WO2021073003A1 - Application, dispositif et système d'évaluation par score de la polyarthrite rhumatoïde faisant appel à l'imagerie photoacoustique/ultrasonore multimodale - Google Patents

Application, dispositif et système d'évaluation par score de la polyarthrite rhumatoïde faisant appel à l'imagerie photoacoustique/ultrasonore multimodale Download PDF

Info

Publication number
WO2021073003A1
WO2021073003A1 PCT/CN2020/071294 CN2020071294W WO2021073003A1 WO 2021073003 A1 WO2021073003 A1 WO 2021073003A1 CN 2020071294 W CN2020071294 W CN 2020071294W WO 2021073003 A1 WO2021073003 A1 WO 2021073003A1
Authority
WO
WIPO (PCT)
Prior art keywords
score
photoacoustic
imaging
ultrasound
joint
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/071294
Other languages
English (en)
Chinese (zh)
Inventor
杨萌
姜玉新
李建初
赵辰阳
王铭
王迁
齐振红
苏娜
陶茜葸
刘思锐
张睿
唐天虹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peking Union Medical College Hospital Chinese Academy of Medical Sciences
Original Assignee
Peking Union Medical College Hospital Chinese Academy of Medical Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201910995355.1A external-priority patent/CN110613430A/zh
Application filed by Peking Union Medical College Hospital Chinese Academy of Medical Sciences filed Critical Peking Union Medical College Hospital Chinese Academy of Medical Sciences
Publication of WO2021073003A1 publication Critical patent/WO2021073003A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room
    • A61B5/0035—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room adapted for acquisition of images from more than one imaging mode, e.g. combining MRI and optical tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0093—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
    • A61B5/0095—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy by applying light and detecting acoustic waves, i.e. photoacoustic measurements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14542—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring blood gases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/45—For evaluating or diagnosing the musculoskeletal system or teeth
    • A61B5/4528—Joints

