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The manuscript presents a miniature implantable pH sensor with ASK modulated wireless output together with a fully passive receiver circuit based on zero-bias Schottky diodes. This solution can be used as a basis in the development of in vivo calibrated electrostimulation therapy devices and for ambulatory pH monitoring.
Ambulatory pH monitoring of pathological reflux is an opportunity to observe the relationship between symptoms and exposure of the esophagus to acidic or non-acidic refluxate. This paper describes a method for the development, manufacturing, and implantation of a miniature wireless-enabled pH sensor. The sensor is designed to be implanted endoscopically with a single hemostatic clip. A fully passive rectenna-based receiver based on a zero-bias Schottky diode is also constructed and tested. To construct the device, a two-layer printed circuit board and off-the-shelf components were used. A miniature microcontroller with integrated analog peripherals is used as an analog front end for the ion-sensitive field-effect transistor (ISFET) sensor and to generate a digital signal which is transmitted with an amplitude shift keying transmitter chip. The device is powered by two primary alkaline cells. The implantable device has a total volume of 0.6 cm3 and a weight of 1.2 grams, and its performance was verified in an ex vivo model (porcine esophagus and stomach). Next, a small footprint passive rectenna-based receiver which can be easily integrated either into an external receiver or the implantable neurostimulator, was constructed and proven to receive the RF signal from the implant when in proximity (20 cm) to it. The small size of the sensor provides continuous pH monitoring with minimal obstruction of the esophagus. The sensor could be used in routine clinical practice for 24/96 h esophageal pH monitoring without the need to insert a nasal catheter. The "zero-power" nature of the receiver also enables the use of the sensor for automatic in-vivo calibration of miniature lower esophageal sphincter neurostimulation devices. An active sensor-based control enables the development of advanced algorithms to minimize the used energy to achieve a desirable clinical outcome. One of the examples of such an algorithm would be a closed-loop system for on-demand neurostimulation therapy of gastroesophageal reflux disease (GERD).
The Montreal Consensus defines gastroesophageal reflux disease (GERD) as "a condition that develops when refluxing the contents of the stomach causes unpleasant symptoms and/or complications". It may be associated with other specific complications such as esophageal strictures, Barrett's esophagus, or esophageal adenocarcinoma. GERD affects approximately 20% of the adult population, mainly in countries with high economic status1.
Ambulatory pH monitoring of pathological reflux (acid exposure time of more than 6%) allows us to distinguish the relationship between symptoms and acidic or non-acidic gastroesophageal reflux2,3. In patients unresponsive to PPI (proton pump inhibitor) therapy, pH monitoring can answer whether it is pathological gastroesophageal reflux and why the patient does not respond to standard PPI therapy. Various pH and impedance monitoring options are currently offered. One of the newer possibilities is wireless monitoring using implantable devices4,5.
GERD is associated with lower esophageal sphincter (LES) disorder, where the contractions shown during esophageal manometry are not pathological but have a reduced amplitude in long-term GERD. LES consists of smooth muscle and maintains tonic contractions due to myogenic and neurogenic factors. It relaxes due to vagal-mediated inhibition involving nitric oxide as a neurotransmitter6.
Electrical stimulation with two pairs of electrodes was proven to increase the contraction time of the LES in a canine reflux model7. The relaxation of the LES including the residual pressure during swallowing was not affected by both low and high frequency stimulation. High-frequency stimulation is an obvious choice because it requires less power and extends the battery life.
Although electrostimulation treatment (ET) of the lower esophageal sphincter is a relatively new concept in the treatment of patients with GERD, this therapy was shown to be safe and effective. This form of treatment has been shown to provide significant and lasting relief from the symptoms of GERD while eliminating the need for PPI treatment and reducing esophageal acid exposure8,9,10.
The current state-of-the-art pH sensor for diagnostics of GERD is the Bravo device11,12. At an estimated volume of 1.7 cm3, it can be implanted directly into the esophagus with or without visual endoscopic feedback and provides 24 h+ monitoring of pH in the esophagus.
Considering that electrostimulation therapy is one of the most promising alternatives for treating GERD not responding to standard therapy8,13, it makes sense to provide the data from the pH sensor to the neurostimulator. The recent research shows a clear path to future development in this field which will lead to rigid all-in-one implantable devices which will reside at the site of neurostimulation14,15. For this purpose, the ISFET (ion-sensitive field-effect transistor) is one of the best types of sensors because of its miniature nature, the possibility of on-chip integration of a reference electrode (gold in this case), and sufficiently high sensitivity. On silicon, the ISFET resembles the structure of a standard MOSFET (Metal Oxide Semiconductor Field Effect Transistor). However, the gate, normally connected to an electrical terminal, is replaced by a layer of active material in direct contact with the surrounding environment. In the case of pH-sensitive ISFETs, this layer is formed by silicon nitride (Si3N4)16.
