Device and method for monitoring the concentration of an analyte in a body fluid

Abstract

The subject invention relates to a novel system capable of long-term in vivo monitoring of the concentration of characteristic biomarkers in body fluids. The invention includes a wireless concentration monitor and an external data logger that do not require built-in traditional batteries to continuously measure the concentration of certain analytes and send signals related to the concentration of the detected biomarkers in real time.

Description

Background Art

[0001] Integrated circuits, advanced materials, and biomedical technologies provide nanowatt-scale platforms and microcircuits with methods for in situ detection of biomarkers in body fluids. Specifically, wearable devices like smart watches equipped with electrocardiograms (ECGs) and photoplethysmograms (PPGs) can simultaneously measure heart rate, heart rate variability, blood pressure, and body temperature. In addition, electronic skins embedded with electrochemical sensors offer the opportunity to detect certain biomarkers in sweat in a noninvasive manner, such as glucose, lactate, and pH.

[0002] Compared to sweat, fluids from the digestive tract have more biomarkers, including hormones, proteins, and a diverse microbiome. Current medical devices equipped with electrochemical sensors offer the opportunity to detect some biomarkers in situ in a non-invasive manner. However, the operating time of these devices embedded with conventional batteries is limited due to high sampling rates and power consumption. Although rechargeable lithium-ion (Li-ion) batteries have been used to extend the shelf life of some medical devices, Li-ion batteries still have safety issues related to the risk of spontaneous combustion and potential leakage of toxic substances.

[0003] The emergence of ingestible electronic devices has opened a new window for monitoring valuable physiological information related to intestinal health in a non-invasive manner. However, current human-machine interactive medical devices (HIMDs), such as electronic skin and ingestible electronic devices, still rely on batteries. Since high sampling rates, electrochemical sensing, and wireless data transmission consume a lot of power, these human-machine interactive medical devices are all limited to a limited working time, and long-term monitors are important for providing more data for more accurate diagnosis. Although rechargeable lithium-ion batteries have been used in some medical devices, safety issues related to spontaneous combustion and leakage of hazardous materials have hindered their application, especially in ingestible electronic devices. In addition, the size of ingestible electronic devices is associated with the risk of intestinal obstruction, while bulky batteries eliminate the possibility of further miniaturization. Summary of the invention

[0004] A medical device for remote sensing and in vivo measurement of analyte concentrations in body fluids is provided. The device of the present invention is capable of long-term monitoring of the concentration of typical analytes in body fluids without any internal batteries, is non-invasive and inexpensive. In some embodiments, the device is a remote concentration monitor system comprising a battery-free concentration monitor powered by energy harvested from body fluids.

[0005] In some embodiments, the remote concentration monitor system includes a wireless, battery-free concentration monitor and an external data logger capable of receiving signals from the concentration detector and interpreting the corresponding biomarker concentration. In a preferred embodiment, the monitor is located within a subject.

[0006] In some embodiments, the external data logger can receive signals from the in vivo concentration detector and parse out the corresponding biomarker concentration. In some embodiments, the concentration monitor includes one or more pairs of anodes and cathodes attached to the surface of the monitor and a packaged circuit powered by energy collected from body fluids through the electrodes.

[0007] In some embodiments, the packaged circuit includes a concentration adaptive energy harvesting circuit, a wireless communication module, and a storage element selected from a capacitor and a supercapacitor. In a preferred embodiment, the wireless communication module is a radio frequency (RF) transmitter.

[0008] Advantageously, the voltage generated at the electrodes of the galvanic cell of the device drives a radio frequency transmitter which sends a signal to an external signal recorder which decodes the frequency of the received signal into concentration data of the analyte present at the electrodes of the galvanic cell and displays the concentration data on a screen. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 A schematic diagram of a remote monitor system including a wireless, battery-free concentration monitor and an external signal receiver is shown.

[0010] Figure 2A A schematic diagram showing the system architecture of a packaged circuit for a wireless, battery-free concentration monitor including a concentration adaptive voltage regulator, a temporary storage capacitor, and a wireless communication module. Figure 2B The galvanic electrodes of a wireless, battery-free concentration monitor are shown extending from a packaged circuit and attached to a surface of the monitor.

[0011] Figure 3A An assembly process for delivering a wireless, battery-free concentration monitor into a portion of the digestive tract is shown, including mounting the monitor onto a standard endoscope. Figure 3B A detailed deployment procedure for securing the monitor to the digestive tract tissue is shown.

[0012] Figure 4 shows the periodic variation of the voltage of the temporary storage capacitor in the packaged circuit when the electrode is immersed in a hydrochloric acid buffer solution.

[0013] Figure 5 The communication signals between the RF receiver and the microcontroller in the external data logger are shown.

[0014] Figure 6 A schematic diagram of a portable receiver is shown, which includes a signal receiver, a storage medium, a microcontroller and a screen.

[0015] Figure 7 A schematic diagram showing radio frequency signals with different frequencies according to pH values ​​from 1 to 4 is shown. DETAILED DESCRIPTION

[0016] A medical device for a remote sensing system is provided, which measures the concentration of certain analytes in body fluids in vivo using a battery-free concentration monitor that harvests energy from the body fluid to activate a wireless communication module. Advantageously, the wireless, battery-free device of the present invention is capable of long-term monitoring of the concentration of typical analytes in body fluids without any internal batteries, which is non-invasive and inexpensive.

[0017] In some embodiments, the present invention provides a system including a wireless, battery-free concentration monitor and a data logger.

[0018] In some embodiments, a wireless, battery-free concentration monitor includes one or more pairs of anodes and cathodes attached to a surface of the monitor and encapsulated circuitry.

[0019] In a preferred embodiment, the wireless, battery-free concentration monitor is present within the subject and the data logger is external or external to the subject.

[0020] In another preferred embodiment, the wireless, battery-free concentration monitor measures the concentration of at least one analyte in real time without any internal battery, the packaged circuit sends a signal generated based on the concentration of the analyte, and the remote data logger receives the signal, stores and analyzes the signal to generate data, and optionally displays the signal data on a screen.

[0021] In some embodiments, the wireless battery-free concentration monitor is a micro-monitor. In a preferred embodiment, the wireless battery-free concentration micro-monitor is present on a chip. The overall size of the concentration monitor chip is subject to the biocompatibility of the electrode. In some embodiments, the electrode of the concentration monitor is a metal foil, such as copper, zinc, iron, magnesium, silver, gold and platinum. In some embodiments, the thickness of the electrode is between 0.05mm and 5mm. In some embodiments, the electrode thickness is about 0.08mm to about 4.8mm; about 0.1mm to about 4.5mm; about 0.15mm to about 4mm; about 0.2mm to about 3.5mm; about 0.3mm to about 3mm; about 0.4mm to about 2.5mm; about 0.5mm or about 2mm; about 0.6mm to about 1.5mm; about 0.7mm to about 1.2mm; about 0.8mm to about 1mm. The length of the electrode is between 1 millimeter and 30 millimeters. In some embodiments, the electrode length is about 1.2mm to about 28mm; about 1.5mm to about 25mm; about 1.8mm to about 20mm; about 2mm to about 18mm; about 2.5mm to about 15mm; about 3mm to about 12mm; about 3.5mm to about 10mm; about 4mm to about 8mm; about 4.5mm to about 7.5mm; about 5mm to about 7mm. In a preferred embodiment, the electrode length is between 3mm and 10mm and the electrode width is between 0.3mm and 1mm. In another preferred embodiment, the thickness of the electrode is 0.2mm. In another preferred embodiment, the length of the electrode is between 5mm and 15mm and the width is between 0.5mm and 1.5mm. In another preferred embodiment, the thickness of the electrode is 0.1mm. In other preferred embodiments, the length of the electrode is between 8mm and 20mm and the width is between 0.8mm and 2mm.