Definitions

  • the invention relates to the technical field of medical diagnosis, in particular to a multimodal photoacoustic/ultrasound imaging rheumatoid arthritis scoring system, equipment and application.
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • the peak age of onset is about 50 years old, and it occurs frequently in women.
  • the prevalence of RA in China is generally on the rise.
  • Most patients with RA show severe clinical symptoms at the first diagnosis, and severe bone and joint structural damage may occur in the later stage of the disease, resulting in disability and inability to take care of themselves, seriously affecting the quality of life and bringing social and economic benefits severely burdened.
  • Early diagnosis, treatment and prevention of RA recurrence and progression are essential to improve the prognosis of patients and improve the quality of life.
  • the main imaging diagnostic methods of RA include X-ray, MRI and high-frequency ultrasound.
  • X-ray examination is not sensitive to early synovial and bone lesions, and has little effect in early diagnosis; magnetic resonance imaging (MRI) can clearly show the intra-articular structure Compared with soft tissue lesions, it is expensive, time-consuming, and not suitable for routine examination.
  • High-frequency ultrasound has played an increasingly important role in the diagnosis and treatment of RA due to its advantages of non-invasive, non-radiation, convenience, high cost performance, and good patient compliance. effect.
  • High-frequency gray-scale ultrasound can evaluate signs of joint local synovial thickening, joint effusion, bone destruction, tenosynovitis, and power Doppler ultrasound can evaluate blood flow in thickened inflammatory lesions to determine the degree of inflammatory activity.
  • High-frequency gray-scale and power Doppler ultrasound are currently being promoted by EULAR guidelines as a routine imaging method for RA-assisted diagnosis. And many studies have shown that ultrasound has clinical application value in multiple diagnosis and treatment links such as early diagnosis of RA, disease activity evaluation, treatment follow-up, efficacy evaluation, and recurrence prediction.
  • the photoacoustic imaging technology is based on the principle of the photoacoustic effect, that is, when the tissue is irradiated with a short pulse laser, the tissue is heated and expanded to generate ultrasonic waves, and the imaging is realized after detecting and reconstructing the image. It combines the advantages of optics and ultrasound. Based on the optical properties of tissues, multispectral imaging can be used to obtain more structural and functional information. At the same time, the resolution of deep tissues is much higher than that of traditional optical imaging. With the development and improvement of photoacoustic imaging technology, its clinical application has also been extended to joint imaging.
  • PAT photoacoustic tomography
  • the multi-modal photoacoustic/ultrasound imaging platform that combines the photoacoustic imaging system with the ultrasound imaging system and is equipped with high-frequency ultrasound probes can display anatomical images through the ultrasound grayscale mode, and the photoacoustic mode provides functional information, which is in overcoming the traditional photoacoustic
  • the advantages of photoacoustic imaging are utilized to the greatest extent, so it has considerable potential clinical application value in joint imaging.
  • foreign countries have begun to develop this type of PA/US multi-modal imaging system with a portable handheld probe, and applied it to multi-wavelength photoacoustic examination of the small joints of RA patients, and successfully quantitatively determined the hemoglobin content and blood oxygen in the joints of RA patients saturation.
  • the research team successfully developed a photoacoustic/ultrasound dual-mode clinical real-time imaging system based on a handheld probe.
  • the system is based on a commercial ultrasound instrument, which can provide higher resolution ultrasound and photoacoustic images, and realizes a variety of ultrasound modes (including color Doppler, power Doppler and ultrasound shear wave elastography) and photoacoustic Combined with real-time multi-modal imaging;
  • the system is equipped with imaging analysis software, which can provide automatic quantitative analysis of photoacoustic multi-parameters, and more accurately reflect the relevant photoacoustic information of the target area; at the same time, due to the application of a handheld integrated photoacoustic/ultrasound probe , In line with the habits of sonographers, and has the advantages of being suitable for clinical staff.
  • the purpose of the present invention is to provide a multi-modal photoacoustic/ultrasound imaging rheumatoid arthritis scoring system, equipment and application, combining energy Doppler imaging, photoacoustic imaging and local blood oxygen information scoring to accurately determine RA joints The degree of imaging inflammation activity.
  • One aspect of the present invention provides the application of multimodal photoacoustic/ultrasound imaging in a rheumatoid arthritis scoring system, which includes the following steps:
  • Photoacoustic/ultrasound dual-modality imaging collects image information of joints in an external form
  • the multimodal photoacoustic/ultrasound scores include power Doppler ultrasound imaging (PDUS) scores and photoacoustic imaging (PAI) scores, and the PDUS scores and PAI scores are both Szkudlarek, etc.
  • PDUS power Doppler ultrasound imaging
  • PAI photoacoustic imaging
  • the 0-3 semi-quantitative scoring system first proposed by people (see Szkudlarek M, Court-Payen M, Jacobsen S, et al. Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis. Arthritis Rheum 2003; 48:955 -62.
  • the PDUS score and the PAI score are evaluated by the following criteria: no ultrasound/photoacoustic signal, score 0; less than 3 ultrasound/photoacoustic signals in the same plane in the hypoechoic area of the synovium, score 1 ; Ultrasound/photoacoustic signal is detected within half (area) of the hypoechoic area of synovium, score 2; Ultrasound/photoacoustic signal is detected in more than half (area) of hypoechoic area of synovium, score 3.
  • hypoechoic area of the synovial membrane is the area of synovial hyperplasia, that is, the abnormal hypoechoic tissue in the joint cavity, which is not transferable and difficult to be compressed, and may show Doppler blood flow signals.
  • the blood flow signal score ROI area region of interest is the area of synovial hyperplasia.
  • the local blood oxygen information includes qualitative evaluation using color judgment.
  • the SO 2 image of the photoacoustic signal SO 2 images of each examined joint thickened inflammatory lesion area is divided into three groups: blue (mainly hypoxic blood flow signal), red (hyperoxia) Blood flow signal mainly) and red and blue phases (mixed blood flow signal), the blue is mainly hypoxic blood flow signal, the red is mainly hyperoxic blood flow signal, and the red and blue phase is mixed blood Stream signal.
  • the local blood oxygen information further includes checking the oxygen saturation value (SO 2 ) of the local thickened area of the joint, and comparing it with the surrounding normal tendons to determine the condition of the joint.
  • the oxygen saturation value SO 2 is calculated by the following formula:
  • Hb is endogenous oxygenated hemoglobin
  • deHb is deoxygenated hemoglobin
  • ⁇ 1 750 nm
  • ⁇ 2 830 nm.
  • ⁇ a ( ⁇ ,r) represents the optical absorption coefficient of blood
  • ⁇ Hb ( ⁇ ) represents the molar extinction of endogenous oxygenated hemoglobin (Hb)
