WO2023249557A1

WO2023249557A1 - A dosimeter assembly and methods of use thereof

Info

Publication number: WO2023249557A1
Application number: PCT/SG2023/050427
Authority: WO
Inventors: Xiaogang Liu; Bo HOU; Luying YI
Original assignee: National University Of Singapore
Priority date: 2022-06-24
Filing date: 2023-06-16
Publication date: 2023-12-28

Abstract

The present disclosure generally relates to a dosimeter assembly. In particular, the dosimeter assembly disclosed herein may be useful for monitoring gastric motility and pH as well as for detecting a radiation dose in a subject.

Description

A DOSIMETER ASSEMBLY AND METHODS OF USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of Singapore Provisional Application No. 10202250285X, filed on 24 June 2022, the disclosure of which is hereby incorporated in its entirety by reference.

FIELD OF THE DISCLOSURE

The present application generally relates to a dosimeter assembly. In particular, the dosimeter assembly disclosed may be useful for monitoring gastric motility and for detecting a radiation dose in a subject.

BACKGROUND

Annually, it is estimated that around 200 to 300 million individuals in the world suffer from acid reflux, irritable bowel syndrome and chronic constipation gastrointestinal (GI) disorders. Efficient monitoring of the GI environment including pH, gastric motility and corresponding biomarkers may play a vital role in the diagnosis and treatment of these disorders.

In addition, tumors of the gastrointestinal tract have become increasingly common. These tumors are commonly treated by radiotherapy using high-dose X-rays and immunotherapy using low-dose X-rays. The complexity of the fast-developing new radiotherapy technology includes hundreds of parameters transmitted by each X-ray beam, making quality assurance increasingly challenging. A 5% change in delivered dose can affect the likelihood of local tumor control by 10 to 20% and the likelihood of complications in normal tissue by up to 30%. Insufficient dosing leads to the risk of recurrence, and overdosing can lead to toxicity and even death.

In recent years, numerous efforts have been directed towards the development of ingestible medical devices that could ultimately be less invasive than gastric electrical-stimulation devices and other implantable electronics. With regards to the dosimeter for monitoring the radiation dose, although there are a variety of in vivo dosimeters, such as silicon diodes, metal oxide semiconductor field effect transistors (MOSFET), thermoluminescence dosimeters, optically excited light and thin films, none of them is fully applicable to in vivo real-time measurement in the digestive system. Most of them place radiation detectors directly on or near the patient’s skin to measure the input or output dose. The in vivo dosimeter for the gastrointestinal tract should ideally be small, inexpensive, able to transmit data wirelessly, and have no toxicity to tissues. In terms of physical properties, it should be able to measure time-resolved dose delivery or dose rate within a fraction of the time while measuring total dose, with little temperature or angle dependence and without interfering with the delivered dose. Such devices are still not available today.

In view of the above, therefore there is a real need for dosimeters that can provide direct and real-time measurements within the target volume.

SUMMARY

In one aspect, there is provided a dosimeter assembly for monitoring a gastric motility and pH in a subject. In accordance with some embodiments of the disclosure, the dosimeter assembly may include a housing. The housing may include a deformation sensing module and a pH sensor. The deformation sensing module may be adapted to measure the degree of deformation of the dosimeter assembly. The pH sensor may be adapted to measure pH of tissue or body fluid in the subject. In accordance with some embodiments of the disclosure, the deformation sensing module may be configured to produce a measurement of the gastric motility in the subject and the pH sensor may be configured to produce a measurement of the pH of tissue or body fluid in the subject when illuminated by an illumination source.

Optionally, the deformation sensing module may comprise one or a plurality of piezoresistive sensors. Optionally, the illumination source may comprise a quantum dot material. In accordance with some embodiments of the disclosure, the pH sensor may include a microfluidic module having multiple inlets to allow an incoming flow of tissue or body fluid, wherein said pH sensor is responsive to the radiation from the illumination source. Further optionally, the microfluidic module is coated by a multilayered coating of polymer. In accordance with some embodiments of the disclosure, the polymer may comprise aniline monomer.

In accordance with some embodiments of the disclosure, the dosimeter assembly described herein may be configured to monitor a radiation dose in the subject. In such an embodiment, the housing may further comprise a scintillator and a radiation sensor. Optionally, the radiation sensor may be adapted to measure the radiation dose and the radiation sensor may be further configured to produce a measurement of the radiation dose in the subject when illuminated by the scintillator. Optionally, the scintillator may comprise a nanoscintillator. Optionally, the nanoscintillator may comprise a rare-earth doped nanoscintillator. In accordance with some embodiments of the disclosure, the rare-earth doped nanoscintillator may comprisee NaLuF4:Tb@NaYF4. Optionally, the scintillator may be a core-shell scintillator. Optionally, the subject may have received a radiotherapy.

In accordance with some embodiments of the disclosure, the dosimeter assembly may further comprise a plurality of additional sensors selected from the group consisting of a temperature sensor, an oxygen sensor, and a carbon dioxide sensor. Optionally, the dosimeter assembly described herein may further comprise a processor and a power supply. Further optionally, the housing may be in the shape of a capsule, the capsule is an ingestible capsule.