[0022] In some embodiments, the concentration monitor chip has a length between 1 μm and 5 cm and a width between 1 μm and 3 cm. In some embodiments, the concentration monitor chip has a length of about 1.2 μm to about 4.8 cm, about 1.5 μm to about 4.5 cm, about 2 μm to about 4.2 cm, about 2.5 μm to about 4 cm, about 3 μm to about 3.8 cm, about 5 μm to about 3.5 cm, about 10 μm to about 3 cm, about 15 μm to about 2.5 cm, about 20 μm to about 2 cm, about 30 μm to about 1.5 cm, about 40 μm to about 1 cm, about 50μm to about 9mm, about 60μm to about 7mm, about 80μm to about 6mm, about 90μm to about 5mm, about 100μm to about 4mm, about 120μm to about 3mm, about 150μm to about 2mm, about 200μm to about 1mm, about 250μm to about 900μm, about 300μm to about 800μm, about 400μm to about 700μm or about 500μm to about 600μm.

[0023] In some embodiments, the width of the monitor chip is about 1.2 μm to about 2.8 cm, about 1.5 μm to about 2.5 cm, about 2 μm to about 2 cm, about 2.5 μm to about 1.5 cm, about 3 μm to about 1 cm, about 5 μm to about 8 mm, about 10 μm to about 5 mm, about 15 μm to about 2.5 mm, about 20 μm to about 2 mm, about 30 μm to about 1.5 mm, about 40 μm to about 1 mm, about 50 μm to about 900 μm, about 60 μm to about 800 μm, about 80 μm to about 600 μm, about 90 μm to about 500 μm, about 100 μm to about 400 μm, about 120 μm to about 300 μm or about 150 μm to about 200 μm.

[0024] In some embodiments, a miniature battery-free concentration monitor includes a galvanic cell that generates electrical current by reaction with body fluids, packaged circuitry for concentration-adaptive energy harvesting, and a wireless data transmission system.

[0025] In some embodiments, an external data logger receives the signal encoding the concentration information and stores the data in a storage medium.

[0026] In some embodiments, the external data logger is capable of displaying data on a screen in real time or daily as a concentration profile of at least one analyte. In some embodiments, the external data logger also records the user's daily events, including but not limited to eating and sleeping. Advantageously, the recorded daily events of the user can be associated with the user's metabolic rate that may affect the concentration of the target analyte.

[0027] Further provided is a novel method for assessing the concentration of at least one analyte based on the concentration adaptive energy harvesting principle. Advantageously, the concentration adaptive energy harvesting principle of the present invention provides a battery-free analyte concentration monitoring system that can achieve long-term detection without sacrificing accuracy and can avoid leakage events commonly associated with battery-powered devices containing toxic substances.

[0028] In addition, the extended monitoring time period of the monitoring system of the present invention provides more data and enables better analysis of changes in certain analytes over long periods of time. In some embodiments, the battery-free remote concentration monitor system of the present invention measures glucose in the bladder of a subject to diagnose and monitor diabetes. In certain embodiments, the battery-free remote concentration monitor system of the present invention measures the concentration of hydrogen ions in the esophagus to diagnose and monitor gastroesophageal reflux disease (GERD). In certain embodiments, the battery-free remote concentration monitor system of the present invention measures the concentration of lactic acid in the small intestine to diagnose lactose intolerance.

[0029] In some embodiments, the battery-free and wireless concentration monitor of the present invention comprises a primary cell and a packaged circuit. In a specific embodiment, the primary cell comprises one or more pairs of anodes and cathodes. In an embodiment of the present invention, when the concentration monitor of the present invention comes into contact with a body fluid containing an analyte to be measured, a reduction reaction occurs at the cathode and oxidation occurs at the anode. Once in contact with the body fluid, the anode loses electrons and the cathode gains electrons, thereby generating an electric current. In some embodiments, the current generated by the electron transfer is collected by a packaged circuit that sends a signal related to the concentration of the ion being detected. In a specific embodiment, the packaged circuit comprises a voltage regulator, a temporary capacitor, and a wireless communication module.

[0030] In some embodiments, the galvanic cell further comprises a separate layer to protect the electrodes from contamination by accumulation of debris present in bodily fluids.

[0031] In some embodiments, a semipermeable membrane that allows the passage of negative ions is used to enhance the performance of the electrode.

[0032] In some embodiments, the surface of the electrode is modified by enzyme immobilization and is capable of performing enzymatic reactions.

[0033] In some embodiments, the surface of the electrode is colonized with bacteria that catalyze a specific analyte, including but not limited to Lactobacillus zeae, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus bulgaricus, and Lactobacillus acidophilus.

[0034] In some embodiments, the packaged circuit is a voltage regulating circuit that is an active energy harvesting integrated circuit (IC). In a particular embodiment, the voltage regulating circuit is a boost converter.

[0035] In some embodiments, the temporary storage device is a capacitor or a supercapacitor, the capacitance of which can store enough energy to drive the wireless communication module.

[0036] In some embodiments, the wireless communication module is a device that generates a magnetic field that can be detected by an external recorder.

[0037] In some embodiments, the wireless communication module is an amplitude shifting keying (ASK) module or an on-off keying (OOK) module that transmits data with varying amplitudes.

[0038] In some embodiments, the circuit is encapsulated by a biocompatible material. In a specific embodiment, the biocompatible material is a polyalkylsiloxane. In a further embodiment, the biocompatible material is selected from polymethylsiloxane (PMS), polydimethylsiloxane (PDMS), polyalkoxysiloxane or polyalkylarylsiloxane.

[0039] In some embodiments, a method for measuring the concentration of a specific analyte in a body fluid is provided. In a specific embodiment, the current is generated by a redox reaction that occurs at the interface between the anode and cathode of the galvanic cell of the present invention and the body fluid. In another specific embodiment, the packaged circuit collects the generated electrical energy and stores it in a temporary storage capacitor. When the voltage of the capacitor reaches a preprogrammed threshold, the wireless communication module will be activated and send a signal to an external recorder.

[0040] Additionally, because the concentration of the analyte determines the charging rate and further determines the frequency of signal transmission, the concentration of the analyte in the body fluid is measured based on the frequency of the pulse signal.

[0041] Also provided is a system including a concentration monitor and a portable recorder capable of receiving a signal from the concentration detector and interpreting a corresponding biomarker concentration.

[0042] In some embodiments, the portable receiver includes a microcontroller, a screen, an SD card, and a signal detector. In some embodiments, an external receiver detects a signal sent from a monitor present in the subject, and decodes the in vivo signal into concentration data processed by a microcontroller. In a preferred embodiment, data is stored on an SD card and is used to draw a graph showing a daily overview of concentration data. In some embodiments, other storage devices are used to store data, including but not limited to RAM memory, ROM memory, EPROM memory, EEPROM memory, flash memory, registers, hard disks, CD-ROMs, and other forms of storage media, including storage components in the cloud.

[0043] In some embodiments, the receiver displays the frequency of the signal in real time.

