanone, benzaldehyde, dimethylcyclohexanol (e.g., 2,2-dimethylcyclohexanol, 2,6-dimethylcyclohexanol, or 4,4-dimethylcyclohexanol), isovaleric acid, 2-pentanol, 4-methylquinazoline, and 2-methylbutanal. Indeed, as shown in Table 1 below, several combinations of benzaldehyde, isovaleric acid, and 2-methylbutanal may indicate microbial infection by Staphylococcus aureus; several combinations of 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 2-pentanol, and 4-methylquinazoline may indicate microbial infection by Pseudomonas aeruginosa; several combinations of indole, methanol, ethyl acetate, and 2-pentanol may indicate microbial infection by Escherichia coli; several combinations of indole, methanol, ethyl acetate, and 2-pentanol may indicate microbial infection by Clostridium sporogenes; and several combinations of methanol and dimethylcyclohexanol may indicate microbial infection by Candida albicans. However, the VOC permeable membrane 120 does not need to be limited to selectively allowing one or more of the aforementioned VOCs to permeate through it for interaction with one or more chemical sensors 134 of the sensor module.In fact, the VOC permeable membrane 120 may be configured to selectively allow one or more other VOCs to permeate through it, indicating microbial infection by even more microorganisms such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Clostridium sporogenes, Candida albicans, or carbapenem-resistant Enterobacteriaceae, extended-spectrum β-lactamase (ESBL)-producing bacteria of the Enterobacteriaceae, vancomycin-resistant Enterococcus, multidrug-resistant Acinetobacter, and multidrug-resistant Klebsiella, with one or more other VOCs being optionally combined with one or more of the aforementioned VOCs.

[0039] [Table 1]

[0040] Notwithstanding the foregoing, it should be understood that the one or more VOCs that the VOC permeable membrane 120 may be configured to selectively allow permeation through it for interaction with one or more chemical sensors 134 of the sensor module are selected in embodiments of a medical device configured as a breath analyzer from at least acetic acid, ethylcyclopropane, and 2-ethyl-1-hexanol exhaled from a patient with tuberculosis, and acetone and isopropanol exhaled from a patient with diabetic ketoacidosis.

[0041] Figure 6 provides a block diagram showing a microcontroller 118 of an indwelling medical device 102 according to several embodiments. As shown, the microcontroller 118 may include components selected from a chemical sensor module 122, a sensor interface 124, a processor 126, a secondary memory 128, a communication module 130, and a power supply 132 such as an internal power supply (e.g., a battery). The chemical sensor module 122 may include one or more chemical sensors 134 configured to generate electrical signals in response to interaction with one or more VOCs associated with the patient, or more specifically, with the patient's microorganisms.

[0042] One or more chemical sensors 134 may include, but are not limited to, those having so-called acceptors selected from metals, metal oxides, and organic molecules ranging from small organic compounds to polymers, such as amino acids, peptides, polypeptides, proteins, nucleosides, nucleotides, oligonucleotides, monosaccharides, disaccharides, oligosaccharides, polysaccharides, or phospholipids, as well as allotropes of carbon such as graphene and various fullerenes, some of which are disclosed in U.S. Patent Application Publication 2020 / 0256793, which is incorporated herein by reference in its entirety. Each sensor of one or more chemical sensors 134 may respond differently to interaction with one or more VOCs, thereby providing one or more observed chemical signatures that are unique like fingerprints, and enabling the comparison of one or more observed chemical signatures with known chemical signatures to determine microbial infection. In particular, the chemical sensor module 122 of the microcontroller 118 or a separate correction sensor module 136 may include, if necessary, one or more additional sensors selected from at least a temperature sensor 138 and a humidity sensor 140 to correct subsequent chemical sensor data with respect to temperature and humidity. The sensor interface 124 may include a signal modifier 142 configured to standardize the electrical signals through voltage or current limiting, anti-aliasing filtering, etc., in particular when electrical signals are generated by multiple chemical sensors 134, and each of the chemical sensors 134 may have a different configuration due to different interactions with the same VOC among one or more VOCs.

