Antenna array or group of antenna elements for biomarker monitoring, neurostimulation and methods of use

Abstract

Provided herein are systems, methods, and devices for biomarker monitoring, antenna array or antenna element group for neural stimulation, and methods of use.

Description

Background Technology

[0001] This invention generally relates to antennas and monitoring devices.

[0002] Many research groups have investigated the potential of radio frequency reflection technology in measuring blood glucose levels. Buford Randall Jean and Eric C, Green of Baylor University explored using antennas to estimate glucose levels. They tested different antenna designs and compared results for each sensor with standard and modified blood components. The optimal design was chosen based on the maximum offset of S11 and S2l as a function of the blood's dielectric constant. A single-spiral microstrip designed to resonate at 1.5 GHz showed changes in its response when exposed to materials with different dielectric constants.

[0003] Another RF system was developed by J. Venkataraman and M. Sidley of the Rochester Institute of Technology. Their device consists of a microstrip antenna mounted on the patient's arm.

[0004] In their early research, they tested three different types of antennas to determine which one delivered the best results in monitoring changes in glucose levels. First, they designed and tested helical and serpentine antennas at 2.45 GHz. Later, they developed a planar dipole with a resonant frequency of 1.4 GHz, which outperformed the two previous designs. For a shift in glucose concentration of 14.62 mg / dl, they were able to achieve a resonant frequency shift of 1 MHz.

[0005] Jinjin Shao et al. proposed a four-armed helical microstrip antenna to detect changes in glucose concentration. It aims to resonate at 5 GHz with a very narrow bandwidth. They tested their sensor using a finger model in HFSS by changing its relative permittivity in steps of 0.01. Their sensor achieved very small frequency shifts. MS Ali et al. investigated another RF sensor to monitor changes in glucose. They designed an ultrawideband rectangular patch antenna that resonates at 4.7 GHz with a bandwidth of 8.77 GHz, ranging from 3.23 to 12 GHz, and a gain of 6.09 dB. Their sensor consists of two UWB planar antennas and signal processing techniques based on artificial neural networks to predict glucose levels.

[0006] HC Garcia et al. [8], in collaboration with mediwise, designed another non-invasive technology. The sensor consists of two rectangular microstrip patch antennas measuring 1.5 x 1.5 mm, designed for resonance at 60 GHz. The sensor was used to monitor several concentrations of water-based glucose-loaded liquid samples sealed in an acrylic container. Recently, they tested the sensing device in their patent during an in vivo intravenous glucose tolerance test (IVGTT). They were able to detect a sensitivity of 1.33 mmol / L (24 mg / dL) in the water-based glucose-loaded liquid sample and 4 mmol / L (= 72 mg / dL) in a clinical trial. This invention attempts to address these and other issues. Summary of the Invention

[0007] This article provides systems, methods, and apparatus for antenna design for biomarker monitoring.

[0008] Some of the methods, systems, and apparatuses described above are set forth in the following description, and others will be apparent from the description or may be learned by practice of these methods, apparatuses, and systems. The advantages of the methods, apparatuses, and systems will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only, and not intended to limit the claimed methods, apparatuses, and systems. Attached Figure Description

[0009] In the accompanying drawings, in several preferred embodiments of the invention, the same elements are identified by the same reference numerals.

[0010] Figure 1A This is a schematic diagram showing the antenna sensor and feed line; Figure 1B yes Figure 1A The terminal S-parameter curve.

[0011] Figure 2 It displays the leg veins, the parallel peroneal veins, and the parallel posterior tibial veins.

[0012] Figure 3A This is a schematic diagram illustrating a sensor array according to one embodiment; and Figure 3B yes Figure 3A The terminal S-parameter curve.

[0013] Figures 4A-4B It is a terminal S-parameter curve of the signal antenna element 100, including the ranges of εr of approximately 2.99 and εr of approximately 2.33.

[0014] Figure 5It is a diagram of the terminal S-parameters of an antenna array 200 including at least four sensor elements, corresponding to a sensitivity of approximately εr of approximately 2.33.

[0015] Figure 6A This is a schematic diagram illustrating an implementation of a longer sensor element; and Figure 6B yes Figure 6A The terminal S-parameter curve.

[0016] Figure 7A This is a schematic diagram illustrating an implementation of a longer sensor array; and Figure 7B yes Figure 7A The terminal S-parameter curve.

[0017] Figure 8A This is a SAR field diagram, showing... Figure 8B The sensor array implementation shown in the figure has a power value of 1W.