[0044] In certain embodiments, the portable receiver can record the user's daily activities, including but not limited to eating and sleeping, which affect the metabolic rate and further affect the concentration of the target analyte. In addition, the recorded activity information is combined with the analyte concentration data to help the user find the relationship between the concentration changes and the user's lifestyle.

[0045] In some embodiments, the external receiver is portable. In some embodiments, the external receiver is waterproof so that data can be recorded without affecting the user's daily activities, such as bathing.

[0046] In some embodiments, the remote signal receiver further comprises a dual-band transceiver that receives sub-1 GHz signals from the in-vivo monitor and uploads the data to a storage medium via 2.4 GHz Bluetooth.

[0047] In some embodiments, the transceiver is embedded in a wearable device that can be attached to the user's skin.

[0048] Also provided is a method for delivering a concentration monitor into a human body. In some embodiments, the concentration monitor is delivered into the digestive tract. In a preferred embodiment, the concentration monitor is delivered into the esophagus of a human subject.

[0049] In some embodiments, the concentration monitor is delivered to the intestine of a human subject. In a preferred embodiment, the concentration monitor is delivered to the small intestine. In other embodiments, the concentration monitor is delivered to the large intestine. In other embodiments, the concentration monitor is delivered to the colon of a human subject.

[0050] In some embodiments, the concentration monitor is delivered to the bladder of a human subject. In other embodiments, the concentration monitor is delivered to the uterus of a human subject. In some embodiments, the concentration monitor is delivered to the vaginal cavity of a human subject.

[0051] In some embodiments, the concentration monitor of the present invention is delivered to the ear canal of a human subject. In some embodiments, the concentration monitor of the present invention is delivered to the cerebral ventricle of a human subject. In some embodiments, the concentration monitor of the present invention is delivered to the anus of a human subject.

[0052] In some embodiments, the monitor is attached to the subject's tissue by a plurality of hemostatic clips. In some embodiments, the monitor is sutured directly to the tissue, such as the intestinal wall. In some embodiments, the monitor is made into a capsule-like shape that facilitates passage through the subject's digestive tract when administered orally.

[0053] In a preferred embodiment, the monitor is administered via gastrointestinal endoscopic administration.In some embodiments, the concentration monitor is affixed to the wall of the digestive tract and guided through the digestive tract by a magnetic field or the natural peristalsis of the digestive tract.

[0054] These and additional embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0055] Although the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts.

[0056] The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention, and do not limit the scope of the invention.

[0057] The present invention provides a novel system that can monitor the concentration of an analyte in a body fluid in real time in vivo. Figure 1The concentration monitor of the present invention includes at least two parts: a wireless battery-free concentration monitor and an external receiver. Based on the concentration adaptive energy harvesting principle, the battery-free monitor can continuously measure the concentration of the target analyte for a long time without any internal battery. In some embodiments, the battery-free monitor is used to evaluate the concentration of certain analytes in the digestive tract, which is full of biomarkers related to the health of the subject.

[0058] Avoiding the use of conventional batteries makes the monitor more compact and safer. The small size of the monitor facilitates passage through the digestive tract and reduces the risk of colon obstruction. To avoid user discomfort, the battery-free monitor is wireless so as not to affect the user's daily activities, including eating. Otherwise, changing daily activities can affect the metabolic rate and affect the concentration of the target analyte in the body fluid. An external receiver detects a signal corresponding to the measured concentration. A built-in microcontroller decodes the signal into a concentration and stores the concentration data in a storage medium. In some embodiments, the recorder can display real-time data or a daily overview of the concentration on a screen.

[0059] Reference Figure 2A The concentration monitor includes two main functional parts, a body fluid driving primary cell that generates current, and a packaged circuit for voltage regulation and wireless communication. The primary cell usually includes one or more pairs of anodes and cathodes. Electrons are transferred through a redox reaction between the anode and cathode. Based on the concentration of the target analyte in the body fluid, the packaged circuit collects the generated electricity and periodically activates the wireless communication module.

[0060] In some embodiments, the concentration monitor is used to measure the pH of stomach acid.

[0061] Anode: A→A n+ +ne -

[0062] Cathode: 2H + +2e - =H 2

[0063] Based on the above equation, hydrogen ions are reduced at the cathode, while the anode of the sacrificial electrons is dissolved in gastric acid. Materials with high reduction potentials, such as platinum (Pt), palladium (Pd) and copper (Cu) are ideal cathodes. The anode should have a relatively high negative standard reduction potential to produce electrons relative to other substances in gastric acid. In some embodiments, copper and zinc are selected as cathodes and anodes, respectively, for low cost and easy manufacture. Once in contact with gastric acid, the anode, such as the zinc anode, dissolves and loses electrons. The cathode collects electrons and reduces hydrogen ions to hydrogen. Due to electron transfer, a sustainable current is generated between the electrodes. In some embodiments, the electrode is coated with a semi-permeable membrane, such as a Nafion membrane, which promotes the transfer of protons and suppresses short circuits due to direct contact between the anode and the cathode.

[0064] In some embodiments, the target analyte is lactate.

[0065]

[0066] Typically, lactic acid is catalyzed to pyruvic acid by lactate oxidase (LOx) at the anode, while oxygen is reduced to water at the cathode. In some embodiments, graphite is selected as the anode due to its stability and fast electron transfer rate. In addition, LOx is fixed on graphite to catalyze the enzymatic reaction. In some embodiments, Ag / AgCl coated with Prussian blue is used as the cathode. The reason for selecting Ag / AgCl is its stability, and Prussian blue minimizes the reduction potential.

[0067] In some embodiments, the monitor measures glucose concentration for diagnosing diabetes.

[0068]

[0069] Typically, glucose is oxidized at the anode under the catalysis of glucose oxidase (GOx). At the same time, oxygen is reduced to water at the cathode. In some embodiments, bacteria capable of producing GOx are colonized on the anode in a conductive hydrogel or chitosan matrix. Typically, platinum (Pt) is selected as the cathode because of its high reduction potential.

[0070] Biofouling, which typically occurs through nonspecific adsorption of various molecules on the electrodes, reduces specificity and sensitivity. Therefore, in order to inhibit biofouling, the apparatus of the present invention includes surface modifications that act as antifouling agents. For example, polyethylene glycol (PEG) is widely used because its hydrophilic groups form a hydration layer that blocks unwanted biomolecules. Therefore, in some embodiments, the electrodes of the monitor are coated with PEG.

[0071] In some embodiments, the coating material is selected from polylactic acid, polyglycolide, polylactic acid polyglycolic acid copolymer (PLGA), polycaprolactone, poly(dioxanone), poly(trimethylene carbonate) copolymer, polyglycerate, poly(propylene fumarate), poly(ethylene terephthalate), poly(butylene terephthalate), polyethylene glycol, polycaprolactone copolymer, polyhydroxybutyrate, polyhydroxyvalerate, tyrosine-derived polycarbonate and any random or (multi) block copolymer, such as a binary copolymer, a ternary copolymer and a tetrapolymer.

[0072] Reference Figure 2A, the packaged circuit of the concentration monitor system of the present invention includes a voltage stabilizing circuit, a temporary storage element and a wireless communication module. In some embodiments, the wireless communication module includes an oscillator, an onboard antenna and an on / off keying RF transmitter, which transmits binary code by an RF signal with a variable amplitude. In some embodiments, the wireless communication module is a coil inductor that generates a magnetic field that can be detected by an external signal receiver. In some embodiments, the circuit is manufactured on a printed circuit board (PCB) and is encapsulated by a biocompatible material selected from polymethylsiloxane (PMS), polydimethylsiloxane (PDMS), polyalkoxysiloxane and polyalkylarylsiloxane. In a preferred embodiment, the biocompatible material is PDMS. For example, electrodes made of copper and zinc are directly soldered on the PCB.