[0043] In addition, the sensor interface 124 may include an amplifier 144 configured to amplify electrical signals, thereby amplifying their signal-to-noise ratio. The processor 126 may include an analog-to-digital converter ("ADC") 146 configured to convert electrical signals from analog to digital, a digital-signal processor ("DSP") 148 configured to generate chemical sensor data from electrical signals, and a primary memory 150 (e.g., cache memory, random-access memory ("RAM"), or both) configured to store programs and data in use. The primary memory 150 may be in the same package as the rest of the processor 126, as indicated in Figure 6, although at least the aforementioned RAM may be distributed within the package of the microcontroller 118 itself, although outside the package of the processor 126. The secondary memory 128 may be configured to store data such as chemical sensor data over time, as well as programs containing instructions, logic, algorithms, or any combination thereof, to be loaded into the primary memory 150 for use by the processor 126. The communication module 130 may be configured for wireless communication of at least chemical sensor data with the communication module 156 of the dedicated computing device 104 via any communication protocol selected from WiFi, Bluetooth®, NFC, and Zigbee® communication protocols. In particular, the communication module 130 may be configured for wired communication of at least chemical sensor data via any serial or parallel communication protocol, either alternatively or additionally.

[0044] Notwithstanding the foregoing, the aforementioned microcontroller 118 is described in relation to one or more chemical sensors 134 of the chemical sensor module 122, which are one or more analog chemical sensors, and it should be understood that the electrical signals generated thereby are analog electrical signals. If, instead, one or more chemical sensors 134 of the chemical sensor module 122 are digital chemical sensors, which may include a digital optical interferometer or built-in signal processing capabilities as described above, the microcontroller 118 may be appropriately modified to process digital electrical signals or chemical sensor data therefrom.

[0045] Figure 7 provides a block diagram showing a dedicated computing device 104 according to several embodiments. As shown, the dedicated computing device 104 may include components selected from a processor 152, secondary memory 154, a communication module 156, and a power supply 158 such as an internal power supply (e.g., a battery) or an external power supply (e.g., commercial power). Furthermore, the dedicated computing device 104 may include one or more input devices 160 (e.g., a keyboard, mouse, touchscreen display screen, etc.) and one or more output devices 162 (e.g., a touchscreen display screen, printer, etc.). The processor 152 may include a control unit 164, an arithmetic unit 166, and primary memory 168 (e.g., cache memory, RAM, or both), the primary memory 168 being configured to store programs and data in use.

[0046] The primary memory 168 may be in the same package as the rest of the processor 152, as suggested in Figure 7, but at least the aforementioned RAM may be distributed outside the package of the processor 152, for example, within its own package. The processor 152 may be configured to generate one or more observed chemical signatures from chemical sensor data generated by the processor 126 of the microcontroller 118. In addition, the processor 152 may be configured to determine whether a patient has a microbial infection by comparing one or more observed chemical signatures with known chemical signatures for microbial infections. In particular, the one or more observed chemical signatures generated by the processor 152 may include multiple time-dependent observed chemical signatures from chemical sensor data stored over time in at least the secondary memory 128 of the microcontroller 118. The secondary memory 154 may be configured to store such time-dependent observed chemical signatures, as well as other data and programs, including instructions, logic, algorithms including machine learning algorithms, artificial intelligence ("AI") models, or some combination thereof, for use by the processor 152, for use by the processor 152, for example, to load the observed chemical signatures into the primary memory 168 for use by the processor 152, for generating one or more observed chemical signatures from chemical sensor data and for comparing the observed chemical signatures with known chemical signatures by statistical analysis, in order to determine microbial infection.

[0047] Figure 8 provides observed chemical signatures superimposed on known chemical signatures according to several embodiments. As shown, one or more observed chemical signatures and known chemical signatures generated by the processor 152 can be displayed as a superimposed radar chart on a display screen, such as the aforementioned touchscreen display screen, if they are available as an output device of one or more output devices 162.