In another aspect, there is provided a scintillator comprising NaLuF4:Tb@NaYF4.

In another aspect, there is provided a method for monitoring a gastric motility and pH in a subject. In accordance with some embodiments of the disclosure, the method may comprise administering the dosimeter assembly as described herein and obtaining one or more readings on a device, wherein said device is connected to the dosimeter assembly. Optionally, the method may be suitable for an in-situ monitoring. Optionally, the method may be useful for detecting or monitoring tumors in the gastrointestinal tract. Further optionally, the method may be useful for detecting a gastrointestinal disorder or condition. The gastrointestinal disorder or condition may include gastroparesis, gastric dysmotility, dumping syndrome and gastroesophageal reflux disease or GERD.

Advantageously, the dosimeter assembly disclosed herein may concurrently monitor the gastric motility and other parameters including pH and temperature of the gastrointestinal tract in the subject.

Further advantageously, the dosimeter assembly disclosed herein may provide highly accurate dose estimations and radiation absorption data for better radiotherapy treatments. Still further advantageously, the dosimeter assembly of the present disclosure may provide insights to the progress of the radiotherapy (for e.g. if the radiation dose or radiotherapy sessions are to be adjusted via monitoring pH and temperature in response to the radiotherapy). BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will be understood and better appreciated from the following detailed description taken in conjunction with the drawings. Identical structures, elements or parts, which appear in more than one figure, are generally labeled with the same or similar number in all the figures in which they appear, wherein:

FIG. 1A is a side view of the dosimeter assembly, according to some embodiment of the disclosure;

FIG. IB is a schematic diagram of the working principle of the pH sensor, according to some embodiment of the disclosure;

FIG. 2 is an exploded side view of the dosimeter assembly, according to some embodiment of the disclosure;

FIG. 3 is a graph showing emission spectra of the scintillator excited by X-rays at different dose rates, according to some embodiment of the disclosure;

FIG. 4 is neural network diagram for dose evaluation based on luminous intensity, afterglow intensity and temperature, according to some embodiment of the disclosure;

FIG. 5 is a graph showing variation of the signal as a function of time for 0.8 cGy delivered at the various dose rates, according to some embodiment of the disclosure;

FIG. 6 is a graph depicting the dose value predicted from luminescence using neural networks and linear regression algorithm, according to some embodiment of the disclosure;

FIG. 7 is a histogram representing quantitative comparison of results processed by the algorithms described in FIG. 6, according to some embodiment of the disclosure;

FIG. 8A illustrates a graph depicting changes in the transmission spectrum of radioluminescence after passing through the film of the pH sensor, in accordance with some embodiments of the disclosure;

FIG. 8B is an image of the front view of the microfluidic module and simulations of the distributions of solution concentration over the bottom surface of the module, in accordance with some embodiments of the disclosure;

FIG. 8C is a graph depicting the color ratio measured by the color sensor in different pH solutions, in accordance with some embodiments of the disclosure;

FIG. 8D is an image of pH sensor at pH 1 and pH 7, respectively, in accordance with some embodiments of the disclosure; FIG. 8E is a graph describing the results of pH test within 4 hours after the radiation source is turned off and the long afterglow was used as the light source, in accordance with some embodiments of the disclosure;

FIG. 8F is a graph describing dynamic temperature response of the capsule in the physiological temperature range, in accordance with some embodiments of the disclosure;

FIGS. 9A-D are images of the dosimeter assembly, described in Example 1; FIG. 9A is an optical image of the electronic capsule; FIG. 9B is an optical image of the capsule under X-ray excitation; FIG. 9C is a computed tomography or CT image of animal experiment with an electronic capsule in its stomach; and FIG. 9D is an image of user interface of the mobile phone application;

FIG. 10A is a graph depicting the power detected by the sensor versus angle between the axis of the capsule and radiation beam (50 kV and 6 MV, respectively) described in Example 2;

FIG. 10B illustrates a schematic diagram describing average percentage angular dependency of dosimeter assembly for different radiation beam angles used in Example 2;

FIG. 11A is a photograph of radiotherapy equipment used in Example 3; and

FIG. 1 IB is a graph depicting radioluminescence of the capsule containing NaLuF4:Tb nanoparticles, described in Example 3.

DETAILED DESCRIPTION

The present disclosure provides a dosimeter assembly for monitoring a gastric motility in a subject. As used herein, the term “gastric motility” refers to the movement of the muscles in the stomach that facilitates digestion of the food in the digestive system. In some embodiments, said movement of the muscles includes contractions and relaxation for example mixing contractions and propulsive contractions. In some embodiments, said gastric motility may be characterized by its rate, intensity and combination thereof. Advantageously, the dosimeter assembly described herein may be used to monitor the gastric motility in a subject including the rate as well as the intensity of the gastric motility. Further advantageously, the dosimeter assembly disclosed herein may be useful in detecting a gastrointestinal disorder or condition including gastroparesis, gastric dysmotility, dumping syndrome and gastroesophageal reflux disease or GERD. Hence, the gastrointestinal disorder or condition may be detected early and thus adequate treatment may be prescribed by a health practitioner to a patient based on the readings obtained from a device coupled to the dosimeter assembly described herein. In some embodiments, said device is an external device. In some embodiments, in addition to monitoring the gastric motility, the dosimeter assembly disclosed herein may advantageously be used for monitoring other parameters including pH and a radiation dose.