[0073] Reference Figure 2B , a portion of the electrode protrudes from the PDMS and is exposed to the body fluid. In some embodiments, a microfluidic channel is fabricated in the PDMS housing to sample body fluid.

[0074] In some embodiments, the size of the capsule is minimized by rigid-flexible PCB manufacturing. Each functional module is mounted separately on a rigid circular substrate (FR4 board). Each rigid board is stacked layer by layer and connected by a flexible substrate (polyimide). Instead of an onboard antenna, a spiral copper antenna wraps around the circular stacked circuit, which not only provides better omnidirectional signal radiation, but also makes the capsule more compact, thereby reducing the risk of capsule retention.

[0075] In some embodiments, the monitor is used to measure the concentration of certain analytes in the digestive tract. To this end, the packaged circuit is further cut into a capsule-like shape to facilitate passage through the digestive tract. In some embodiments, the monitor is delivered by oral administration. The monitor can pass through the esophagus, stomach, small intestine and colon. The monitor of the present invention can record the concentration curve of the target analyte to study the changes of the target analyte in the entire digestive tract.

[0076] In some embodiments, the monitor is fixed to a site in a body cavity to study changes in biomarkers in the target area. Figure 3A The monitor is mounted on the distal tip of a standard endoscope via a custom holder. An endoscopic hemostatic clip is then inserted through the biopsy port of the endoscope and tied to the monitor via surgical sutures. Figure 3B The delivery process is generally shown. After assembly, the monitor is inserted through the esophagus together with the endoscope. The two ends of the monitor are then fixed in the esophageal wall by hemostatic clips in sequence. Eventually, the monitor will detach from the esophageal wall due to tissue growth. In some embodiments, the surgical suture is made of an enteric material that remains intact in gastric acid. After entering the small intestine, the clip is detached from the monitor due to degradation of the surgical suture.

[0077] In some embodiments, the monitor also includes a permanent magnet for magnetic control and navigation. The monitor is delivered to the target area by an external magnetic field such as a magnetic field generated by an electromagnetic system or an external permanent magnet. In some embodiments, a belt embedded with a permanent magnet is used to attract the monitor into a target area such as the small intestine. In some embodiments, the monitor is sutured directly to GI tissue such as the stomach for long-term assessment of biomarkers.

[0078] Reference Figure 4 , the voltage of the storage capacitor reveals the working principle of the concentration adaptive voltage regulation circuit. In some embodiments, a redox reaction occurs when two electrodes contact body fluids. The current generated by the electrode is proportional to the concentration of the target analyte in the body fluid, while the potential generated between the two electrodes is constant. Then, the concentration adaptive energy collects the current and begins to charge the temporary storage capacitor. In one embodiment, a pair of NPN bipolar transistors and a P-type MOSFET are used as a voltage-controlled switch connected between the temporary storage capacitor and the wireless communication module. When the voltage of the storage capacitor reaches a preprogrammed threshold, the wireless signal transmitter will be activated and send a pulse signal to an external receiver. Instantly, the energy stored in the capacitor is consumed and the voltage drops below the threshold. The wireless signal transmitter is turned off and the capacitor is charged again. The frequency of the pulse signal can be described by the following formula:

[0079]

[0080] Since it takes less time to charge the storage capacitor to the lower threshold, reducing the threshold V threshold will increase the frequency resulting in shorter cycles. But the threshold should be high enough to turn on the switch. Also, the capacitance C of the temporary capacitor store It also affects the period of the signal. The frequency decreases with increasing capacitance because it takes more time to charge a large capacitance capacitor to the threshold. In addition, the energy stored in the capacitor should be high enough to drive the wireless communication transmitter. The charging current I charge Proportional to the concentration of the target analyte catalyzed in the body fluid. After careful setting of the threshold and selection of the capacitor, the signal frequency is determined only by the charging current I charge Therefore, the frequency of the pulse signal can be calibrated to the corresponding analyte concentration.

[0081] In some embodiments, the packaged circuit includes a boost converter circuit and a multimode microcontroller, which extracts energy from the primary battery and raises the voltage of the temporary storage capacitor to a threshold value, and the multimode microcontroller has a radio frequency transceiver for wireless communication. A normally open single-pole single-throw analog switch is connected between the microcontroller and the storage capacitor. When the target analyte is not detected, the microcontroller will remain in sleep mode. When the temporary storage capacitor is charged to a constant voltage, the analog switch is turned on. In concentration adaptive operation, the charging rate is related to the concentration of the target analyte in the body fluid. When the voltage of the capacitor reaches the threshold value, the microcontroller is awakened and a pulse signal is sent. Therefore, the measured analyte concentration is encoded in the frequency of the radio frequency signal. Once the control signal is transmitted, the voltage of the storage capacitor drops below the threshold value. Then, the analog switch is cut off and the storage capacitor is charged again.

[0082] In some embodiments, the microcontroller sends control signals to other components, including but not limited to a drug release system or an electrical stimulation system. In some embodiments, the drug release system comprises a micromotor driven by a pulse signal. Advantageously, the microcontroller can send a pulse signal to control the rate of drug release according to the analyte concentration. In other embodiments, the electrical power generated by the device of the present invention is used to apply electrical stimulation to restore weakened muscles.

[0083] In some embodiments, the device of the present invention uses near field communication (NFC) technology. Instead of an RF transmitter module, a passive radio frequency identifier (RFID) is connected to a temporary storage capacitor via a normally open single-pole single-throw analog switch. When the voltage of the capacitor reaches a threshold, the analog switch is turned on. The RFID is then activated and a signal is sent. In some embodiments, the RFID includes a built-in temperature sensor that can also send a signal encoded with temperature information. Therefore, the temperature inside the human body can also be obtained.

[0084] In some embodiments, the wireless communication module is a coil inductor to eliminate the trade-off between RF signal performance and sensitivity of the concentration monitor. Specifically, good RF signal performance requires a larger capacitor, while a relatively smaller capacitor results in better sensitivity. Instead of an RF signal transmitter module, a coil inductor generates a magnetic field when activated.

[0085] Reference Figure 5, in some embodiments, the microcontroller communicates with the RF signal receiver through a digital signal pin. In one embodiment, the in vivo concentration monitor remains silent when no analyte is detected and the RF signal receiver within the portable device emits a random signal. When a body fluid containing a target analyte is detected, the monitor sends a pulse signal to an external receiver. The RF signal receiver then sends a low-level signal lasting about 200 microseconds to the microcontroller. The microcontroller then decodes the signal into concentration information based on its frequency. In other embodiments, certain types of RF signal receivers send a high-level pulse signal when receiving an RF signal to wake the microcontroller from sleep mode. Similarly, the microcontroller decrypts the signal into concentration data based on the signal frequency.

[0086] Reference Figure 6 In some embodiments, the portable receiver includes a signal receiver for wireless communication, a microcontroller for signal processing, an SD card for data storage, and a screen with a user interface. In some embodiments, the portable receiver can plot real-time data on the screen. In addition, the device can also record data and process the data into a chart that shows a daily overview of the target analyte concentration. In some embodiments, the portable device can record the user's daily events, like eating and sleeping. This feature helps doctors find the relationship between changes in analyte concentrations and the user's lifestyle.