  • C Hb (r) represents endogenous oxygenated hemoglobin (Hb)
  • the concentration of ⁇ deHb ( ⁇ ) represents the molar extinction of deoxyhemoglobin (deHb)
  • C deHb (r) represents the concentration of deoxyhemoglobin (deHb).
  • PA( ⁇ 1 ,r)* is the PA that ignores ⁇ ( ⁇ 1 ,r)
  • PA( ⁇ 2 ,r)* is the PA that ignores ⁇ ( ⁇ 2 ,r).
  • the PA value can be directly collected by the ultrasound probe. Any pixels with negative SO 2 values were removed in the subsequent analysis.
  • the multi-modal photoacoustic/ultrasound scoring image score is selected by at least two sonographers who do not know the patient’s information to use one of the three PA imaging pictures with the strongest PA signal. Scoring, when there is a disagreement between the ultrasound radiologists, re-evaluate the image until a consensus is reached.
  • the joints in step (1) include the second metacarpophalangeal joint (MCP 2), the third metacarpophalangeal joint (MCP 3), and the second metacarpophalangeal joint (MCP 2) on the side with obvious symptoms (the dominant side of clinical symptoms).
  • MCP 2 the second metacarpophalangeal joint
  • MTP 3 the third metacarpophalangeal joint
  • MTP 5 the third metatarsophalangeal joint
  • the present invention also provides a rheumatoid arthritis scoring system based on multi-modal photoacoustic ultrasound imaging, which includes an information acquisition module, an information analysis module, and an output module,
  • the information collection module adopts photoacoustic/ultrasound dual-modality imaging to collect image information of joints in an external form to obtain image information of the local inflammatory area of rheumatoid joints;
  • the information analysis module classifies and calculates the collected image information to obtain characteristic parameters of the image
  • the judgment output module combines the characteristic parameters of the image to judge the disease activity of the rheumatoid arthritis patient and output data.
  • the information analysis module includes a semi-quantitative scoring module for statistically calculating the sum of the power Doppler ultrasound imaging score and the photoacoustic imaging score, the power Doppler ultrasound imaging score and the light Acoustic imaging scoring uses a semi-quantitative scoring system of 0, 1, 2, and 3 points, and the maximum score of each joint is used as the final score of each joint.
  • the power Doppler ultrasound imaging score and the photoacoustic imaging score are evaluated by the following criteria: there is no ultrasound/photoacoustic signal, the score is 0; there are less than 3 ultrasound in the same plane in the hypoechoic area of the synovium /Photoacoustic signal, score 1; ultrasonic/photoacoustic signal detected within half of the hypoechoic area of the synovium, score 2; PD/PA signal detected in more than half of the hypoechoic synovial area, score 3.
  • the information analysis module further includes a local blood oxygen information scoring module, which is used to calculate or process the local blood oxygen information according to a specific standard.
  • the local blood oxygen information includes the photoacoustic signal SO 2 image of the thickened inflammatory lesion area of the joint, and the photoacoustic signal SO 2 image is specifically divided into three groups: blue and red Alternately with red and blue, the blue is mainly a hypoxic blood flow signal, the red is a hyperoxic blood flow signal, and the red and blue alternates are a mixed blood flow signal.
  • the local blood oxygen information further includes the judgment result of comparing the oxygen saturation value of the local thickened area of the joint with the surrounding normal tendon.
  • the SO 2 value of the thickened inflammatory area was measured by calculating the ratio of the PA signal pixels in the target area at wavelengths of 750 nm and 830 nm.
  • the joint with the highest PA signal is selected to calculate the SO 2 for each patient. Perform three calculations for each joint and determine the average value as a representative of the oxygenation status of each patient.
  • the patient was classified as hyperoxia with SO 2 value >90%, and hypoxia with SO 2 value ⁇ 85%.
  • the high level of PA signal represents inflammatory activity in the joint. Calculate the PA+SO 2 score and comprehensively judge the degree of inflammation of the patient.
  • Another aspect of the present invention provides a rheumatoid arthritis scoring system based on multi-modal photoacoustic ultrasound imaging, which includes an information acquisition module, an information analysis module, and a judgment output module,
  • the information collection module adopts photoacoustic/ultrasound dual-modality imaging to collect image information of joints in an external form to obtain image information of the local inflammatory area of rheumatoid joints;
  • the information analysis module classifies and calculates the image information collected by analysis to obtain the characteristic parameters of the image
  • the judgment output module combines the characteristic parameters of the image to judge the disease activity of the rheumatoid arthritis patient and output data.
  • the information analysis module includes a semi-quantitative scoring module, the semi-quantitative scoring module statistically calculates the sum of the power Doppler ultrasound imaging score and the photoacoustic imaging score, the power Doppler ultrasound imaging score and the photoacoustic imaging score A semi-quantitative scoring system of 0, 1, 2, and 3 points is used, and the maximum score of each joint is used as the final score of each joint.
  • Both the power Doppler ultrasound imaging (PDUS) score and the photoacoustic imaging (PAI) score use the 0-3 semi-quantitative scoring system first proposed by Szkudlarek et al. (see Szkudlarek M, Court-Payen M, Jacobsen S, et al. .Interobserver agreement in ultrasonography of the fingers and toe joints in rheumatoid arthritis.Arthritis Rheum 2003; 48:955–62. and
  • the PDUS score and PAI score are evaluated by the following criteria: no ultrasound/photoacoustic signal, score 0; less than 3 ultrasound/photoacoustic signals in the same plane in the hypoechoic area of the synovial membrane, score 1; hypoechoic synovial membrane Ultrasound/photoacoustic signal is detected within half (area) of the area, score 2; Ultrasound/photoacoustic signal is detected in hypoechoic region of synovium over half (area), score 3.
  • the hypoechoic area of the synovial membrane is the area of synovial hyperplasia, that is, the abnormal hypoechoic tissue in the joint cavity, which is not transferable and difficult to be compressed, and may show Doppler blood flow signals.
  • the blood flow signal score ROI area is the area of synovial hyperplasia.
  • the information analysis module further includes a local blood oxygen information scoring module, and the local blood oxygen information scoring module performs calculation or software calculation processing on the local blood oxygen information according to a specific standard.
  • the local blood oxygen information includes a photoacoustic signal SO 2 image of a thickened inflammatory lesion area of a joint, and a photoacoustic signal of a thickened inflammatory lesion area of each joint (including synovitis, tenosynovitis, or perianinitis)
  • the SO 2 images are divided into three groups: blue (mainly hypoxic blood flow signal), red (mainly hyperoxic blood flow signal) and red and blue (mixed blood flow signal), the blue is hypoxic blood flow The signal is dominant, the red is the hyperoxic blood flow signal, and the red and blue phases are the mixed blood flow signal.