The main disadvantage of endoscopically implantable devices is the inherent limitation of the battery size, which may lead to a reduced lifetime of these devices or motivate the manufacturers to develop advanced algorithms that will deliver the required effect at a lower energy cost. One of the examples of such an algorithm would be a closed-loop system for on-demand neurostimulation therapy of GERD. Similar to continuous glucose meters (CGM) + insulin pump systems17, such a system would employ an esophageal pH sensor or another sensor to detect the current pressure of the lower esophageal sphincter together with a neurostimulation unit.
The response to the neurostimulation therapy and the requirements for neurostimulation patterns can be individual13. Thus, it is important to develop independent sensors that could be used either for diagnosis and characterization of the dysfunction or to actively participate in calibrating the neurostimulation system according to the individual requirements of the patients18. These sensors should be as small as possible to not affect the normal functionality of the organ.
This manuscript describes a method of design and fabrication of an ISFET based pH sensor with amplitude-shift keying (ASK) transmitter and a small footprint passive rectenna-based receiver. Based on the simple architecture of the solution, the pH data can be received by an external receiver or even the implantable neurostimulator without any significant volume or power penalty. The ASK modulation is chosen because of the nature of the passive receiver, which is only capable of detection of received RF signal power (often called "received signal strength"). The schematic diagram, which is embedded as Supplementary material, shows the construction of the device. It is powered directly from two AG1 alkaline batteries, which provide a voltage between 2.0-3.0 V (based on the state of charge). The batteries power the internal microcontroller, which utilizes its ADC (analog-to-digital converter), DAC (digital-to-analog converter), internal operation amplifier, and FVR (fixed-voltage reference) peripherals to bias the ISFET pH sensor. The resulting "gate" voltage (the gold reference electrode) is proportional to the pH of the surrounding environment. A stable Ids current is provided by a low-side R2 sensing resistor. The source of the ISFET sensor is connected to the non-inverting input of the operational amplifier, while the inverting input is connected to the output voltage of the DAC module set to 960 mV. The output of the operational amplifier is connected to the drain pin of the ISFET. This operational amplifier regulates the drain voltage so that the voltage difference on the R2 resistor is always 960 mV; thus, a constant bias current of 29 µA flows through the ISFET (when in normal operation). The gate voltage is then measured with an ADC. The microcontroller then powers on the RF transmitter via one of the GPIO (general purpose input/output) pins and transmits the sequence. The RF transmitter circuit involves a crystal and matching network which matches the output to 50 Ω impedance.
For the experiments demonstrated here, we used a pig stomach with a long section of the esophagus mounted in a standardized plastic model. This is a commonly used model for practicing endoscopic techniques such as ESD (endoscopic submucosal dissection), POEM (oral endoscopic myotomy), endoscopic mucosal resection (EMR), hemostasis, etc. Concerning the closest possible anatomical parameters approaching human organs, we used the stomach and esophagus of pigs weighing 40-50 kg.
No living animals were involved in this study. The experiment was performed on an ex vivo model consisting of a porcine esophagus and stomach. The stomach and esophagus were purchased from a local butchery as their standard product. This procedure is in accordance with Czech laws, and we prefer it because of the "3R" principle (Replacement, Reduction, and Refinement).
1. Fabrication of the pH sensor assembly
NOTE: Observe precautions for handling electrostatic discharge (ESD) sensitive components throughout the fabrication of the pH sensor assembly. Be careful when working with the soldering iron.
2. Fabrication of the electronic assembly
NOTE: Observe precautions for handling ESD-sensitive components throughout the fabrication of the electronics. Be careful when working with the soldering iron and hot-air gun.
3. Fabrication of passive rectenna receiver
4. Testing of the device
NOTE: The following steps require the use of chemicals. Study the material safety data sheets of the chemicals beforehand and use proper protective equipment and common lab practices when manipulating them.
5. Endoscopic implantation of the sensor
6. Experiment after implantation
NOTE: The following steps require the use of chemicals. Study the material safety data sheets of the chemicals beforehand and use proper protective equipment and common lab practices when manipulating them.
A device capable of autonomous pH sensing and wireless transmitting of the pH value was successfully constructed, as shown in Figure 8. The constructed device is a miniature model; it weighs 1.2 g and has a volume of 0.6 cm3. The approximate dimensions are 18 mm x 8.5 mm x 4.5 mm. As shown in Figure 15, Figure 16, and Figure 17, it can be implanted to the proxi...
This method is suitable for researchers who work on the development of novel active implantable medical devices. It requires a level of proficiency in the manufacturing of electronic prototypes with surface mount components. The critical steps in the protocol are related to the manufacturing of the electronics, especially populating the PCBs, which is prone to operator error in placement and soldering of small components. Then, correct encapsulation is crucial to prolong the lifetime of the device when exposed to moistur...
The authors have nothing to declare.