[0087] Reference Figure 7 , in vitro measurements are used to calibrate the remote concentration monitor of the present invention. In some embodiments, a packaged prototype with extended electrodes is immersed in an acidic buffer solution of hydrochloric acid (HCl) with a pH value (pH) of 1 to 4. The pH value represents the concentration of hydrogen ions in the solution, which determines the efficiency of the redox reaction on the concentration monitor electrode. For example, a lower pH value results in a more active redox reaction, resulting in more efficient energy harvesting. After immersing the packaged prototype, energy harvesting begins to charge the temporary storage capacitor. Since the RF transmitter sends a signal when the voltage of the storage capacitor reaches a threshold, the frequency of the signal varies depending on the pH value, such as Figure 7 shown.

[0088] Materials and methods

[0089] Non-limiting embodiments of the present invention will be described by way of example in conjunction with the accompanying drawings, which are schematic and are not intended to be drawn to scale. In the accompanying drawings, each identical or nearly identical component shown is generally represented by a single numeral. For the sake of clarity, where illustration is not necessary to enable a person of ordinary skill in the art to understand the present invention, not every component is labeled in each of the drawings, nor is every component of each embodiment of the present invention shown.

[0090] All patents, patent applications, provisional applications, and publications referenced or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0091] The following are examples illustrating the methods of implementing the present invention. These examples should not be construed as limiting. Unless otherwise indicated, all percentages are by weight and all solvent mixture ratios are by volume.

[0092] Example 1—Remote Concentration Monitor System

[0093] A wireless concentration monitor without built-in traditional batteries and an external receiver are combined to produce a remote concentration monitor system of the present invention. Using the concentration adaptive energy harvesting principle, the battery-free monitor can continuously measure the concentration of the target analyte for a long time without using a built-in battery. The battery-free monitor can be used, for example, to evaluate the concentration of certain analytes in the digestive tract of a subject. The digestive tract is full of biomarkers related to human health, and using the monitor system to measure the target analyte no longer requires traditional batteries, and due to the small size of the monitor, it can be easily passed through the digestive tract and reduces the risk of intestinal obstruction. In order to avoid user discomfort, the battery-free monitor is also wireless and will not affect the user's daily life, such as diet. Advantageously, the monitor of the present invention does not need to change the daily routine, because changes in the daily routine can affect the metabolic rate and the concentration of the target analyte in the body fluid. The external receiver receives a signal from the concentration monitor in the subject, wherein the signal corresponds to the measured concentration of at least one analyte. The built-in single-chip microcomputer of the receiver decodes the signal into a concentrated signal and stores the data in a storage medium. The recorder can also display real-time data or a daily overview of the concentration on the screen.

[0094] Example 2 - Wireless, Battery-Free Concentration Monitor

[0095] The wireless battery-free concentration monitor of the system of the present invention includes at least a body fluid driven primary cell for generating electric current, and a packaged circuit for voltage regulation and wireless communication. The primary cell generally includes one or more pairs of anodes and cathodes. Electrons are transferred through a redox reaction between the anodes and cathodes. The packaged circuit periodically collects electrical power and activates a wireless communication module based on the concentration of at least one target analyte in the body fluid in contact with the primary cell. The concentration monitor is used, for example, to measure the pH value of gastric acid.

[0096] Anode: A→A n+ +ne -

[0097] Cathode: 2H + +2e - =H 2

[0098] Based on the above equation, the hydrogen ions present in the gastric juice are reduced at the cathode, while the anode of the sacrificial electrons is dissolved in the gastric acid. Materials with high reduction potentials, such as platinum (Pt), palladium (Pd) and copper (Cu) are ideal cathodes. The anode should have a high negative standard reduction potential to produce electrons relative to other substances in gastric acid. In some embodiments, copper and zinc are selected as cathodes and anodes, respectively, for low cost and easy manufacture. For example, once in contact with gastric acid, the zinc anode will dissolve and lose electrons, while the cathode will collect electrons and reduce hydrogen ions to hydrogen. Due to electron transfer, a sustainable current is generated between the electrodes. In some embodiments, the electrode is coated with a semipermeable membrane, including but not limited to a Nafion membrane, which promotes the transfer of protons and avoids short circuits caused by direct contact between the anode and the cathode.

[0099] Example 3 - Wireless, Battery-Free, Lactate Concentration Monitor

[0100] Typically, lactate oxidase (LOx) catalyzes lactate to pyruvate at the anode, while oxygen is reduced to water at the cathode.

[0101]

[0102] In one example, graphite was selected as the anode because of its stability and fast electron transfer rate. LOx was then immobilized on the graphite to catalyze the enzymatic reaction. In other examples, Ag / AgCl coated with Prussian blue was used as the cathode. Ag / AgCl was selected because of its stability, while Prussian blue minimized the reduction potential.

[0103] Example 4 - Wireless Battery-Free Glucose Level Monitor

[0104] The monitor of the present invention evaluates the glucose concentration for diagnosing diabetes. To this end, glucose is oxidized under the catalysis of glucose oxidase (GOx) on the anode and oxygen is reduced to water on the cathode:

[0105]

[0106] Since some bacteria are able to produce GOx, the anode is colonized by bacteria in a conductive hydrogel or chitosan matrix. Typically, platinum (Pt) is chosen as the cathode due to its high reduction potential.

[0107] Example 5 - Preventing Electrode Biofouling

[0108] Although biofuel cells offer a promising solution for implantable medical devices, the electrodes used in biofuel cells often suffer from biofouling. Typically, nonspecific adsorption of various molecules on the electrodes reduces specificity and sensitivity. Therefore, several surface modification methods are used as antifouling strategies. For example, polyethylene glycol (PEG) is a widely used coating because its hydrophilic groups form a hydration layer that blocks unwanted biomolecules.

[0109] Other materials according to the invention may be used as antifouling agents.

[0110] Example 6 - Additional Circuit for Concentration Monitor

[0111] The package circuit of the concentration monitor of the present invention comprises a voltage regulating circuit, a temporary storage element and a wireless communication module ( Figure 2A ). The wireless communication module includes an oscillator, an onboard antenna, and an on / off keyed RF transmitter that transmits binary code via a variable amplitude RF signal. In some examples, the wireless communication module is a coil inductor that generates a magnetic field that can be detected by an external signal receiver. In some examples, the circuit is fabricated on a printed circuit board (PCB) and encapsulated by a biocompatible material including, but not limited to, polydimethylsiloxane (PDMS).

[0112] Other biocompatible materials used include polymethylsiloxane (PMS), polyalkoxysiloxanes, and polyalkylarylsiloxanes.

[0113] Electrodes made of copper and zinc, respectively, were soldered directly onto the PCB. A portion of the electrode protruded from the PDMS and was exposed to the body fluid ( Figure 2B ). In some PCBs, microfluidic channels are fabricated in the PDMS housing to sample body fluids.

[0114] The circuit is encapsulated in a small size capsule, and the size of the GI capsule can be minimized by rigid-flex PCB manufacturing. Each functional module is mounted on a rigid circular substrate (FR4 board) separately. Each rigid board is stacked layer by layer and connected through a flexible substrate (polyimide). Instead of the on-board antenna, a spiral copper antenna wraps the circular stacked circuit, which not only provides better omnidirectional signal radiation, but also makes the capsule more compact, thereby reducing the risk of capsule retention.