[0048] An overlaid radar chart, including one or more observed chemical signatures and component radar charts of known chemical signatures, may include multiple isometric axes for multiple concentric shapes such as circles and regular polygons, as shown in the figure. Each axis of the multiple isometric axes corresponds to a different sensor of the multiple chemical sensors 134 (e.g., sensor n, sensor n+1, sensor n+2, etc.), and each concentric shape of the multiple concentric shapes represents an increase in signal intensity from the smallest shape to the largest shape. Radar charts, such as those shown in Figure 8, or their alternatives, such as parallel coordinate plots, are useful for clinicians to optionally analyze the presence, absence, or intensity of one or more component VOCs in one or more observed chemical signatures over time. However, it should be understood that the dedicated computing device 104 does not need to overlay and display any radar charts of the processor 152 itself to determine whether a patient has a microbial infection. In fact, one or more observed chemical signatures and known chemical signatures may exist as data structures in at least the secondary memory 154 of the dedicated computing device 104 in order to compare the observed chemical signatures with the known chemical signatures in order to determine microbial infection.

[0049] Known chemical signatures for microbial infections, which may be updated over time as needed, may be selected from: a Staphylococcus aureus chemical signature containing several combinations of benzaldehyde, isovaleric acid, and 2-methylbutanal; a Pseudomonas aeruginosa chemical signature containing several combinations of 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 2-pentanol, and 4-methylquinazoline; an Escherichia coli chemical signature containing several combinations of indole, methanol, ethyl acetate, and 2-pentanol; a Clostridium sporogenes chemical signature containing several combinations of indole, methanol, ethyl acetate, and 2-pentanol; and a Candida albicans chemical signature containing several combinations of methanol and dimethylcyclohexanol.

[0050] In particular, one or more observed chemical signatures can be at least semi-quantitative to the parts-per-million (ppm) concentration of one or more constituent VOCs, which may require a correction factor predetermined, for example, by a photoionization detector, for each of the one or more VOCs. Thus, multiple time-dependent observed chemical signatures can indicate semi-quantitative changes in one or more constituent VOCs of the time-dependent observed chemical signatures over time, and consequently, any changes in the patient's condition over time. In one example, an increase in one or more constituent VOCs of a time-dependent observed chemical signature may indicate an increase in microbial infection, and consequently, a deterioration in the patient's condition over time. In another example, a decrease in one or more constituent VOCs of a time-dependent observed chemical signature may indicate a decrease in microbial infection, and consequently, an improvement in the patient's condition over time. Therefore, the processor 152 may be configured as appropriate to determine any changes in the patient's condition over time, such as a deterioration of the patient's condition over time due to an increase in microbial infection, or an improvement in the patient's condition over time due to a decrease in microbial infection. Similarly, the processor 152 may be configured to determine that there are no changes in the patient's condition over time if there is neither an increase in microbial infection nor a decrease in microbial status.

[0051] method The method includes methods for the infection detection medical system 100 itself, as well as methods for using the infection detection medical system 100.

[0052] The methods of the infection detection medical system 100 may include one or more operations selected from water permeation operations, VOC permeation operations, electrical signal generation operations, data generation operations, data storage operations, communication operations, chemical signature generation operations, microbial infection determination operations, and patient status determination operations.

[0053] The water permeability operation may include selectively allowing water vapor to permeate through the water vapor permeable membrane 108 of the wound dressing 106 more than one or more VOCs. As described above, the infection sensing medical system 100 may include the insertion site, any portion of the internal conduit 110 of the indwelling medical device 102 extending from the insertion site, and the wound dressing 106 sized to cover the hub 114 of the indwelling medical device 102.

[0054] The VOC permeation operation may include selectively allowing one or more VOCs to permeate through the VOC permeable membrane 120 rather than water vapor. As described above, the implantable medical device 102 may include the VOC permeable membrane 120 on at least the chemical sensor module 122. Furthermore, one or more VOCs that may be configured to selectively allow permeation for interaction with one or more chemical sensors 134 of the sensor module are selected from at least indole, methanol, 1-undecene, ethyl acetate, 2,4-dimethyl-1-heptane, 2-butanone, benzaldehyde, dimethylcyclohexanol (e.g., 2,2-dimethylcyclohexanol, 2,6-dimethylcyclohexanol, or 4,4-dimethylcyclohexanol), isovaleric acid, 2-pentanol, 4-methyl-quinazoline, and 2-methyl-butanal.