  • the local blood oxygen information further includes the determination result of the comparison of the oxygen saturation value (SO 2 value) of the inflammatory area of the local thickening of the joint with the surrounding normal tendon.
  • SO 2 value oxygen saturation value
  • Hb is endogenous oxygenated hemoglobin
  • deHb is deoxygenated hemoglobin
  • ⁇ 1 750 nm
  • ⁇ 2 830 nm.
  • ⁇ a ( ⁇ ,r) represents the optical absorption coefficient of blood
  • ⁇ Hb ( ⁇ ) represents the molar extinction of endogenous oxygenated hemoglobin (Hb)
  • C Hb (r) represents endogenous oxygenated hemoglobin (Hb)
  • the concentration of ⁇ deHb ( ⁇ ) represents the molar extinction of deoxyhemoglobin (deHb)
  • C deHb (r) represents the concentration of deoxyhemoglobin (deHb).
  • PA( ⁇ 1 ,r)* is the PA that ignores ⁇ ( ⁇ 1 ,r)
  • PA( ⁇ 2 ,r)* is the PA that ignores ⁇ ( ⁇ 2 ,r).
  • the PA value can be directly collected by the ultrasound probe. Any pixels with negative SO 2 values were removed in the subsequent analysis.
  • the SO 2 value of the thickened inflammatory area is measured by calculating the ratio of the PA signal pixels in the target area at wavelengths of 750 nm and 830 nm.
  • the joint with the highest PA signal is selected to calculate the SO 2 for each patient. Perform three calculations for each joint and determine the average value as a representative of the oxygenation status of each patient.
  • the patient was classified as hyperoxia with SO 2 value >90%, and hypoxia with SO 2 value ⁇ 85%.
  • the high level of PA signal represents inflammatory activity in the joint. Calculate the PA+SO 2 score and comprehensively judge the degree of inflammation of the patient.
  • the joints include the second metacarpophalangeal joint (MCP 2), the third metacarpophalangeal joint (MCP 3), the second proximal interphalangeal joint (PIP 2), and the third proximal joint on the side with obvious symptoms (the dominant side of clinical symptoms) Interphalangeal joint (PIP 3), second metatarsophalangeal joint (MTP 2), third metatarsophalangeal joint (MTP 5) and wrist joint.
  • the present invention also provides a device including the above-mentioned scoring system, which includes an ultrasonic probe that collects audio-visual information; the host is respectively connected to the light transmitting and light transmitting module and the ultrasonic phased array transmitting and receiving module through a two-core cable, It is used to drive the emission of laser and ultrasound signals, and receive photoacoustic signals and reflected ultrasound signals for imaging; the processor converts specific parameters of the imaging signal into specific values; the output device outputs specific images and values.
  • the above-mentioned scoring system which includes an ultrasonic probe that collects audio-visual information; the host is respectively connected to the light transmitting and light transmitting module and the ultrasonic phased array transmitting and receiving module through a two-core cable, It is used to drive the emission of laser and ultrasound signals, and receive photoacoustic signals and reflected ultrasound signals for imaging; the processor converts specific parameters of the imaging signal into specific values; the output device outputs specific images and values.
  • the ultrasonic probe includes a phased array probe, a convex array probe, and a linear array probe.
  • the processor is any commercially available charge-coupled device capable of converting photoacoustic images into digital signals.
  • the output device is a printer.
  • the present invention uses a multi-modal photoacoustic/ultrasound imaging system and equipment for the evaluation of rheumatoid arthritis for the first time.
  • the advantage lies in that the multi-modal system and equipment adopts a handheld photoacoustic/ultrasound probe, which conforms to the usage habits of clinicians.
  • the scoring system of the present invention performs a semi-quantitative evaluation of the blood flow in the local inflammatory area of rheumatoid joints, determines the degree of imaging inflammation, and uses 7 typical joints for evaluation, which is consistent with the latest international traditional ultrasound assessment of joint selection methods ,
  • the implementation process and calculation process are simple and easy to implement, which is conducive to clinical implementation.
  • Figure 1 is an image of the wrist joint of a patient with RA.
  • the PD score of the hypoechoic area with thickened synovium is 0 point, PA is 1 point, and the PA blood oxygen group is red, showing hyperoxic blood flow signals;
  • Figure 2 is an image of the wrist joint of a patient with RA.
  • the PD score of the hypoechoic inflammatory area adjacent to the tendon sheath is 2 points, PA is 3 points, and the PA blood oxygen group is red, showing hyperoxic blood flow signals;
  • Fig. 3 is a block diagram of the structure of a rheumatoid arthritis scoring system based on multi-modal photoacoustic ultrasound imaging of the present invention
  • Figure 4 is a box plot of the relative SO 2 values of 26 RA patients (PA-sum>0);
  • Fig. 5 is an image of the wrist joint of a female RA patient (the first person) in Example 3;
  • Figure 6 is a schematic diagram of the hypoechoic area of the synovial membrane, that is, the striped irregular area circled in the figure, marked with the letter A in the figure;
  • FIG. 7 is an image of the wrist joint of a male patient (second person) in Embodiment 3;
  • Figure 8 is an image of the MCP2 joint (inflammation around the tendon) of the male patient (second) in Example 3;
  • Figure 9 is an image of the PIP2 joint of the male patient (third person) in Example 3.
  • Figure 10 is an image of the MCP2 joint (inflammation around the tendon) of the male patient (third person) in Example 3;
  • Fig. 11 is an image of the wrist joint of a male patient (third person) in Example 3;
  • Fig. 12 is a structural diagram of a rheumatoid arthritis scoring device based on multi-modal photoacoustic ultrasound imaging of the present invention.
  • the upper left is an energy Doppler ultrasound image
  • the upper right is a photoacoustic blood oxygen saturation image
  • the lower left is a 750nm photoacoustic imaging image
  • the lower right is an 850nm light.
  • PA photoacoustic
  • US ultrasound
  • PAI photoacoustic imaging
  • PDUS photoacoustic imaging
  • CDUS Doppler ultrasound
  • RA rheumatoid arthritis
  • SO 2 refers to oxygen saturation
  • Hb oxygenated hemoglobin
  • deHb deoxygenated hemoglobin
  • the dual-mode system in this study is based on a high-end clinical ultrasound machine (Resona 7, Mindray Bio-Medical Electronics Co., Ltd.), which can perform and collect data required for PA imaging. The delay and sum algorithm is used to reconstruct the PA imaging results online.
  • the clinical linear probe (L9-3U, Mindray Bio-Medical Electronics Co., Ltd.) has 192 elements, the size of each element is 0.2 mm, and the center frequency is 5.8 MHz.
  • the laser source is an OPO tunable laser (Spitlight 600-OPO, Innolas laser GmbH), which generates 700-850 nm laser pulses at 10 Hz.
  • the time division multiplexing method is used to realize real-time imaging of PA/US with two wavelengths and SO 2 mapping at a frame rate of 5 Hz.
  • the screen is divided into 4 parts to provide multi-modal imaging.
  • the first part of the screen is traditional ultrasound imaging, and provides three different ultrasound mode options, including grayscale US imaging, CDUS and PDUS.
  • the second part and the third part are PA imaging, integrated on the gray-scale US imaging, with wavelengths of 750nm and 830nm, used to detect oxyhemoglobin and deoxyhemoglobin respectively.
  • the fourth part of the screen is the SO 2 content in pseudo-color form, calculated by measuring oxygenated and deoxygenated hemoglobin, and integrated from two PA images of two different wavelengths.