[0115] When the monitor is used to measure the concentration of certain analytes in the digestive tract, the packaged circuit is further made into a capsule-like shape to facilitate the passage of the monitor through the digestive tract after being placed endoscope-wise in the digestive tract. In some clinical applications, the monitor is delivered by oral administration. The monitor passes through the esophagus, stomach, small intestine, and colon, and records the profile of the target analyte concentration, so that the spatial variation of the target analyte in the entire digestive tract can be studied.

[0116] Example 7—Fixation of an In Vivo Concentration Monitor

[0117] Typically, the monitor of the present invention is fixed to a site in a body cavity to study changes in biomarkers in the target area. To this end, the monitor is mounted to the distal tip of a standard endoscope via a custom-made holder.

[0118] Then, an endoscopic hemostatic clip is inserted through the biopsy port of the endoscope and tied to the monitor ( Figure 3A ). After assembly, the monitor is inserted into the esophagus together with the endoscope. The two ends of the monitor are fixed to the target site in the esophagus by hemostatic clips. Due to tissue growth, the monitor will be detached from the esophagus after a certain period of time. The surgical sutures used are made of enteric materials that remain intact in stomach acid. When the monitor enters the small intestine, the clips usually detach from the monitor due to degradation of the surgical sutures.

[0119] Some monitors also include permanent magnets for magnetic control and navigation.Such monitors are transported to the target area by an external magnetic field such as an electromagnetic system or an external permanent magnet.

[0120] In addition, a belt embedded with a permanent magnet is used to attract the monitor to the target area, such as the small intestine. For long-term assessment of biomarkers, the monitor is sutured directly to the tissue of the digestive tract, such as the stomach.

[0121] Example 8 - Concentration Adaptive Voltage Regulation Circuit

[0122] Because a redox reaction occurs when both electrodes are in contact with body fluids, the electrodes generate a current proportional to the concentration of the target analyte in the body fluid, while the potential generated between the two electrodes is constant. Concentration-adaptive energy harvesting begins to charge the temporary storage capacitor. In one embodiment, a pair of NPN bipolar transistors and a P-type MOSFET are used as a voltage-controlled switch connected between the temporary storage capacitor and the wireless communication module. When the voltage of the storage capacitor reaches a preprogrammed threshold, the wireless signal transmitter is activated and sends a pulse signal to an external receiver. Instantaneously, the energy stored in the capacitor is consumed and the voltage drops below the threshold. As a result, the wireless signal transmitter is turned off and the capacitor is charged again. The frequency of the pulse signal is described by the following formula:

[0123]

[0124] When the threshold V threshold When is decreased, the frequency increases. Lowering the threshold results in a shorter cycle since it takes less time to charge the storage capacitor to the lower threshold. When adjusting the threshold, it is important to choose a threshold that is high enough to turn on the switch.

[0125] Furthermore, the capacitance C of the temporary capacitor store It also affects the period of the signal. Since it takes more time to charge a capacitor with a large capacitance to the threshold, the frequency decreases with increasing capacitance. In addition, the energy stored in the capacitor should be high enough to drive a wireless communication transmitter. The charging current I charge is proportional to the concentration of the target analyte catalyzed in the body fluid. Therefore, after careful setting of the threshold and selection of the capacitor, the frequency of the signal is determined only by the charging current I charge Therefore, the frequency of the pulse signal can be calibrated to the corresponding concentration of the analyte.

[0126] In addition, a package circuit is produced that includes a boost converter circuit that extracts energy from the primary battery and boosts the voltage of the temporary storage capacitor to a threshold. The package circuit also includes a single-chip microcomputer with a radio frequency transceiver for wireless communication. The package circuit also includes a normally open single-pole single-throw analog switch that is connected between the microcontroller and the storage capacitor. When the target analyte is not detected, the microcontroller will remain in a sleep state; when the temporary storage capacitor is charged to a constant voltage, the analog switch is turned on.

[0127] In concentration adaptive operation, the charging rate is related to the concentration of the target analyte in the body fluid. When the voltage of the capacitor reaches a threshold, the microcontroller wakes up and transmits a pulse signal.

[0128] The measured concentration is thus encoded as the frequency of the radio frequency signal. As soon as the control signal is transmitted, the voltage of the storage capacitor drops below the threshold, the analog switch opens, and the storage capacitor is charged again.

[0129] In some embodiments, the microcontroller sends control signals to other components, like a drug release system or an electrical stimulation system. The drug release system used comprises a micro motor driven by a pulse signal. The microcontroller sends pulse signals to control the drug release rate according to the analyte concentration.

[0130] In other embodiments, the electrical power generated in the packaged circuit is used to apply electrical stimulation to the muscle to restore weakened muscles.

[0131] In other embodiments, near field communication (NFC) technology provides another solution. Instead of the RF transmitter module, a passive radio frequency identifier (RFID) is connected to a temporary storage capacitor through a normally open single-pole single-throw analog switch. When the voltage of the capacitor reaches a threshold, the analog switch is turned on. Subsequently, the RFID is activated and sends a signal. In some embodiments, the RFID includes a built-in temperature sensor that also sends a signal encoded with temperature information to obtain the temperature inside the human body.

[0132] Advantageously, the wireless communication module can be made from inexpensive coil inductors to eliminate the trade-off between the performance of the radio frequency signal and the sensitivity of the concentration monitor.

[0133] Specifically, good performance of RF signals requires large capacitors, while relatively smaller capacitors result in better sensitivity.Instead of the RF transmitter module, the coil inductor generates a magnetic field when activated.

[0134] Example 9 – Communication between RF receiver and microcontroller

[0135] A concentration monitor is produced in which a microcontroller communicates with a radio frequency receiver through a digital signal pin. When implanted in the body, the concentration monitor remains silent when nothing is detected and the radio frequency receiver inside the portable device emits a random signal. When a body fluid containing a target analyte is detected, the monitor transmits a pulse signal to an external receiver, and the radio frequency receiver sends a low-level signal lasting 200 microseconds to the microcontroller. The microcontroller decodes the signal into concentration information based on the frequency of the signal. In other embodiments, certain types of radio frequency receivers are used, and when these radio frequency receivers receive radio frequency signals, these radio frequency receivers send high-level pulse signals to wake up the microcontroller from sleep mode. The microcontroller then decrypts the subsequent signal into concentration data based on its frequency.

[0136] Example 10 - Portable Receiver

[0137] The portable receiver used in the concentration monitor includes, for example, a signal receiver for wireless communication, a microcontroller for signal processing, an SD card for data storage, and a screen with a user interface ( Figure 6 ). In some embodiments, the portable receiver plots real-time data on a screen. In addition, the device records the data and processes the data into a graph that shows a daily overview of the concentration of the target analyte. In some embodiments, the portable device also records the user's daily events, like eating and sleeping, to help the doctor determine the relationship between changes in analyte concentration and the user's lifestyle.

[0138] Example 11 - Measurement of pH in a fluid

[0139] An in vitro experiment for concentration monitor calibration was performed. The packaged prototype with the electrodes extended was immersed in a hydrochloric acid (HCl) acidic buffer solution with a pH value of 1-4. The pH value indicates the concentration of hydrogen ions in the solution, and the concentration of hydrogen ions determines the efficiency of the redox reaction. Therefore, a lower pH value results in a more active redox reaction, which results in more efficient energy harvesting using the system of the present invention.