In some embodiments, the dosimeter assembly disclosed herein is used for monitoring a gastric motility and pH in a subject. In some embodiments, said dosimeter assembly is provided in the form of a capsule used to house or enclose at least part of the various components or parts including sensors (refer to capsule 100 in FIG. 1A or capsule 200 in FIG. 2). Therefore, in some embodiments, the dosimeter assembly comprises a housing (110 in FIG. 1). In some embodiments, said housing enclose or house at least part of the various components or parts of the dosimeter assembly.

In some embodiments, the housing of the dosimeter assembly of the present disclosure may be provided in the shape of a capsule. It is to be appreciated that other shapes of the housing may also be used. In some embodiments, in the case of the housing being the capsule, said capsule may be an electronic capsule. In some embodiments, said capsule may comprise two caps (272 in FIG. 2). Advantageously, the capsule may be dimensioned to the standard size of a human capsule. In some embodiments, the dosimeter assembly disclosed herein may be useful for in situ sensing of gastric motility and other parameters such as radiation dose (including X-ray dose), pH, and temperature. In some embodiments, the capsule may detect the gastric motility and pH concurrently or sequentially. In some embodiments, the capsule may detect the gastric motility, radiation dose and pH concurrently or sequentially. In some embodiments, the capsule may detect the gastric motility, radiation dose, pH and temperature concurrently or sequentially. In some embodiments, the capsule may be an ingestible or a swallowable capsule.

According to some embodiments, the housing of the dosimeter assembly disclosed herein comprises a deformation sensing module (102 in FIG. 1) adapted to measure the degree of deformation of the dosimeter assembly. In some embodiments, the degree of deformation is associated with the rate and intensity of the gastric motility. In some embodiments, due to movement and contraction of the muscles in the stomach, pressure (stress or strain) generated from said movement and contraction of the muscles may be applied to the housing of the dosimeter assembly causing the housing to deform. In some embodiments, the deformation sensing module comprises one or a plurality of piezoresistive sensors. In some embodiments, the electrical resistance of the material forming the housing changes according to the applied stress or strain. In some embodiments, the material of the housing may exhibit piezoresistive effect and thus may be used to measure or quantify one or more mechanical parameters including force, pressure, acceleration and deformation. In some embodiments, any changes in the one or more mechanical parameters may be converted to electrical signals, the readouts of the gastric motility on the device or external device may be associated with said electric signals.

In some embodiments, the piezoresistive sensor is a piezoresistive pressure sensor configured to measure changes in pressure (including peristaltic pressure) of the digestive tract. In some embodiments, the deformation sensing module further comprises one or more sensor interface. In some embodiments, the sensor interface is a sensor interface integrated circuit. In such an embodiment, input signal from the sensor is converted to output signal for readouts of the parameters mentioned above. In some embodiments, the measured voltage from the pressure sensor is converted to a 24-bit digital value. In an alternative embodiment, the deformation sensing module comprises a pressure sensor and a temperature sensor. In such an embodiment, the measured voltage from the pressure sensor is converted to a 24-bit digital value and the measured voltage from the temperature sensor is converted to a 24-bit digital value. In some embodiments, the deformation sensing module may be characterized by low hysteresis and high stability of both pressure and temperature signals.

In some embodiments, the dosimeter assembly disclosed herein may further include a pH monitoring unit or a pH sensor (104 in FIG. 1 or 222 in FIG. 2). The pH sensor is used to detect and/ or measure the pH of tissues or body fluids in a subject. In some embodiments, the tissues or body fluids may comprise gastric juices. In some embodiments, the pH monitoring unit or pH sensor is responsive to the emission or radiation from an illumination source, when said pH sensor or at least part thereof is illuminated by the illumination source. It is to be appreciated that any suitable illumination source may be used. In some embodiments, the pH sensor is configured to produce a measurement of the pH of tissue or body fluid in the subject when illuminated by an illumination source (114 in FIG. IB). In such an embodiment, the pH monitoring is performed with an internal light source. In some embodiments, the illumination source comprises a quantum dot material (116 in FIG. IB). In an exemplary embodiment, the quantum dot material is illuminated by the LED source at about 405 nm. It is to be appreciated that other suitable wavelengths than 405 nm may be used. In some embodiments, as will be described below, the pH monitoring may be undertaken using the photon emitted by a scintillator. In other words, emission from scintillator may be used for the pH monitoring as the pH sensor is responsive to the emission (or radiation) from the scintillator. In some embodiments, the emission is a long-lasting afterglow emission. In some embodiments, the pH monitoring is undertaken without an external light source. As used herein, the term “external light source” refers to any light source found outside of the housing of the dosimeter assembly disclosed herein. Accordingly, the dosimeter assembly of the present disclosure may advantageously reduce the power consumption and extend the service life of the dosimeter assembly.