  • the red PA signal represents the hyperoxia of the local tissue, and the hypoxia is reflected by the blue PA signal.
  • Example 1 Construction of a multi-modal photoacoustic/ultrasound imaging system
  • the first part of the screen can be switched to any mode of ultrasound for a complementary comparison of US and PA imaging.
  • the inspection time for conventional US is about 30 seconds to 1 minute, and the multimodal PA/US imaging time for each joint is about 2 minutes.
  • the operator of ultrasound scanning and multimodal imaging has two years of experience in musculoskeletal ultrasound and has received one month of system operation training.
  • the 0-3 semi-quantitative PDUS scoring method first proposed by Szkudlarek et al. was used in this study.
  • PA score we use a 0-3 point semi-quantitative scoring method similar to the PDUS score as a reference, see the scoring standard for details.
  • the maximum score (0-3) of synovitis or tenosynovitis/peritenonitis observed from the back, palm, or lateral side is used as the final score for each joint. Calculate the sum of each participant's PDUS score (0-21) and PA score (0-21).
  • the scoring criteria are: score 0, no PD/PA signal; score 1, PD/PA signal less than 3 bar in the same plane; score 2, PD/PA signal in the hypoechoic area of hypertrophic synovium, tenosynovitis, and perianinitis With a score of 3, PD/PA signals in more than half of the inflammation area.
  • the traditional US and PA/US images are evaluated by two sonographers who do not know the patient's information and only examine the clinical manifestations of the joints. One of the three images of PA imaging with the strongest PA signal will be selected for scoring. The inter-observer agreement of the two radiologists was evaluated. When a discrepancy is found between the two sonographers, the images are re-evaluated until a consistent score is obtained.
  • SPSS SPSS statistical software
  • the mean ⁇ standard deviation of quantitative parameters, including imaging scores, clinical scores, and laboratory data.
  • the correlation between the imaging scores (PDUS score and PA score) was evaluated by the two-sided accurate Spearman correlation coefficient.
  • the observer agreement between the two sonographers is measured by the kappa statistic.
  • Table 2 shows the three clinical scores calculated by spss and the patient’s average PDUS and PA scores and standard deviation (SD).
  • the three clinical scores include disease activity score (DAS28), clinical disease activity index (CDAI) and simplified disease activity Index (SDAI), three clinical scoring standards: DAS28 evaluation of disease activity level can be interpreted as remission (DAS28 ⁇ 2.6), low (2.6 ⁇ DAS28 ⁇ 3.2), moderate (3.2 ⁇ DAS28 ⁇ 5.1) or high (DAS28>5.1) ); CDAI evaluation of disease activity level can be interpreted as remission (CDAI ⁇ 2.8), low (2.8 ⁇ CDAI ⁇ 10), moderate (10 ⁇ CDAI ⁇ 22) or high (CDAI>22); SDAI evaluation of disease activity level can explain To relieve (SDAI ⁇ 3.3), low (3.3 ⁇ SDAI ⁇ 11), moderate (11 ⁇ SDAI ⁇ 26), or high (SDAI>26); clinical scoring uses existing conventional scoring standards (see Anderson JK, Zimmerman L, Caplan L, Michaud K.
  • rheumatoid arthritis disease activity Patient (PtGA) and Provider (PrGA) Global Assessment of Disease Activity, Disease Activity Score (DAS) and Disease Count Activity Score, with 28-Joint Activity Score, with 28-Joint Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Patient Activity Score (PAS) and Patient Activity Score-II (PASII), Routine Assessment of Patient Index Data (RAPID), Rheumatoid Activity and Arthritis Disease Index (Activity AI) Disease Activity Index-5 (RADAI-5), Chronic Arthritis Systemic Index (CASI), Patient-Based Disease Activity Score With ESR(PDAS1) and Patient-Based Disease Activity Score without ESR (PDAS2), and Mean Overall Index for Rheumatoid Arthritis (MOI-RA).
  • the PA score was significantly higher than the PD score, and the p value was ⁇ 0.001.
  • a total of 175 joints were examined using the PA/US system, including MCP, PIP, MTP and wrist joints.
  • the 16 joints are divided into the highest level of PA imaging and PDUS, that is, the score is 3 points.
  • the score is 3 points.
  • the average value of DAS28 is 4.08
  • the disease activity index is medium
  • the SDAI value is 23.74
  • the disease activity index is medium
  • the CDAI value is 22.01
  • the disease activity index is high.
  • the inventor's preliminary judgment is that the average PDUS score is greater than or equal to The disease activity index at 2.87 is medium or above, and the average PA score is 4.43 or higher.
  • the disease activity index is medium or above.
  • Table 3 lists the correlation between multimodal photoacoustic/ultrasound scores, imaging scores and clinical scores.
  • Table 3 it can be seen that the PA and PD scores are respectively All of them are significantly positively correlated with the three clinical scores, and have passed the hypothesis test, indicating that the PA and PD scores are clinically verified and accurate.
  • Example 2 Rheumatoid arthritis scoring system based on multimodal photoacoustic/ultrasound imaging
  • a scoring system for rheumatoid arthritis based on multi-modal photoacoustic ultrasound imaging including an information acquisition module, an information analysis module, and an output module,
  • the information collection module adopts photoacoustic/ultrasound dual-modality imaging to collect image information of joints in vitro to obtain image information of the local inflammatory area of rheumatoid joints;
  • the information analysis module classifies and calculates the collected image information to obtain the characteristic parameters of the image
  • the judgment output module combines the characteristic parameters of the image to judge the disease activity of patients with rheumatoid arthritis and output data.
  • the information analysis module includes a semi-quantitative scoring module, as well as a local blood oxygen information scoring module, which is used for statistical calculation of the power Doppler ultrasound imaging score and the sum of the photoacoustic imaging scores. Both power Doppler ultrasound imaging scores and photoacoustic imaging scores are used A semi-quantitative scoring system of 0, 1, 2, and 3 points, and the maximum score of each joint is used as the final score of each joint.
  • the local blood oxygen information scoring module is used to calculate or process the local blood oxygen information according to specific standards.
  • the power Doppler ultrasound imaging score and the photoacoustic imaging score are evaluated by the following criteria: no ultrasound/photoacoustic signal, a score of 0; less than 3 ultrasound/photoacoustic signals in the same plane in the hypoechoic area of the synovium, a score of 1. ; Ultrasound/photoacoustic signal detected within half of the hypoechoic area of the synovium, score 2; PD/PA signal detected in more than half of the hypoechoic synovial area, score 3.
  • the local blood oxygen information includes a photoacoustic signal SO 2 image of a thickened inflammatory lesion area of a joint, and the photoacoustic signal SO 2 image is specifically divided into three groups: blue, red, and red and blue. Blue is a hypoxic blood flow signal, the red is a hyperoxic blood flow signal, and the red and blue phases are mixed blood flow signals. Still preferably, the local blood oxygen information further includes a determination result of comparing the oxygen saturation value of the local thickened area of the joint with the surrounding normal tendon.
  • the SO 2 value of the thickened inflammatory area was measured by calculating the ratio of the PA signal pixels in the target area at wavelengths of 750 nm and 830 nm.