[0140] After immersion in the packaged prototype, energy harvesting begins to charge the temporary storage capacitor. Since the RF transmitter sends a signal when the voltage of the storage capacitor reaches a threshold, the frequency of the signal changes depending on the pH value ( Figure 7 ). Therefore, at a higher pH value of 4, only two signals are emitted in a period of 1 minute, while at a lower pH value of 1, 11 signals are emitted in the same period. These results demonstrate the superior performance of the concentration monitor system of the present invention in measuring pH values ​​in a living body.

[0141] Exemplary Embodiments

[0142] Embodiment 1 A remote concentration monitor system comprises:

[0143] A wireless concentration monitor without the need for built-in traditional batteries, the wireless concentration monitor without the need for built-in traditional batteries comprising one or more pairs of anodes and cathodes and a packaged circuit, the one or more pairs of anodes and cathodes being attached to the surface of the monitor, the packaged circuit being powered by energy collected from body fluids through electrodes; and

[0144] An external data logger configured to receive the signal from the concentration detector and parse out the corresponding biomarker concentration.

[0145] Embodiment 2 is a remote concentration monitor system according to embodiment 1, wherein the monitor is present in a subject, the subject including but not limited to mammals, the mammals including but not limited to humans, pigs or monkeys.

[0146] Example 3 A remote concentration monitor system according to Example 2, wherein the external data recorder receives a signal from a detector within the subject.

[0147] Embodiment 4 is a remote concentration monitor system according to embodiment 1, wherein the electrode is made of a biocompatible material, the biocompatible material catalyzes redox reactions and generates electric current once in contact with the body fluid.

[0148] Example 5: A remote concentration monitor system according to Example 1, wherein the electrode is modified by immobilizing an enzyme, and the enzyme catalyzes the enzymatic reaction to generate electric current.

[0149] Embodiment 6 The remote concentration monitor system according to embodiment 1, wherein the electrode is colonized by bacteria that catalyze specific biomarkers to generate an electric current.

[0150] Embodiment 7 A remote concentration monitor system according to embodiment 1, wherein the electrode is coated with a semi-permeable membrane to facilitate electron transfer.

[0151] Example 8 The remote concentration monitor system of Example 1, wherein the electrode is coated with an anti-biofouling layer to protect the electrode from contamination by debris in the body fluid.

[0152] Embodiment 9 A remote concentration monitor system according to embodiment 1, wherein the electrode is attached to the surface of the monitor and is electrically connected to the packaged circuit.

[0153] Example 10 The remote concentration monitor system of Example 1, wherein the packaged circuit is sealed with at least one biocompatible material.

[0154] Embodiment 11 A remote concentration monitor system according to Embodiment 10, wherein the biocompatible material is selected from the group consisting of polymethylsiloxane (PMS), polydimethylsiloxane (PDMS), polyalkoxysiloxane and polyalkylarylsiloxane.

[0155] Example 12 A remote concentration monitor system according to Example 1, wherein the packaged circuit also includes a microfluidic channel for sampling the body fluid.

[0156] Embodiment 13 The remote concentration monitor system of Embodiment 1, wherein the encapsulated circuit has a capsule-like shape to facilitate passage of the encapsulated circuit through the digestive (GI) tract.

[0157] Embodiment 14 The remote concentration monitor system according to embodiment 1, wherein the packaged circuit comprises:

[0158] Concentration adaptive energy harvesting circuit;

[0159] a wireless communication module; and

[0160] Storage elements, including but not limited to capacitors and supercapacitors.

[0161] Embodiment 15 is a remote concentration monitor system according to embodiment 14, wherein the wireless communication module is a radio frequency (RF) transmitter, and the radio frequency (RF) transmitter is selected from an amplitude shift keying (ASK) RF module and an on-off keying (OOK) RF module.

[0162] Embodiment 16 A remote concentration monitor system according to embodiment 15, wherein the frequency transmitted by the radio frequency (RF) transmitter has a radio frequency signal range within the industrial, scientific and medical (ISM) band.

[0163] Embodiment 17 The remote concentration monitor system according to Embodiment 14, wherein the wireless communication module is a near field communication (NFC) module like a radio frequency identifier (RFID).

[0164] Embodiment 18 is a remote concentration monitor system according to Embodiment 14, wherein the wireless communication module is a wireless microcontroller (MCU) embedded with an RF transceiver.

[0165] Embodiment 19 A remote concentration monitor system according to Embodiment 14, wherein the wireless communication module is a magnetic field modulator comprising a coil inductor that generates a magnetic field when current passes through it.

[0166] Embodiment 20 A remote concentration monitor system according to Embodiment 14, wherein the concentration adaptive energy harvesting circuit adjusts the voltage generated between the electrodes to a fixed threshold to drive the wireless communication module.

[0167] Embodiment 21 A remote concentration monitor system according to embodiment 14, wherein the wireless communication module sends a variable frequency signal, and the frequency of the signal encodes information on the concentration of at least one target analyte.

[0168] Embodiment 22 A remote concentration monitor system according to Embodiment 14, wherein the wireless communication module further comprises an antenna, and the antenna is selected from the group consisting of an onboard printed circuit board antenna, a helical antenna, and a ceramic chip type antenna.

[0169] Embodiment 23 A remote concentration monitor system according to Embodiment 1, wherein the external data logger is portable and includes a microcontroller, a screen, an antenna, a storage medium, a battery and a signal receiver.

[0170] Embodiment 24 A remote concentration monitor system according to Embodiment 23, wherein the microcontroller decodes the frequency of the signal into data of the concentration of the analyte and stores the data in the storage medium.

[0171] Embodiment 25 is a remote concentration monitor system according to embodiment 24, wherein the storage medium is an SD card, a hard disk, a magnetic disk or an optical disk.

[0172] Embodiment 26 A remote concentration monitor system according to Embodiment 24, wherein the screen displays the data of the concentration of the analyte in real time and displays a daily summary of the concentration of the analyte.

[0173] Example 27 A remote concentration monitor system according to Example 2, wherein the wireless concentration monitor that does not require a built-in traditional battery is fixed to the wall of the digestive tract and is guided through the digestive tract by a magnetic field or the natural peristalsis of the digestive tract.

[0174] Embodiment 28 According to the remote concentration monitor system described in embodiment 27, it also includes a permanent magnet controlled by an external permanent magnet or electromagnetic system.

[0175] Embodiment 29 According to the remote concentration monitor system of embodiment 1, wherein the wireless concentration monitor without the need for internal traditional batteries is delivered through the digestive tract by oral administration.

[0176] Embodiment 30 is a remote concentration monitor system according to Embodiment 1, wherein the wireless concentration monitor which does not require a built-in traditional battery is sutured to the tissue of the digestive tract through an endoscope.

[0177] Embodiment 31 is a remote concentration monitor system according to Embodiment 1, wherein the wireless concentration monitor which does not require a built-in traditional battery is attached to the tissue of the digestive tract via an endoscopic clip.

[0178] Example 32 A remote concentration monitor system according to Example 31, wherein the wireless concentration monitor that does not require a built-in traditional battery is inserted into a custom accessory connected to an endoscope, and the endoscope is deployed via an endoscopic hemostatic clip.

[0179] Example 33 A remote concentration monitor system according to Example 1, wherein the packaged circuit further comprises a pulse generator for applying electrical stimulation to digestive tract tissue.

[0180] Embodiment 34 According to the remote concentration monitor system of embodiment 1, wherein the packaged circuit also includes a light emitting diode (LED) for photodynamic therapy.