In some embodiments, the pH sensor may comprise a microfluidic module (222 in FIG. 2). In some embodiments, said microfluidic module comprises one or more microfluidic channels within the microfluidic module. In some embodiments, the microfluidic module comprises one or more microcavities (252 in FIG. 2) within the microfluidic module. In some embodiments, the microfluidic module may have a plurality of inlets for pH monitoring of the tissues or body fluids in the subject. In some embodiments, the microfluidic module may be pH sensitive. In some embodiments, the pH sensor may be characterized by fast and/ or accurate response during the pH measurements. In some embodiments, the pH sensor may exhibit a stable response to pH variations (see FIG. 8E) with a sensitivity of from about 1%/pH to about 20%/pH for example about 1%/pH, about 2%/pH, about 3%/pH, about 5%/pH, about 10%/pH, about 15%/pH or about 20%/pH. In some embodiments, the sensitivity of the pH sensor may be about 0.2/pH or lower for example about 0.15/pH, about 0.1/pH, about 0.05/pH or about 0.01/pH. In some embodiments, the sensitivity of the pH sensor may be expressed in percentage. In some embodiments, the sensitivity of the pH sensor is about 11.2%/pH. It is to be appreciated that the sensitivity of pH sensor may include any value of 0.2/pH or lower other than those mentioned above.

In some embodiments, as mentioned herein above, the microfluidic module may comprise a plurality of channels, wherein said channels are dimensioned in micrometer scale for sampling of tissues or body fluids (i.e. microchannels or microfluidic channels). In some embodiments, the microfluidic module may be coated by a monolayer or multilayered coating of polymer (226 in FIG. 2). In some embodiments, the monolayer or multilayered coating of polymer may be a biocompatible pH-sensitive film. In some embodiments, the polymer may comprise aniline monomer. In some embodiments, the polymer may comprise a poly aniline or PANI ( 118 in FIG. IB). In some embodiments, the polymer may be a polydimethylsiloxane or PDMS. In some embodiments, the polymer may be PANI-containing PDMS. In some embodiments, the polymer may be a monodisperse polymer, a polydisperse polymer or combination thereof. In some embodiments, in the case of the multilayered coating of polymer comprising PANI-coated film, the absorption spectra of PANI-coated film may exhibit sensitivity to pH changes in the range of pH 1 to pH 7 (acidic to neutral region, see FIG. 8D) for example pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7 or any other values between pH 1 to pH 7. In an exemplary embodiment, the pH change of the body fluids may change the transmission spectrum of the light emitted by the illumination source, scintillator or the optical fiber comprising the scintillator as the light passes through the film (refer to FIG. 8A). Advantageously, the PANI-coated film exhibits the beneficial properties of repeatability, reversibility and long lifetime. As aforementioned, the response of the pH- sensitive film provided herein may be reversible. Accordingly, the response provided by the pH sensor is associated with the color of the PANI-coated film. In some embodiments, the dosimeter assembly described herein comprises pH sensor and a color sensor (242 and 252 in FIG. 2), wherein the color sensor is adapted to detect the color transmitted by the PANI-coated film upon irradiation of the PANI-coated film by the illumination source.

In some embodiments, the microfluidic module of the pH sensor may be provided with multiple inlets (see FIG. 8B) for allowing the tissues or body fluids flow or enter the microfluidic module and the pH of the tissue or body fluid to be detected. In some embodiments, the tissues or body fluids may flow into the microfluidic module via the multiple inlets continuously or periodically. Advantageously, the continuous supply of the tissues or body fluids may improve the sampling process to achieve higher temporal resolution for pH measurement. In some embodiments, the pH resolution may about 0.05 pH. In some embodiments, the inlet flowrate of the tissues or body fluids may be in the range of 40 mL/min to 70 mL/min for example 40 mL/min, 42 mL/min, 45 mL/min, 47 mL/min, 50 mL/min, 52 mL/min, 55 mL/min, 57 mL/min, 60 mL/min, 65 mL/min, 70 mL/min or any other values between 40 mL/min to 70 mL/min. Accordingly, time taken to reach 90% of new sample of tissues or body fluids may be in the range of about 20 to 60 seconds for example 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds or any other values between 20 to 60 seconds. In some embodiments, the sampling process above may be a dynamic sampling process. In some embodiments, as described herein, the pH detected may be associated with the color sensed by the color sensor. In such an embodiment, the dosimeter assembly described herein further comprises at least one color sensor. In some embodiments, a plot or calibration curved establishing the relationship between the color or color change and pH is necessary (refer to FIG. 8C).

In some embodiments, the dosimeter assembly comprises a housing, whereby said housing comprises a deformation sensing module adapted to measure the degree of deformation of the dosimeter assembly a pH sensor adapted to measure pH of tissue or body fluid in the subject. In such an embodiment, the deformation sensing module is configured to produce a measurement of the gastric motility in the subject and the pH sensor is configured to produce a measurement of the pH of tissue or body fluid in the subject when illuminated by an illumination source.