[0018] Figure 9A This is a schematic diagram illustrating the configuration of a sensor array including different sensors; and Figure 9B yes Figure 9A The terminal S-parameter curve.

[0019] Figure 10A This is a schematic diagram illustrating the configuration of a sensor including different sensor slot portions operatively connected to a single substrate, and Figure 10B yes Figure 10A The terminal S-parameter curve.

[0020] Figure 11 This indicates when the load comes from Figure 9A The figure shows the S11 measured by the human model of the sensor.

[0021] Figure 12 This is a photograph of a sensor embodiment 200 according to one implementation, which uses a flexible substrate design for easy insertion into a sock. Detailed Implementation

[0022] The foregoing and other features and advantages of the present invention will become apparent from the following detailed description of exemplary embodiments, which are read in conjunction with the accompanying drawings. The detailed description and drawings are merely illustrative and not limiting of the invention, the scope of which is defined by the appended claims and their equivalents.

[0023] Embodiments of the invention will now be described with reference to the accompanying drawings, wherein like reference numerals consistently reflect like elements. The terminology used in the description presented herein is not intended to be interpreted in any limiting or restrictive manner, but merely because it is used in conjunction with the detailed description of certain particular embodiments of the invention. Furthermore, embodiments of the invention may include several novel features, none of which alone is responsible for its desired properties or is essential for practicing the invention described herein.

[0024] Unless otherwise stated herein or clearly contradicted by the context, the terms “a / an” and “the” and similar designations used in the context of describing the invention should be interpreted as including both the singular and plural. It should also be understood that the terms “comprises,” “comprising,” “includes,” and / or “including”, when used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0025] Unless otherwise stated herein, the enumeration of value ranges herein is intended only as a shorthand method of individually referring to each individual value falling within that range, and each individual value is incorporated into the specification as if it were individually referenced herein. When accompanied by numerical values, the term “about” should be interpreted as indicating a deviation from the specified numerical value by up to and including 10%. Unless otherwise stated, the use of any and all instances or exemplary language (“e.g.” or “such as”) provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention. No language in the specification should be construed as indicating that any unclaimed element is essential for the practice of the invention.

[0026] References to "one embodiment," "implementation," "exemplary embodiment," "various embodiments," etc., may indicate that one or more embodiments of the invention described herein may include specific features, structures, or characteristics, but not every embodiment must include specific features, structures, or characteristics. Furthermore, the repeated use of the phrases "in one embodiment" or "in an exemplary embodiment" does not necessarily refer to the same embodiment, although they may refer to the same embodiment.

[0027] As used herein, the term "method" means the manner, means, technique, and procedure for accomplishing a given task, including but not limited to those manner, means, techniques, and procedures known to or readily developed from known methods, means, techniques, and procedures in the fields of chemistry, pharmacology, biology, biochemistry, and medicine. Unless expressly stated otherwise, it is not intended to interpret any method or aspect set forth herein as requiring its steps to be performed in a particular order. Therefore, unless a method claim specifically states in the claim or specification that the steps are limited to a particular order, it is not intended to infer the order in any way. This applies to any possible non-express basis for interpretation, including logical questions regarding the arrangement of steps or operational procedures, the simple meaning of atomic grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0028] Antenna designs for biomarker monitoring measure biological and chemical biomarkers and tracers in blood, including glucose concentration, without any blood extraction. These designs utilize non-invasive methods employing radio frequency and antenna circuitry and systems. Antenna designs for biomarker monitoring are wearable devices, which can be gloves, semi-gloves, or socks, or any similar wearable devices, that can non-invasively measure these blood physiological biomarkers, such as glucose levels, in both transient and continuous modes.

[0029] This device and its design continuously measure biological and chemical biomarkers and other tracers in the bloodstream to perform physiological and pathophysiological screening for health and disease in a non-invasive manner. Biomarkers can include novel / exotic / malignant or non-malignant cells or other newly developed molecules that may not be part of the typical components of the biological system. Biomarkers can be tracked not only in the blood but also in other parts of the biological system, such as saliva, tissues, etc.