[0055] The electrical signal generation operation may include generating an electrical signal by one or more chemical sensors 134 of the chemical sensor module 122 in response to an interaction with one or more VOCs associated with the patient, or more specifically, with the patient's microorganisms.

[0056] The data generation operation may include the processor 126 generating chemical sensor data from electrical signals. Both the chemical sensor module 122 and the processor 126 are part of a microcontroller 118 integrated into the implantable medical device 102 described above.

[0057] The data storage operation may include storing chemical sensor data in the secondary memory 128 of the microcontroller 118 over time. The communication operation may include wirelessly transmitting chemical sensor data from the communication module 130 of the microcontroller 118 to the communication module 156 of the dedicated computing device 104. Such communication operation may include wirelessly transmitting chemical sensor data from the communication module 130 of the microcontroller 118 to the communication module 156 of the dedicated computing device 104 via any communication protocol selected from WiFi, Bluetooth®, NFC, and Zigbee® communication protocols.

[0058] The chemical signature generation operation may include the generation of one or more observed chemical signatures from chemical sensor data by the processor 152 of the dedicated computing device 104. The one or more observed chemical signatures generated by the processor 152 in the chemical signature generation operation may include multiple time-dependent observed chemical signatures based on chemical sensor data stored over time in the secondary memory 128 of the microcontroller 118 during the data storage operation.

[0059] The microbial infection determination operation may include determining whether a patient has a microbial infection by comparing one or more observed chemical signatures with chemical signatures known for microbial infections using the processor 152 of a dedicated computing device 104. As described above, chemical signatures known for microbial infections may be selected from: Staphylococcus aureus chemical signatures containing several combinations of benzaldehyde, isovaleric acid, and 2-methylbutanal; Pseudomonas aeruginosa chemical signatures containing several combinations of 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 2-pentanol, and 4-methylquinazoline; Escherichia coli chemical signatures containing several combinations of indole, methanol, ethyl acetate, and 2-pentanol; Clostridium sporogenes chemical signatures containing several combinations of indole, methanol, ethyl acetate, and 2-pentanol; and Candida albicans chemical signatures containing several combinations of methanol and dimethylcyclohexanol.

[0060] The patient status determination operation may include determining any changes in the patient's status over time. As described above, one or more observed chemical signatures may be at least semi-quantitative with respect to one or more constituent VOCs. Multiple time-dependent observed chemical signatures thereby indicate the semi-quantitative changes in one or more constituent VOCs over time for the patient status determination operation.

[0061] A method of using the infection detection medical system 100 may include a medical device placement action, which may include placing an indwelling medical device 102 into a patient's blood vessel; a wound covering action, which may include covering the insertion site, any portion of the internal conduit 110 of the indwelling medical device 102 extending from the insertion site, the hub 114 of the indwelling medical device 102, or a combination thereof, with a wound dressing 106; and optionally, a systemic inflammatory response syndrome (e.g., body temperature ≥ 100°F, heart rate ≥ 90 beats / min, or respiratory rate) to instantiate one or more of the actions described above in the method of using the infection detection medical system 100. The medical system power supply operation may include powering the indwelling medical device 102, the dedicated computing device 104, or both the indwelling medical device 102 and the dedicated computing device 104 after observing one or more clinical criteria (≥20 breaths / min), inflammation around the insertion site, or a combination thereof; and one or more operations selected from a reading operation, which may include a clinician reading the output from one or more output devices 162 of the dedicated computing device 104 regarding whether the patient has a microbial infection. The reading operation may be performed repeatedly by the clinician for any changes in the patient's condition over time.