As used herein, the term “scintillator” refers to any materials or particles that can absorb X-rays, alpha-rays or gamma-rays and emit photons. The emitted photons can have energies ranging from the ultraviolet to infrared (including visible light). The scintillator may have particle size in nanometers range and may therefore be termed as “nanoscintillator”. Upon X-ray irradiation, scintillator or nanoscintillator can transfer energy to nearby or conjugated photosensitizer molecules.

During a radiotherapy or a combination of radiotherapy -immunotherapy session, a subject having a dosimeter assembly of the present disclosure in his or her body will be subjected to a radiation of X-rays, alpha-rays or gamma-rays from a light or radiation source. Therefore, the dosimeter assembly of the present disclosure may be suitable for monitoring a radiation dose in a subject having received a radiotherapy. The dosimeter assembly of the present disclosure may be an in vivo dosimeter. In some embodiments, the dosimeter assembly may be suitable for monitoring low X-ray dose. In some embodiments, the dosimeter assembly of the present disclosure may be suitable for monitoring and measuring a radiation dose of from about 1 gray (or Gy) to about 20 Gy, wherein Gy is a derived unit of ionizing radiation dose in the International System of Units (SI). Gy is defined as the absorption of one joule of radiation energy per kilogram of matter. The radiation dose measured may be about 1 Gy, about 2 Gy, about 3 Gy, about 4 Gy, about 5 Gy, about 10 Gy, about 15 Gy or about 20 Gy. In some embodiments of the disclosure, the housing may comprise a scintillator. In some embodiments, the housing may comprise a scintillator and a radiation sensor adapted to measure the radiation dose. In some embodiments, the radiation dose may be an absolute or a relative radiation dose. For the relative radiation dose, the reading of the radiation dose is being compared to a reference or a control.

In some embodiments, the housing may comprise a scintillator, a radiation sensor adapted to measure the radiation dose and a pH sensor adapted to measure pH of tissue or body fluid in the subject. In some embodiments, the radiation sensor may be adapted to produce a measurement of the radiation dose in the subject when illuminated by the scintillator (as a result of emission of photons as will be described below). In some embodiments, the pH sensor may be adapted to produce a measurement of the pH of tissue or body fluid in the subject when illuminated by the illumination source including scintillator.

In some embodiments, the scintillator may be embedded in an optical fiber within the housing (232 in FIG. 2). In some embodiments, the optical fiber may be a highly sensitive optical fiber. When housing of the dosimeter assembly comprises other components as will be described below, it is to be understood that the housing is configured to house or encase those other elements at least partly in addition to the optical fiber and scintillator.

In some embodiments of the dosimeter assembly of the present disclosure, a scintillator may absorb a high energy radiation from the radiation source and subsequently emit a photon in the form of a lower energy radiation (for example near visible or visible light). Therefore, it is to be understood that the scintillator converts the high energy radiation to the lower energy radiation.

In some embodiments, the scintillator comprises a nanoscintillator that is scintillator having an average particle size in the nanometers range (for example from about 0.1 nm to about 500 nm such as 0.1 nm, 0.5 mm, 1 nm, 5 mm, 10 nm, 20 nm, 50 nm, 100 nm, 150 nm, 200 nm or 500 nm). In some embodiments, the nanoscintillator may comprise a rare-earth doped nanoscintillator. The term rare-earth as used herein refers to rare-earth metals or rare-earth elements found in the Periodic Table. Examples of the rare-earth elements include Scandium (Sc), Yttrium (Y), Lanthanum (La), Cerium (Ce), Praseodymium (Pr), Neodymium (Nd), Promethium (Pr), Samarium (Sm), Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb), and Lutetium (Lu). The rare-earth doped nanoscintillator refers to nanoscintillator having the rare-earth elements or metals incorporated into matrix of nanoscintillator. In some embodiments, the rare-earth doped nanoscintillator comprises NaLuF4. In some embodiments, rare-earth doped nanoscintillator comprises NaLuF4:Tb. In some embodiments, the scintillator or nanoscintillator may be a core- shell scintillator or nanoscintillator, wherein the core may comprise material that is different from the shell. In some embodiments, the shell may partially or fully encapsulate the core such that the core is partly exposed or not exposed. In some embodiments, the scintillator or nanoscintillator may comprise NaLuF4 as the core and NaYF4 as the shell. In some embodiments, when the scintillator or nanoscintillator is NaLuF4:Tb@NaYF4, NaLuF4:Tb is the core and NaYF4 is the shell.

In some embodiments, other suitable scintillators or nanoscintillators including ZnS:Mn/Cu and Nal may also be used. In some embodiments, ZnS:Mn/Cu and Nal may be embedded to the optical fiber within the housing as described above. In some embodiments, ZnS:Mn/Cu and Nal may be embedded to the highly sensitive optical fiber within the housing.

In converting the high energy radiation to the lower energy radiation, the scintillator may emit a photon and absorb part of the radiation from the radiation source. In some embodiments, the nanoscintillator or the rare-earth doped nanoscintillator may emit a photon. In some embodiments, when the rare-earth doped nanoscintillator is NaLuF4:Tb@NaYF4 excited by an X- ray source, a radioluminescence with emission peaks at 489 nm, 546 nm and 584 nm may be detected (refer to FIG. 3). Advantageously, the afterglow of NaLuF4:Tb@NaYF4 may persist for more than 30 days after switching off the X-ray source. In some embodiments, the afterglow may persist for more than 31 days, 32 days, 33 days, 34 days, 35 days, 40 days, 45 days, 50 days, 60 days or 70 days after switching off the X-ray source.