[0030] As used herein, biomarker is a broad term and should be given its common and conventional meaning (and not limited to a specific or custom-defined meaning) to those skilled in the art, and also refers to, but not limited to, substances or chemical components in biological fluids (e.g., blood, interstitial fluid, cerebrospinal fluid, lymph, or urine) that can be analyzed. Biomarkers can include naturally occurring substances, artificial substances, metabolites, and / or reaction products. In some embodiments, a biomarker is a biomarker used for measurement by a sensor head, device, and method. However, other biomarkers were also considered, including but not limited to: prothrombin; acylcarnitine; adenine transphosphoribosylase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profile (arginine (Krebs cycle), histidine / uric acid, homocysteine, phenylalanine / tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecone (cocaine); biotinylate; biopterin; C-reactive protein; carnitine; pro-BNP; BNP; troponin; carnosine; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-hydroxycholic acid; cortisol; creatine kinase; creatine kinase MM isoenzyme; cyclosporine A; d-penicillamine; deethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylation polymorphism, alcohol dehydrogenase, α1-antitrypsin, cystic fibrosis, Duchenne / Becker muscular dystrophy, analyte-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, β-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax) Plasmodium v1vax), sex differentiation, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diphtheria / tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids / acylglycines; free human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free triiodothyronine (FT3); fumarate acetylacetase; galactose / gal-1-phosphate; galactose-1-phosphate uridine transferase; gentamicin; analyte-6-phosphate dehydrogenase; glutathione; glutathione peroxidase; glycocholic acid; glycated hemoglobin; halofantrine; hemoglobin variants; hexosaminease A; human erythrocyte carbonic anhydrase 1 ; 17-α-hydroxyprogesterone; hypoxanthine phosphoribosyltransferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a), B / A-1, β); lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin; phytanoic acid / norphytanoic acid; progesterone; prolactin; aminoacylproline dipeptidase; purine nucleoside phosphorylase; quinine; reverse triiodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; somatostatin C; specific antibodies (adenovirus, antinuclear antibody, antizeta antibody, arbovirus, Aujeszky virus, dengue virus, dracunculiae of Medina) Dracunculus medinensis Echinococcus granulosus ( Echinococcus granulosus ), Entamoeba histolytica, enteroviruses, Giardia lamblia ( Giardia duodenalisa Helicobacter pylori ( Helicobacter pylori Hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani (He ... Leishmania donovani ), Leptospira ( leptospira ), measles / mumps / rubella, Mycobacterium leprae ( Mycobacterium leprae Mycoplasma pneumoniae () Mycoplasma pneumoniae ), myoglobin, and *Discocera spiralis* ( Onchocerca volvulus Parainfluenza virus, Plasmodium falciparum ( Plasmodium falciparum ), poliovirus, Pseudomonas aeruginosa ( Pseudomonas aeruginosa ), respiratory syncytial virus, rickettsia ( rickettsia (Typhus), Schistosoma mansoni ( Schistosoma mansoni ), Toxoplasma gondii ( Toxoplasma gondii ), pale spirochetes ( Trepenoma pallidium Trypanosoma cruzi (), Trypanosoma cruzi () Trypanosoma cruzi Trypanosoma bluei ( ) / Trypanosoma bluei Trypanosoma rangeli), vesicular stomatitis virus, Bancroftian filariasis (W) uchereria bancrofti (Hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyroid-stimulating hormone (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; leukocytes; and zinc porphyrin. In some embodiments, naturally occurring salts, sugars, proteins, fats, vitamins, and hormones in blood or interstitial fluid may also constitute biomarkers. Biomarkers can be naturally present in biological fluids, such as metabolites, hormones, antigens, antibodies, etc. Alternatively, biomarkers can be introduced into the body, such as contrast agents for imaging, radioactive isotopes, chemical reagents, fluorocarbon-based synthetic blood, or drugs or pharmaceutical compositions, including but not limited to insulin; ethanol; anabolic steroids; and nicotine. Metabolites of drugs and pharmaceutical compositions are also considered biomarkers. It can also analyze biomarkers generated in the body, such as neurochemicals and other chemicals, such as ascorbic acid, uric acid, dopamine, norepinephrine, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA).

[0031] Examples of pathophysiological changes leading to disease include, but are not limited to, hyperglycemia / diabetes, hypercholesterolemia, and heart disease. Biomarkers and other biological changes involve measuring changes in glucose levels, cholesterol levels, Pro-BNP (brain natriuretic peptide), and troponin levels, as well as other molecular biomarkers in living tissue. For example, in diabetes, the proposed prototype is envisioned to help monitor transient glucose levels for: determining changes in blood glucose and their variation relative to normal values; and for autonomous interventions, such as insulin injections; and for providing improved and self-controlled disease management for patients with diabetes. Therefore, along with estimates of volumetric concentration, the device monitors the rate of change in concentration to predict potential hyperglycemia and hypoglycemia as early as possible.