The authors gratefully acknowledge Charles University (project GA UK No 176119) for supporting this study. This work was supported by the Charles University research program PROGRES Q 28 (Oncology).
Name | Company | Catalog Number | Comments |
AG1 battery | Panasonic | SR621SW | Two batteries per one implant |
Battery holder | MYOUNG | MY-521-01 | |
Copper enamel wire for the antenna | pro-POWER | QSE Wire - 0.15 mm diameter, 38 SWG | |
Epoxy for encapsulation | Loctite | EA M-31 CL | Two-part medical-grade ISO10993 compliant epoxy |
FEP cable for pH sensor | Molex / Temp-Flex | 100057-0273 | |
Flux cleaner | Shesto | UTFLLU05 | Prepare 5% solution in deionized water for cleaning by sonication |
Hemostatic clip | Boston Scientific | Resolution | |
Hot air gun + soldering iron | W.E.P. | Model 706 | Any soldering iron capable of soldering with tin and hot-air gun capable of maintaining 260 °C can be used |
Impedance matching software | Iowa Hills Software | Smith Chart | Can be downloaded from http://www.iowahills.com/9SmithChartPage.html - alternatively, any RF design software supports calculation of impedance matching components |
ISFET pH sensor on a PCB | WinSense | WIPS | Order a model pre-mounted on a PCB with on-chip gold reference electrode |
Laboratory pH meter | Hanna Instruments | HI2210-02 | Used with HI1131B glass probe |
Microcontorller programmer | Microchip | PICkit 3 | Other PIC16 compatible programmers can be also used |
Pig stomach with esophagus | Local pig farm | Obtained from approx. 40–50 kg pig | It is important that the stomach includes a full length of the esophagus. |
Printed circuit board - receiver | Choose preferred PCB supplier | According to pcb2.zip data | One layer, 0.8 mm thickness, FR4, no mask |
Printed circuit board - sensor | Choose preferred PCB supplier | According to pcb1.zip data | Two-layer with PTH, 0.6 mm thickness, FR4, 2x mask |
Receiver - 0R | Vishay | CRCW04020000Z0EDC | See Figure 12 and Figure 13 for placement |
Receiver - 1.5 pF | Murata | GRM0225C1C1R5CA03L | See Figure 12 and Figure 13 for placement |
Receiver - 100 pF | Murata | GRM0225C1E101JA02L | See Figure 12 and Figure 13 for placement |
Receiver - 33 nH | Pulse Electronics | PE-0402CL330JTT | See Figure 12 and Figure13 for placement |
Receiver - RF schottky diodes | MACOM | MA4E2200B1-287T | See Figure 12 and Figure 13 for placement |
Receiver - SMA antenna | LPRS | ANT-433MS | |
Receiver - SMA connector | Linx Technologies | CONSMA001 | See Figure 12 and Figure 13 for placement |
Sensor - C1 | Murata | GRM0225C1H8R0DA03L | 8 pF 0402 capacitor |
Sensor - C2 | Murata | GRM0225C1H8R0DA03L | 8 pF 0402 capacitor |
Sensor - C3 | Murata | GCM155R71H102KA37D | 1 nF 0402 capacitor |
Sensor - C4 | Murata | GRM0225C1H1R8BA03L | 1.8 pF |
Sensor - C5 | Vishay | CRCW04020000Z0EDC | Place 0R 0402 resistor or use to match the antenna |
Sensor - C6 | Murata | GRM155C81C105KE11J | 1 uF 0402 capacitor |
Sensor - C7 | Murata | GRM155C81C105KE11J | 1 uF 0402 capacitor |
Sensor - C8 | Murata | GRM022R61A104ME01L | 100 nF 0402 capacitor |
Sensor - IC1 | Microchip | MICRF113YM6-TR | MICRF113 RF transmitter |
Sensor - IC2 | Microchip | PIC16LF1704-I/ML | PIC16LF1704 low-power microcontroller |
Sensor - R1 | Vishay | CRCW040210K0FKEDC | 10 kOhm 0402 resistor |
Sensor - R2 | Vishay | CRCW040233K0FKEDC | 33 kOhm 0402 resistor |
Sensor - R3 | Vishay | CRCW04021K00FKEDC | 1 kOhm 0402 resistor |
Sensor - R5 | Vishay | CRCW040210K0FKEDC | 10 kOhm 0402 resistor |
Sensor - X1 | ABRACON | ABM8W-13.4916MHZ-8-J2Z-T3 | 3.2 x 2.5 mm 13.4916 MHz 8 pF crystal |
Titanium wire | Sigma-Aldrich | GF36846434 | 0.125 mm titanium wire |
Vector network analyzer | mini RADIO SOLUTIONS | miniVNA Tiny | Other vector network analyzers can be used - the required operation frequency is 300–500 MHz, resolution bandwidth equal or lower than 1 MHz, output power of no more than 0 dBm and dynamic range preferably better than 60 dB for the receiving front-end |
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