[0062] The infection detection medical system 100 and method advantageously provide rapid and accurate results with respect to at least one or more VOC biomarkers for determining microbial infection and patient status, which otherwise currently requires at least 24-48 hours of laboratory work. This facilitates microbial-specific treatment with a faster response time to such microbial infections and improves patient outcomes.

[0063] example An experimental system was set up that included the following: 1) a HeptaValve Mini (Aryballe Technologies, Grenoble France) for switching between sample and control without modifying the rest of the experimental system; 2) an amplifier (Aryballe Technologies, Grenoble France) containing a cartridge of hydrophobic Tenax® TA adsorbent (20 mg, 60-80 mesh) for concentrating VOCs by adsorption and subsequent desorption by flash heating; and 3) the NeOse Advance (Aryballe Technologies, Grenoble France) for digital olfaction. The NeOse Advance includes a pump for managing airflow, a core sensor containing an array of 42 peptide-based sensors immobilized on a Mach-Zehnder interferometer for digitizing interactions with VOCs, humidity and temperature sensors for normalizing electrical signals, and a photoionization detector for determining correction factors for semi-quantification of VOCs.

[0064] Samples of fluids containing Candida albicans or Escherichia coli were tested against a control fluid that did not contain such microorganisms using an experimental system, and the results showed that the experimental system distinguished the samples containing microorganisms from the control fluids. In one example, Figure 9 shows the PCA of two fluid samples containing Candida albicans, namely "CANDIDAFLUIDA" and "CANDIDAFLUIDB," and a control fluid that does not contain Candida albicans, namely "FLUIDA" and "FLUIDB," thereby demonstrating the distinction between the aforementioned fluids by the experimental setup. In another example, Figure 10A shows the PCA of a fluid sample containing Escherichia coli at a relatively low level of 320 colony-forming units ("CFU"), namely "ECOLI1," and a control fluid A that does not contain Escherichia coli, namely "FLUIDA," thereby demonstrating the distinction between the aforementioned fluids by the experimental setup. Furthermore, Figure 10B shows the PCA of a fluid sample containing a relatively high level of E. coli at 2700 CFU, i.e., "ECOLI2," and a control fluid A that does not contain E. coli, i.e., "FLUIDA," thereby illustrating the distinction between the aforementioned fluids based on the experimental setup.

[0065] While several specific embodiments are disclosed herein, and these specific embodiments are disclosed in some degree of detail, they are not intended to limit the scope of the concepts provided herein. Further adaptations or modifications may be apparent to those skilled in the art, and these adaptations or modifications are also encompassed in broader embodiments. Thus, it is possible to implement developments from specific embodiments disclosed herein without departing from the scope of the concepts provided herein.

Claims

1. It is an infection detection medical system, It is an indwelling medical device, An internal conduit configured to be inserted percutaneously into the patient's blood vessels, One or more extracorporeal conduits fluidly connected to the internal conduit, configured to remain outside the patient's body, A hub between the proximal portion of the internal conduit and the distal portions of one or more of the one or more external conduits, A microcontroller integrated into the part of the aforementioned indwelling medical device and The microcontroller is equipped with, A chemical sensor module including one or more chemical sensors configured to generate an electrical signal in response to interaction with one or more volatile organic compounds (VOCs) associated with the patient, A microcontroller processor configured to generate chemical sensor data from the aforementioned electrical signal, Dedicated computing devices including computing device processors and The computing device processor includes, It is configured to generate one or more observed chemical signatures from the chemical sensor data, and An infection detection medical system configured to determine whether a patient has a microbial infection by comparing one or more observed chemical signatures with chemical signatures known for microbial infections.

2. The infection detection medical system according to claim 1, wherein the indwelling medical device further includes one or more connectors for one or more extracorporeal conduits, and the portion of the indwelling medical device on which the microcontroller is integrated is one of the connectors.

3. The portion of the implantable medical device into which the microcontroller is integrated is a hub, according to claim 1, for the infection detection medical system.

4. The infection detection medical system according to any one of claims 1 to 3, wherein the microcontroller further includes a microcontroller communication module configured for wireless communication with the computing device communication module of the dedicated computing device, and the wireless communication includes at least the chemical sensor data.