[0181] Embodiment 35 A remote concentration monitor system according to embodiment 1, wherein the external data logger further comprises a dual-band radio frequency (RF) transceiver, which uploads data to a storage medium via Bluetooth.

[0182] Embodiment 36 The external data logger according to embodiment 23, wherein the battery supports the operation of the external data logger for more than one week.

[0183] Embodiment 37 An external data logger according to embodiment 23, wherein the battery is rechargeable via a cable or wireless power transmission.

[0184] It should be understood that the examples and embodiments described herein are for exemplary purposes only, and various modifications or changes thereto will be suggested to those skilled in the art, and are to be included within the spirit and authority of the present application and the scope of the appended claims. In addition, any element or limitation of any invention or embodiment thereof disclosed herein may be combined with any and / or all other elements or limitations disclosed herein (alone or in any combination) or any other invention or embodiment thereof, and all such combinations are considered within the scope of the present invention, but are not limited thereto.

Claims

1. A remote concentration monitor system, include: A wireless concentration monitor without the need for built-in traditional batteries, the wireless concentration monitor without the need for built-in traditional batteries comprising: one or more pairs of anodes and cathodes and a packaged circuit, the one or more pairs of anodes and cathodes being attached to the surface of the wireless concentration monitor, the packaged circuit being powered by energy collected from body fluids through electrodes; and an external data logger, the external data logger being used to receive signals from the wireless concentration monitor and parse out corresponding biomarker concentrations, The packaged circuit comprises a voltage regulating circuit, a temporary storage element, a wireless communication module and a multi-mode microcontroller. wherein the body fluid is gastric acid, when the one or more pairs of anodes and cathodes contact gastric acid, a redox reaction occurs and current is generated, the temporary storage element is charged, and when the voltage of the temporary storage element reaches a preprogrammed threshold, the wireless communication module is activated and sends a pulse signal to the external data logger, and Wherein when the gastric acid is not detected, the multi-mode microcontroller remains in sleep mode.

2. The remote concentration monitor system according to claim 1, in, The wireless concentration monitor is present in a subject, which includes a mammal, including a human, a pig, or a monkey.

3. The remote concentration monitor system according to claim 2, in, The external data logger receives signals from the wireless concentration monitor in the subject.

4. The remote concentration monitor system according to claim 1, in, The electrodes are made of biocompatible materials, which catalyze redox reactions and generate electric current once in contact with the body fluid.

5. The remote concentration monitor system according to claim 1, in, The electrode is modified by the immobilization of an enzyme which catalyzes an enzymatic reaction, thereby generating an electric current.

6. The remote concentration monitor system according to claim 1, in, The electrodes are colonized with bacteria that catalyze specific biomarkers to generate an electrical current.

7. The remote concentration monitor system according to claim 1, in, The electrodes are coated with a semipermeable membrane to facilitate electron transfer.

8. The remote concentration monitor system according to claim 1, in, The electrodes are coated with an anti-biofouling layer to protect the electrodes from contamination by debris in the body fluids.

9. The remote concentration monitor system according to claim 1, in, The electrodes are attached to the surface of the wireless concentration monitor and are electrically connected to the packaged circuit.

10. The remote concentration monitor system according to claim 1, in, The packaged circuit is sealed with at least one biocompatible material.

11. The remote concentration monitor system according to claim 10, in, The biocompatible material is selected from the group consisting of polymethylsiloxane, polydimethylsiloxane, polyalkoxysiloxane and polyalkylarylsiloxane.

12. The remote concentration monitor system according to claim 1, in, The packaged circuit also includes a microfluidic channel to sample the body fluid.

13. The remote concentration monitor system according to claim 1, in, The encapsulated circuit has a capsule-like shape to facilitate passage of the encapsulated circuit through the digestive tract.

14. The remote concentration monitor system of claim 1, wherein the temporary storage element is a capacitor or a supercapacitor.

15. The remote concentration monitor system according to claim 14, in, The wireless communication module is a radio frequency transmitter, and the radio frequency transmitter is selected from an amplitude shift keying radio frequency module or an on-off keying radio frequency module.

16. The remote concentration monitor system according to claim 15, in, The frequency transmitted by the radio frequency transmitter has a radio frequency signal range within the industrial, scientific and medical frequency band.

17. The remote concentration monitor system of claim 14, in, The wireless communication module is a near field communication module.

18. The remote concentration monitor system of claim 14, in, The wireless communication module is a wireless single chip microcomputer embedded with a radio frequency transceiver.

19. The remote concentration monitor system of claim 14, in, The wireless communication module is a magnetic field modulator including a coil inductor that generates a magnetic field when current passes through it.

20. The remote concentration monitor system of claim 14, in, The voltage regulating circuit regulates the voltage generated between the electrodes to a fixed threshold value to drive the wireless communication module.

21. The remote concentration monitor system of claim 14, in, The wireless communication module transmits a variable frequency signal, the frequency of which encodes information about the concentration of at least one target analyte.

22. The remote concentration monitor system of claim 14, in, The wireless communication module further includes an antenna selected from an onboard printed circuit board antenna, a helical antenna, and a ceramic chip antenna.

23. The remote concentration monitor system of claim 1, in, The external data logger is portable and includes a microcontroller, a screen, an antenna, a storage medium, a battery and a signal receiver.

24. The remote concentration monitor system of claim 23, in, The microcontroller decodes the frequency of the signal into data of the concentration of the analyte and stores the data in the storage medium.

25. The remote concentration monitor system of claim 24, in, The storage medium is an SD card, a hard disk, a magnetic disk or an optical disk.

26. The remote concentration monitor system of claim 24, in, The screen displays data of the concentration of the analyte in real time and displays a daily summary of the concentration of the analyte.

27. The remote concentration monitor system of claim 2, in, The wireless concentration monitor, which does not require a built-in conventional battery, is fixed to the wall of the digestive tract and is guided through the digestive tract by a magnetic field or the natural peristalsis of the digestive tract.

28. The remote concentration monitor system of claim 27, further comprising a permanent magnet controlled by an external permanent magnet or electromagnetic system.

29. The remote concentration monitor system of claim 1, in, The wireless concentration monitor, which does not require conventional internal batteries, is delivered through the digestive tract via oral administration.

30. The remote concentration monitor system of claim 1, in, The wireless concentration monitor, which does not require a built-in conventional battery, is sutured to the tissue of the digestive tract through an endoscope.

31. The remote concentration monitor system of claim 1, in, The wireless concentration monitor, which does not require a built-in conventional battery, is attached to the tissue of the digestive tract via an endoscopic clip.

32. The remote concentration monitor system of claim 31, in, The wireless concentration monitor, which does not require conventional internal batteries, is inserted into a custom attachment that connects to an endoscope that is deployed via an endoscopic hemostatic clip.

33. The remote concentration monitor system of claim 1, in, The packaged circuit also includes a pulse generator for applying electrical stimulation to tissue of the digestive tract.

34. The remote concentration monitor system of claim 1, in, The packaged circuit also includes a light emitting diode for photodynamic therapy.

35. The remote concentration monitor system of claim 1, in, The external data logger also includes a dual-band radio frequency transceiver that uploads data to a storage medium via Bluetooth.

36. The remote concentration monitor system of claim 23, in, The battery powered the external data logger for more than one week.

37. The remote concentration monitor system of claim 23, in, The battery can be charged via an electrical cable or wireless power transfer.

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