  • the joint with the highest PA signal is selected to calculate the SO 2 for each patient. Perform three calculations for each joint and determine the average value as a representative of the oxygenation status of each patient.
  • the patient was classified as hyperoxia with SO 2 value >90%, and hypoxia with SO 2 value ⁇ 85%.
  • the high level of PA signal represents inflammatory activity in the joint. Calculate the PA+SO 2 score and comprehensively judge the degree of inflammation of the patient.
  • Embodiment 3 Rheumatoid arthritis scoring system and equipment based on multimodal photoacoustic/ultrasound imaging
  • a scoring system for rheumatoid arthritis based on multi-modal photoacoustic ultrasound imaging including an information acquisition module, an information analysis module, and an output module,
  • the information collection module adopts photoacoustic/ultrasound dual-modality imaging to collect image information of joints in vitro to obtain image information of the local inflammatory area of rheumatoid joints;
  • the information analysis module classifies and calculates the collected image information to obtain the characteristic parameters of the image
  • the judgment output module combines the characteristic parameters of the image to judge the disease activity of patients with rheumatoid arthritis and output data.
  • the information analysis module includes a semi-quantitative scoring module, as well as a local blood oxygen information scoring module, which is used for statistical calculation of the power Doppler ultrasound imaging score and the sum of the photoacoustic imaging scores. Both power Doppler ultrasound imaging scores and photoacoustic imaging scores are used A semi-quantitative scoring system of 0, 1, 2, and 3 points, and the maximum score of each joint is used as the final score of each joint.
  • the local blood oxygen information scoring module is used to calculate or process the local blood oxygen information according to specific standards.
  • the power Doppler ultrasound imaging score and the photoacoustic imaging score are evaluated by the following criteria: no ultrasound/photoacoustic signal, a score of 0; less than 3 ultrasound/photoacoustic signals in the same plane in the hypoechoic area of the synovium, a score of 1. ; Ultrasound/photoacoustic signal detected within half of the hypoechoic area of the synovium, score 2; PD/PA signal detected in more than half of the hypoechoic synovial area, score 3.
  • the local blood oxygen information includes a photoacoustic signal SO 2 image of a thickened inflammatory lesion area of a joint, and the photoacoustic signal SO 2 image is specifically divided into three groups: blue, red, and red and blue. Blue is a hypoxic blood flow signal, the red is a hyperoxic blood flow signal, and the red and blue phases are mixed blood flow signals. Still preferably, the local blood oxygen information further includes a determination result of comparing the oxygen saturation value of the local thickened area of the joint with the surrounding normal tendon.
  • the present invention also provides a device including the above-mentioned scoring system, including an ultrasonic probe 1 for collecting sound and image information;
  • the receiving module is connected to drive the emission of laser and ultrasound signals, and to receive photoacoustic signals and reflected ultrasound signals for imaging;
  • the processor 3 converts specific parameters of the imaging signal into specific values;
  • the output device 4 outputs specific images and values.
  • the ultrasonic probe 1 includes a phased array probe, a convex array probe, and a linear array probe.
  • the processor 3 is any commercially available charge coupled device capable of converting photoacoustic images into digital signals.
  • the output device 4 is a printer.
  • the local blood oxygen information includes a photoacoustic signal SO 2 image of a thickened inflammatory lesion area of a joint, and the photoacoustic signal SO 2 image is specifically divided into three groups: blue, red, and red and blue. Blue is a hypoxic blood flow signal, the red is a hyperoxic blood flow signal, and the red and blue phases are mixed blood flow signals. Still preferably, the local blood oxygen information further includes a determination result of comparing the oxygen saturation value of the local thickened area of the joint with the surrounding normal tendon.
  • the SO 2 value of the thickened inflammatory lesion area was measured by calculating the ratio of the PA signal pixels in the target area at the wavelengths of 750 nm and 830 nm.
  • the joint with the highest PA signal is selected to calculate the SO 2 for each patient. Perform three calculations for each joint, and determine the average value as a representative of the oxygenation status of each patient.
  • the patient was classified as hyperoxia with SO 2 value >90%, and hypoxia with SO 2 value ⁇ 85%.
  • the high level of PA signal represents inflammatory activity in the joint. Calculate the PA+SO 2 score and comprehensively judge the degree of inflammation of the patient.
  • the comprehensive score of the patient by the method of this application is low, the disease activity level is low, and the multimodal photoacoustic/ultrasound score is consistent with the clinical score.
  • a 68-year-old male RA patient (the second) was selected in June 2019, complaining of pain in both fingers and wrist joints. A total of 7 joints with obvious clinical manifestations were examined. The results are shown in Figure 7-9.
  • the synovium of the MCP2 joint cavity is significantly thickened, the photoacoustic (PA) score is 2 points, the color Doppler (PD) score is 2 points, the PIP2 and PIP3 joint synovium is thickened, and the photoacoustic (PA) score is 2 points.
  • PA) score is 2 points, color Doppler (PD) score is 1 point, wrist synovial membrane is obviously thickened, photoacoustic (PA) and color Doppler (PD) can show abundant blood flow signals, both scores are 3. Minute.
  • the patient’s DAS28 score was 6.28 points, SDAI was 51.60 points, CDAI was 39.00 points, SO 2 value: 97.33 (hyperoxia), PA+SO 2 score was 3 points, the patient’s comprehensive score was higher by the method of this application, and the disease The activity level is in a highly active period, and further medication is needed.
  • the patient's multimodal imaging examination results showed that the color Doppler ultrasound semi-quantitative scoring results and the photoacoustic semi-quantitative scoring results were basically the same, and consistent with the clinical score.
  • DAS28 score was 4.83 points
  • SDAI was 29.94 points
  • CDAI was 29.30 points
  • PA+SO 2 score was 4 points
  • the patient had a high comprehensive score by the method of this application, and disease activity The level is in a period of high activity, and further medication is needed.
  • the patient's multimodal imaging examination results showed that the color Doppler ultrasound semi-quantitative scoring results and the photoacoustic semi-quantitative scoring results were basically the same, and consistent with the clinical score.
  • the multi-modal photoacoustic/ultrasound imaging rheumatoid arthritis scoring system, equipment and application of the present invention can be used in industry and have industrial practicability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Medical Informatics (AREA)
  • Surgery (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Dentistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Optics & Photonics (AREA)
  • Acoustics & Sound (AREA)
  • Radiology & Medical Imaging (AREA)
  • Ultra Sonic Daignosis Equipment (AREA)