5. The infection detection medical system according to any one of claims 1 to 4, wherein the microcontroller further includes a memory configured to store the chemical sensor data over time, and the one or more observed chemical signatures generated by the computing device processor include a plurality of time-dependent observed chemical signatures based on the chemical sensor data stored in the memory over time.

6. The infection detection medical system according to claim 5, wherein the one or more observed chemical signatures are at least semi-quantitative with respect to one or more constituent VOCs, and the plurality of time-dependent observed chemical signatures indicate a semi-quantitative change in one or more constituent VOCs over time, and consequently any change in the patient's condition over time.

7. The infection detection medical system according to any one of claims 1 to 6, wherein the implantable medical device further includes a VOC permeable membrane on the chemical sensor module, the VOC permeable membrane being configured to selectively allow one or more VOCs to pass through the VOC permeable membrane rather than water vapor.

8. The infection sensing medical system according to any one of claims 1 to 7, wherein the one or more VOCs are selected from indole, methanol, 1-undecene, ethyl acetate, 2,4-dimethyl-1-heptane, 2-butanone, benzaldehyde, dimethylcyclohexanol, isovaleric acid, 2-pentanol, 4-methylquinazoline, and 2-methylbutanal.

9. An infection-sensing medical system according to any one of claims 1 to 8, wherein the known chemical signature for a microbial infection is selected from: a Staphylococcus aureus chemical signature comprising several combinations of benzaldehyde, isovaleric acid, and 2-methylbutanal; a Pseudomonas aeruginosa chemical signature comprising several combinations of 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 2-pentanol, and 4-methylquinazoline; an Escherichia coli chemical signature comprising several combinations of indole, methanol, ethyl acetate, and 2-pentanol; a Clostridium sporogenes chemical signature comprising several combinations of indole, methanol, ethyl acetate, and 2-pentanol; and a Candida albicans chemical signature comprising several combinations of methanol and dimethylcyclohexanol.

10. An infection-sensing medical system according to any one of claims 1 to 9 further comprises an insertion site, any portion of an internal conduit of an indwelling medical device extending from the insertion site, and a wound dressing sized to cover the hub of the indwelling medical device, wherein the wound dressing includes a water vapor permeable membrane, the water vapor permeable membrane being configured to selectively allow water vapor to pass through the membrane more than the one or more VOCs.

11. The infection detection medical system according to any one of claims 1 to 10, wherein the indwelling medical device is a central venous catheter (CVC), a peripherally inserted central venous catheter (PICC), a midline catheter, a peripheral venous catheter (PIVC), or an acute dialysis catheter.

12. A disease-detecting medical system, A breath analyzer, An exhalation receiving tube configured to receive the patient's exhaled breath, A microcontroller integrated into a part of the aforementioned breath analyzer and The microcontroller includes, A chemical sensor module including one or more chemical sensors configured to generate an electrical signal in response to interaction with one or more volatile organic compounds (VOCs) associated with the patient, A microcontroller processor configured to generate chemical sensor data from the aforementioned electrical signal, Dedicated computing devices including computing device processors and The computing device processor includes, It is configured to generate one or more observed chemical signatures from the chemical sensor data, and A disease-sensing medical system configured to determine whether a patient has a disease by comparing one or more observed chemical signatures with chemical signatures known for that disease.

13. The disease-sensing medical system according to claim 12, wherein the one or more VOCs are selected from acetic acid, ethyl cyclopropane, 2-ethyl-1-hexanol, acetone, and isopropanol.

14. The disease-sensing medical system according to claim 12 or 13, wherein the known chemical signature for a disease is selected from the chemical signature for tuberculosis, which comprises several combinations of acetate, ethyl-cyclopropane, and 2-ethyl-1-hexanol, and the chemical signature for diabetic ketoacidosis, which comprises several combinations of acetone and isopropanol.

15. The disease-sensing medical system according to any one of claims 12 to 14, wherein the breath analyzer and the dedicated computing device are integrated into a single disease-sensing medical device that is in the same range as the disease-sensing medical system.

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