In some embodiments, benefiting from these scintillating nanomaterials with high X-ray responsivity and the structure of the optical fiber, the minimum detectable X-ray radiation dose rate may be below 10 nGrys ¹.

In some embodiments, the housing of the dosimeter assembly of the present disclosure may further comprise a plurality of additional sensors selected from the group consisting of a temperature sensor, an oxygen sensor, and a carbon dioxide sensor. In an exemplary embodiment, the dosimeter assembly of the present disclosure may comprise the temperature sensor, wherein the temperature sensor is a built-in or an integrated temperature sensor. In some embodiments, the temperature sensor is integrated with the color sensor (242 and 252 in FIG. 2). In some embodiments, the temperature sensor may be used to obtain correction factors that compensate for the effect of body temperature on the dosimeter assembly. In some embodiment, the average measurement error of temperature is about from 0.1 °C to 1.0°C for example 0.1 °C, 0.15°C, 0.2°C, 0.25°C, 0.3°C, 0.4°C, 0.5°C, 0.6°C, 0.7°C, 0.8°C, 0.9°C, 1.0°C or any other values between 0.1°C to 1.0°C. In some embodiments, the average measurement error may be about 0.12°C (refer to FIG. 8F).

In some embodiments, the housing of the dosimeter assembly of the present disclosure may further comprise a processor (108 in FIG. 1A and 262 in FIG. 2) and a power supply (106 in FIG. 1A and 206 in FIG. 2). In some embodiments, the processor may be a small-printed circuit board (PCB) with microcontrollers (MCUs) - 242 and 262 in FIG. 2. In some embodiments, the power supply may be a silver oxide battery. It is apparent to a person skilled in the art that other suitable power supply may also be used. In some embodiments, the processor may be in communication with an external device to display a plurality of parameters including radiation dose, pH, temperature, oxygen level and carbon dioxide level. In some embodiments, the communication between the processor and the external device may be wireless. In some embodiments, the communication between the processor and the external device may be via an antenna (252 in FIG. 2).

In some embodiments, the dose monitoring using the dosimeter assembly of the present disclosure may be an in-situ monitoring. In some embodiments, the dose monitoring using the dosimeter assembly of the present disclosure may be a real time monitoring. In some embodiments, the in-situ dose monitoring using the dosimeter assembly of the present disclosure may be a realtime in situ monitoring. In some embodiments, the real-time in situ dose monitoring using the dosimeter assembly of the present disclosure may be a continuous or intermittent real-time in situ monitoring.

In some embodiments, the dosimeter assembly is configured to determine the radiation dose via a machine learning.

In some embodiments, the housing of the dosimeter assembly of the present disclosure may be provided in the shape of a capsule. In some embodiments, the capsule may be an electronic capsule. Advantageously, the capsule may be dimensioned to the standard size of a human capsule and may allow in situ sensing of gastric motility, pH, and optionally X-ray dose as well as temperature of the gastrointestinal tract. In some embodiments, the capsule may detect the gastric motility and pH concurrently or sequentially within a defined period. In some embodiments, the capsule may detect the gastric motility, radiation dose and pH concurrently or sequentially within a defined period. In some embodiments, the capsule may detect the gastric motility, radiation dose, pH and temperature at the same time. In some embodiments, the capsule may be an ingestible or a swallowable capsule. Advantageously, the capsule combines a flexible radiation-sensitive light tube together with ultra-low power consumption and miniaturized luminescence readout electronics that wirelessly communicate with an external device.

In some embodiments, the dosimeter assembly of the present disclosure is suitable for monitoring the gastric motility. In some embodiments, additionally, the dosimeter assembly of the present disclosure is suitable for use in detecting tumors of the gastrointestinal tract. Advantageously, the electronic capsules may simultaneously monitor doses and biochemical indicators in situ. Monitoring dose delivery and the effects of radiotherapy on physiological indicators may transform the treatment and diagnosis of gastrointestinal diseases. Therefore advantageously, the dosimeter assembly disclosed in the present application may be useful to monitor the response of the body after a patient received the radiotherapy (via monitoring changes in pH, temperature and other parameters including oxygen level and carbon dioxide level).

In some embodiments, there is provided a dosimeter assembly for monitoring a radiation dose in a subject comprising: a housing, the housing comprises a scintillator and a radiation sensor adapted to measure the radiation dose; the radiation sensor is adapted to produce a measurement of the radiation dose in the subject when illuminated by the scintillator and wherein said scintillator comprises NaLuF4:Tb@NaYF4.

In some embodiments, there is provided a scintillator comprising NaLuF4:Tb@NaYF4.