Abstract

L'invention concerne une application, un dispositif et un système d'évaluation par score de la polyarthrite rhumatoïde faisant appel à l'imagerie photoacoustique/ultrasonore multimodale. L'application comprend les étapes suivantes consistant à : (1) collecter des informations d'images d'articulations au moyen d'une imagerie bimodale photoacoustique/ultrasonore à l'extérieur d'un corps ; (2) analyser les informations d'images collectées et les données cliniques pour une évaluation par score photoacoustique/ultrasonore multimodale ; et (3) déterminer l'activité d'une maladie chez un patient atteint de polyarthrite rhumatoïde sur la base de l'évaluation par score photoacoustique/ultrasonore multimodale en association avec des informations locales d'oxygénation du sang. Le système multimodal utilise une sonde photoacoustique/ultrasonore portative, et est ainsi conforme aux habitudes d'utilisation des cliniciens ; de plus, un système d'imagerie photoacoustique/ultrasonore multimodale est utilisé pour la première fois dans l'évaluation de la polyarthrite rhumatoïde. Des articulations caractéristiques sont utilisées pour l'évaluation, et leur sélection est cohérente avec l'approche internationale de sélection d'articulations pour l'évaluation par ultrasons, et le processus de mise en œuvre et le processus de calcul sont simples et réalisables, ce qui permet de faciliter l'implantation clinique.
PCT/CN2020/071294 2019-10-18 2020-01-10 Application, dispositif et système d'évaluation par score de la polyarthrite rhumatoïde faisant appel à l'imagerie photoacoustique/ultrasonore multimodale Ceased WO2021073003A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN201910995355.1 2019-10-18
CN201910995355.1A CN110613430A (zh) 2019-10-18 2019-10-18 多模态光声/超声成像的类风湿性关节炎评分系统及应用
CN201921756110.5 2019-10-18
CN201921756110 2019-10-18
CN201922329244.5 2019-12-23
CN201911338339.1 2019-12-23
CN201911338339.1A CN111134619B (zh) 2019-10-18 2019-12-23 多模态光声/超声成像的类风湿性关节炎评分系统及应用
CN201922329244 2019-12-23

Publications (1)

Publication Number Publication Date
WO2021073003A1 true WO2021073003A1 (fr) 2021-04-22

Family

ID=75537708

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/071294 Ceased WO2021073003A1 (fr) 2019-10-18 2020-01-10 Application, dispositif et système d'évaluation par score de la polyarthrite rhumatoïde faisant appel à l'imagerie photoacoustique/ultrasonore multimodale

Country Status (2)

Country Link
LU (1) LU102579B1 (fr)
WO (1) WO2021073003A1 (fr)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080173093A1 (en) * 2007-01-18 2008-07-24 The Regents Of The University Of Michigan System and method for photoacoustic tomography of joints
EP2749209A1 (fr) * 2012-12-28 2014-07-02 Canon Kabushiki Kaisha Appareil d'acquisition d'informations d'objet, procédé d'affichage et programme
CN104023635A (zh) * 2011-12-30 2014-09-03 皇家飞利浦有限公司 用于在us成像中使用pa效应进行针导航的系统和方法
US20160135782A1 (en) * 2014-11-14 2016-05-19 General Electric Company Finger joint ultrasound imaging
US20160220710A1 (en) * 2015-01-30 2016-08-04 The Regents Of The University Of Michigan Compositions and methods for delivering pharmaceutical agents
JP2018015262A (ja) * 2016-07-28 2018-02-01 国立大学法人京都大学 光音響イメージング装置
CN109998484A (zh) * 2019-02-27 2019-07-12 广东工业大学 一种多功能关节炎检测与治疗系统及其方法
CN209285474U (zh) * 2018-10-09 2019-08-23 深圳先进技术研究院 光声成像探头及光声成像系统
CN110613430A (zh) * 2019-10-18 2019-12-27 中国医学科学院北京协和医院 多模态光声/超声成像的类风湿性关节炎评分系统及应用