In some embodiments, the dosimeter assembly of the current disclosure comprises a piezoresistive module and a photoelectric module. The piezoresistive module is configured to monitor the gastric motility and the photoelectric module is configured to monitor and measure pH as well as pH changes. In some embodiments, the piezoresistive module comprises one or more piezoresistive sensors and the photoelectric module comprises a pH sensor configured to produce a measurement of the pH of tissue or body fluid when illuminated by an illumination source. In some embodiments, both piezoresistive module and photoelectric module are integrated in the housing. In some embodiments, the housing is a capsule. In some embodiments, both piezoresistive module and photoelectric module are integrated on a 3D-printed capsule. In some embodiments, the capsule is a standard size 000, standard size 00, standard size 0, standard size 1, standard size 2, standard size 3, standard size 4, or standard size 5. In some embodiments, the housing or capsule comprises gaps formed between parts or components described above. The term “gap” refers to free space(s) or space(s) unoccupied by parts or elements including the piezoresistive module and the photoelectric module. In some embodiments, the gaps may be filled with one or more biocompatible polymers. In some embodiments, the one or more biocompatible polymers include PDMS.

In some embodiments, there is provided a method for monitoring gastric motility in a subject using the dosimeter assembly described herein. In some embodiments, the method comprises administering a dosimeter assembly to the subject. In some embodiments, the subject is suspected to have a gastrointestinal disorder or condition. In some embodiments, the gastrointestinal disorder or condition comprises gastroparesis, gastric dysmotility, dumping syndrome and gastroesophageal reflux disease or GERD. In some embodiments, the method additionally comprises obtaining one or more readings on a device, wherein said device is connected to the dosimeter assembly. In some embodiments, the method is useful for monitoring a radiation dose in a subject, using the dosimeter assembly disclosed herein.

In some embodiments, there is provided a method for monitoring a radiation dose in a subject, comprising: administering a dosimeter assembly to the subject having received a radiotherapy; wherein said dosimeter assembly comprises: a housing, the housing comprises a scintillator, a radiation sensor arranged to measure the radiation dose and a pH sensor arranged to measure pH of tissue or body fluid in the subject; the radiation sensor is adapted to produce a measurement of the radiation dose in the subject when illuminated by the scintillator; and the pH sensor is adapted to produce a measurement of the pH of tissue or body fluid in the subject when illuminated by the scintillator.

In some embodiments, multiple data obtained in time series with the same measurement purpose may be fused together or integrated to obtain a more accurate reading. It is hypothesized that fusion of radioluminescence (for example during the radiotherapy) and afterglow (when the X-ray source is switched off) may provide a more accurate assessment of dose. In addition, in high-precision dosimetry, the influence of temperature on the radioluminescence and afterglow of nanoscintillators may be considered. To fit the complex relationship between the dose (D) and radioluminescence (L), afterglow with time (Ai, i represents time), and temperature (T), a machine learning technique based on a neural network (NN) regression for high-precision evaluation may be used (refer to FIG. 4). The scintillators or nanoscintillators may be excited by X-rays with different dose rates but the same dose to obtain training data (refer to FIG. 5). Two different algorithms were tested, based on simple linear regression using only L as input and NN using (L, Ai, T) as input (refer to FIG. 6). For excitation currents up to 79 pA, the root mean square error (RMSE) of NN is only approximately 0.2 pA, which is about 4 times lower than linear regression.

In some embodiments, a precision cloud radiotherapy, a new Internet-based service model for tumor radiotherapy, may be integrated to the dosimeter assembly of the present disclosure. In some embodiments, a receiving system may be integrated to the dosimeter assembly of the present disclosure and developed on a portable device (for example a mobile phone). The receiving system may interact with multiple dosimeter assemblies or electronic capsules at the same time. Such a platform may enable radiotherapy practitioners to manage data for multiple patients, and also provide training data for the NN algorithm described above.

EXAMPLES

Example 1 - Animal Model Study

The dosimeter assembly of capsule standard size 2 is provided as can be seen in FIG. 9A for an animal study using rabbit. The image of the capsule under X-ray excitation is as shown in FIG. 9B. The dosimeter assembly further includes wireless antenna to allow wireless communication between the dosimeter assembly and an external device to display the readout. As described above, the external device includes a mobile phone. FIG. 9C is an image of the dosimeter assembly used in an animal model where adjustment of the excitation dose from 100% to 10% resulted in a reduction in the dose measured by the capsule from approximately 20 pGy to about 5 pGy. From the readout shown on the mobile phone (see FIG. 9D), the wireless electronic capsule accurately detects the changes in pH in the rabbit’s gastric juice after ingestion of acidic and alkaline foods. As can be seen from FIG. 9D, the mobile phone can interact with the electronic capsule. In an alternative embodiment, the mobile phone can interact with multiple electronic capsules at the same time and thus allowing the practitioner to manage data of multiple patients.

Example 2 - Angular Response of the Dosimeter Assembly

The angular response is one of the most important parameters for in vivo dosimeter. To evaluate the response of the dosimeter, a reference was used. Since the detector and other electronic components in the electronic capsule block the rays when the radiotherapy beam is parallel to the axis of the capsule, the capsule is oriented forming a certain angle and thus the response is termed as “angular response”. It was observed that when the ray energy of 18 MV was used, the response difference in the reference was less than 10 %. On the other hand, in the case of the capsule according to some embodiment of the disclosure, when the ray energy of 50 kV was used, the response was reduced to 20% when the rays and capsule are parallel. However, under 6 MV ray excitation, the angular response of the capsule disclosed herein is reduced by approximately 3.2 % (refer to FIGS. 10A-B). As ultrasound or CT imaging of the capsule posture may be performed before the radiotherapy, a low angular response difference of 3.2% does not affect the clinical application of the dosimetry assembly disclosed herein.

Example 3 - Minimum Radiation

The dose rate of a range from about 0.58 Gy/minutes to about 5.76 Gy/minutes was tested to mimic the actual radiotherapy. The radiation beam used in the experiment was obtained from a professional radiotherapy device shown in FIG. HA (6 MV and 10 MV, Device model: TrueBeam®, Varian medical system, Palo alto, California). It can be seen that the dosimeter assembly produces the readouts of the real dose rate accurately and timely. It was further observed that the specific measurable dose rate range depends on the radiation energy. The test result shows that the swallowable capsule dosimeter can measure 50 kV radiation with a dose rate of 0.1 mGy/minute to 100 mGy /minute. The dosimeter can also be used to measure 6 MV radiation with a dose rate of 0.58 Gy/minute to 5.76 Gy/minute (see FIG. 11B). The measurable range can be expanded by adjusting the irradiance responsivity factor as well as the conversion time of the color sensor. The integrated color sensor AS73211 has the light detection range from 0 to 16.4 mW/cm² and with an irradiance responsivity per count down to 0.5 pW/cm².

It should be appreciated that the dosimeter assembly and method of using the dosimeter assembly as described above may be varied in many ways, including omitting or adding elements or steps (in case of the method of using the dosimeter assembly), changing the order of steps and the types of optional components or parts used. It should be appreciated that different features may be combined in different ways. In particular, not all the features shown above in a particular embodiment are necessary in every embodiment of the disclosure. Further combinations of the above features may be contemplated and are considered to be within the scope of some embodiments of the disclosure.

It will be appreciated by a person skilled in the art that the present disclosure is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present disclosure is defined by the claims, which follow.

Claims

1. A dosimeter assembly for monitoring a gastric motility and pH in a subject, wherein said dosimeter assembly comprises: a housing, said housing comprising: a deformation sensing module adapted to measure the degree of deformation of the dosimeter assembly; and a pH sensor adapted to measure pH of tissue or body fluid in the subject; wherein the deformation sensing module is configured to produce a measurement of the gastric motility in the subject; and wherein the pH sensor is configured to produce a measurement of the pH of tissue or body fluid in the subject when illuminated by an illumination source.

2. The dosimeter assembly of claim 1, wherein the deformation sensing module comprises one or a plurality of piezoresistive sensors.

3. The dosimeter assembly of claim 1, wherein the illumination source comprises a quantum dot material.

4. The dosimeter assembly of claim 1, wherein the pH sensor comprises a microfluidic module having multiple inlets to allow an incoming flow of tissue or body fluid, wherein said pH sensor is responsive to the radiation from the illumination source.

5. The dosimeter assembly of claim 4, wherein said microfluidic module is coated by a multilayered coating of polymer.

6. The dosimeter assembly of claim 5, wherein said polymer comprises aniline monomer.

7. The dosimeter assembly of claim 1, being further configured to monitor a radiation dose in the subject, wherein the housing further comprising: a scintillator; and a radiation sensor adapted to measure the radiation dose and the radiation sensor is configured to produce a measurement of the radiation dose in the subject when illuminated by the scintillator.

8. The dosimeter assembly of claim 7, wherein the scintillator comprises a nanoscintillator.

9. The dosimeter assembly of claim 8, wherein the nanoscintillator comprises a rare-earth doped nanoscintillator.

10. The dosimeter assembly of claim 3, wherein the rare-earth doped nanoscintillator comprises NaLuF4:Tb@NaYF4.

11. The dosimeter assembly of claim 1, further comprising a plurality of additional sensors selected from the group consisting of a temperature sensor, an oxygen sensor, and a carbon dioxide sensor.

12. The dosimeter assembly of claim 1, further comprising a processor and a power supply.

13. The dosimeter assembly of claim 1, wherein the housing is in the shape of a capsule, the capsule is an ingestible capsule.

14. The dosimeter assembly of claim 7, wherein the scintillator is a core-shell scintillator.

15. A scintillator comprising NaLuF4:Tb@NaYF4.

16. A method for monitoring a gastric motility and pH in a subject, comprising: administering the dosimeter assembly of claim 1 ; and obtaining one or more readings on a device, wherein said device is connected to the dosimeter assembly.

17. The method of claim 16, wherein the monitoring is an in-situ monitoring.

18. The method of claim 16, wherein said method is useful for detecting or monitoring tumors in the gastrointestinal tract.

19. The method of claim 16, wherein said method is useful for detecting a gastrointestinal disorder or condition.

20. The method of claim 19, wherein the gastrointestinal disorder or condition comprises gastroparesis, gastric dysmotility, dumping syndrome and gastroesophageal reflux disease or GERD.