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080173093A1 (en) * 2007-01-18 2008-07-24 The Regents Of The University Of Michigan System and method for photoacoustic tomography of joints
CN104023635A (zh) * 2011-12-30 2014-09-03 皇家飞利浦有限公司 用于在us成像中使用pa效应进行针导航的系统和方法
EP2749209A1 (fr) * 2012-12-28 2014-07-02 Canon Kabushiki Kaisha Appareil d'acquisition d'informations d'objet, procédé d'affichage et programme
US20160135782A1 (en) * 2014-11-14 2016-05-19 General Electric Company Finger joint ultrasound imaging
US20160220710A1 (en) * 2015-01-30 2016-08-04 The Regents Of The University Of Michigan Compositions and methods for delivering pharmaceutical agents
JP2018015262A (ja) * 2016-07-28 2018-02-01 国立大学法人京都大学 光音響イメージング装置
CN209285474U (zh) * 2018-10-09 2019-08-23 深圳先进技术研究院 光声成像探头及光声成像系统
CN109998484A (zh) * 2019-02-27 2019-07-12 广东工业大学 一种多功能关节炎检测与治疗系统及其方法
CN110613430A (zh) * 2019-10-18 2019-12-27 中国医学科学院北京协和医院 多模态光声/超声成像的类风湿性关节炎评分系统及应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HUANG DOUDOU, QIU QI; LIN WENZHEN; LIU JIYAN; HUANG YALI; ZHAO QINGLIANG: "Recent Advances in Biomedical Applications of Dual-Modality Photoacoustic/Ultrasound Imaging Technology", THE JOURNAL OF LIGHT SCATTERING, vol. 31, no. 1, 1 March 2019 (2019-03-01), pages 1 - 10, XP055801383, DOI: 10.13883/j.issn1004-5929.201901001 *
WEN CHAOMEI: "Application of Ultrasound in the Evaluation of Finger, Toe and Wrist Joints Involvement in Patients with Rheumatoid Arthitis", CHONGQING MEDICAL UNIVERSITY MASTER'S THESES, 1 May 2016 (2016-05-01), XP055801371 *
XIAO JIAYING: "Quantitative Photoacoustic Tomography and Its Application to the Diagnosis of Osteoarthritis", CENTRAL SOUTH UNIVERSITY DOCTORAL DISSERTATIONS, 1 January 2011 (2011-01-01), XP055801376 *

Also Published As

Publication number Publication date
LU102579B1 (en) 2021-06-30
LU102579A1 (en) 2021-04-22

Similar Documents

Publication Publication Date Title
CN111134619B (zh) 多模态光声/超声成像的类风湿性关节炎评分系统及应用
Fell et al. Ultrasonic duplex scanning for disease of the carotid artery.
Wang et al. Quantitative assessment of skin stiffness in localized scleroderma using ultrasound shear-wave elastography
Yang et al. Assessment of diffuse thyroid disease by strain ratio in ultrasound elastography
Wang et al. Quantitative analysis of pleural line and B-lines in lung ultrasound images for severity assessment of COVID-19 pneumonia
Gao et al. Comparison of superb microvascular imaging to conventional color Doppler ultrasonography in depicting renal cortical microvasculature
Huang et al. Multimodal PA/US imaging in Rheumatoid Arthritis: Enhanced correlation with clinical scores
RU2499560C1 (ru) Способ диагностики метастатического поражения сторожевого лимфатического узла при раке щитовидной железы
CN111599467A (zh) 模型训练方法、装置、电子设备及介质
Olchowy et al. Dentists can provide reliable shear wave elastography measurements of the stiffness of masseter muscles: A possible scenario for a faster diagnostic process
Sabr et al. Role of ultrasound in diagnosis of thoracic outlet syndrome: a review article
Fukae et al. Screening for rheumatoid arthritis with finger joint power Doppler ultrasonography: quantification of conventional power Doppler ultrasonographic scoring
LU102579B1 (en) Rheumatoid arthritis (ra) scoring system based on multimodal photoacoustic/ultrasonic imaging, device having same, and application thereof
Zou et al. Diagnostic accuracy of ultrasound in carpal tunnel syndrome: analysis of established and novel parameters
Qiu et al. Ultrasound shear wave viscoelastic imaging combined with shear wave elastography for characterization of focal liver lesions
Xu et al. Ultrasonography of the rectus femoris, a tool to assess the severity of sarcopenia in lung cancer patients: An observational study
Xiao et al. Deep learning-based automated detection and diagnosis of gouty arthritis in ultrasound images of the first metatarsophalangeal joint
Ghannam et al. Exploring the Utility of Optoacoustic Imaging in Differentiation of Benign and Malignant Breast Masses: Gen 2 Study
CN112998651B (zh) 光声成像在乳腺肿瘤评分系统中的应用及评分系统
Zhang et al. Oxygenation-driven multimodal photoacoustic/ultrasonic imaging enhances evaluation of enthesitis disease activity in psoriatic arthritis.
Liu et al. Contrast‐Enhanced Ultrasound Evaluation of Lymphatic Function in Breast Cancer‐Related Lymphedema: A Comparative Study With Normal Controls
Luo et al. Efficacy Assessment and Influencing Factors on Superb Microvascular Imaging (SMI) Microflow Patterns in Solid Thyroid Nodules: What Matters?
WO2021017418A1 (fr) Application de l'imagerie photoacoustique tridimensionnelle dans un système et un dispositif de classification de tumeur mammaire
Liu et al. Evaluation of treatment response in oral chronic graft-versus-host patients by power doppler ultrasound: a prospective study
Elma et al. Dynamic microvascular imaging with provocative testing in lateral epicondylitis: associations with tendon vascularity and clinical severity

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: LU102579

Country of ref document: LU

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20877993

Country of ref document: EP

Kind code of ref document: A1

WWG Wipo information: grant in national office

Ref document number: LU102579

Country of ref document: LU

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20877993

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205 DATED 29.11.2022)

122 Ep: pct application non-entry in european phase

Ref document number: 20877993

Country of ref document: EP

Kind code of ref document: A1