[0032] The embodiments disclosed herein measure biological and chemical markers and tracers in blood, including but not limited to glucose concentration, without any blood extraction. A non-invasive method using radio frequency and antenna circuitry and systems is a wearable device, which may be a sock, or any similar wearable device, that can non-invasively measure these blood physiological markers in a transient and continuous manner.

[0033] The sensor comprises an antenna array having a number of elements or groups of antenna elements, biologically configured via arteries and veins and / or nerves at specific locations in the human body. The sensor can be used to stimulate specific nerves for therapeutic purposes, muscle spasms, pain management in peripheral neuropathy, and other applications using non-invasive monitoring or non-invasive nerve stimulation at the same frequency and power level used for glucose monitoring.

[0034] Antenna arrays or groups of antenna elements can be homogeneous, heterogeneous, uniform, or non-uniform to fit specific locations within the human anatomy or vascular system.

[0035] In one implementation, the antenna element or array element is biologically configured from the arteries and veins in the lower leg to continuously and non-invasively detect the concentration of blood components in the human bloodstream via electromagnetic radiation. Blood components include, but are not limited to, glucose, cholesterol, lactate, and many other components.

[0036] In another implementation, the antenna element or array element is configured with a neural topology that can be used to stimulate specific nerves for treatment, muscle spasms, pain management of peripheral neuropathy, and other applications of non-invasive monitoring or non-invasive nerve stimulation.

[0037] In another embodiment, the antenna element or array element is configured with a neural topology and an arterial or venous topology for both blood component monitoring and neural stimulation, with a portion of the element targeting a vascular system network and other portions of the same element targeting a neural topology. The power and frequency used for neural monitoring and stimulation are the same as those used for biomarker monitoring, between approximately 0.5 GHz and approximately 4 GHz, and have the same power level (SAR limit = 1.6 W / kg).

[0038] In another embodiment, the elements in the sensor reflect the shape of the parallel fibular veins and the posterior tibial veins. In one embodiment, the sensor is used to emit electromagnetic waves into human tissue in a region immediately adjacent to the main parallel veins, in order to better monitor and detect changes in blood component concentrations compared to other embodiments that do not track venous structures. In one embodiment, the sensor slot corresponds to the anterior tibial veins and the posterior tibial veins.

[0039] In another embodiment, the antenna array or antenna element group consists of homogeneous or non-uniform array elements with a topology that optimally tracks the underlying target vascular system or neural anatomy. In another embodiment, a heterogeneous antenna element group is designed in a uniform or non-uniform array with a topology that matches the target's underlying vascular system or neural anatomy.

[0040] In another embodiment, the antenna array or antenna element group consists of elements of a linear antenna, loop antenna, broadband antenna, traveling wave antenna, frequency-independent, miniature, fractal, aperture, microstrip patch, tunable (active), reconfigurable, passive, or integrated antenna.

[0041] In another embodiment, the antenna array topology or configuration includes any distribution, including but not limited to: linear, planar, or circular distribution.

[0042] In another embodiment, an antenna array or group of antenna elements is disposed on a textile or any other type of substrate to form socks or any type of wearable or apparel.

[0043] In another embodiment, the antenna is designed to operate in different frequency bands, including below or above UHF and microwave, an example of which could be the mm wave region.

[0044] In another embodiment, the antenna array or antenna element group comprises at least four sensor elements or at least four different sensor elements with different slot designs or slot configurations. The antenna array or antenna element group operates at multiple frequencies within the microwave region. In particular, the antenna is designed to operate in the UHF, L-band, and lower S-band range between 500 MHz and 4 GHz.

[0045] In another embodiment, the antenna array or antenna element group is disposed on a flexible dielectric substrate for easy placement into socks or leg accessories.

[0046] In another embodiment, the elements of the antenna array or antenna element group are microstrip patch antennas composed of a network of slots representing veins in the lower leg. In one embodiment, the array elements consist of homogeneous or identical slots that best track the underlying target vascular system anatomy. In another embodiment, an antenna element group is designed with different slots that match the target's underlying vascular system anatomy.

[0047] In other implementations, the slot design is adjusted to accommodate the physiological functions of multiple users by relying on a stretchable antenna material. For example, socks with an embedded stretchable antenna array can be stretched to fit the venous topology of a particular user.

[0048] In another embodiment, a computer program is used to convert signals measured from an antenna array or group of antenna elements. This computer program allows the amplitude and phase of reflected and / or transmitted signals to be converted into the concentration of blood components via a trained model.

[0049] The antenna design for monitoring includes sensor 100, such as Figure 1AAs shown, according to one embodiment, it comprises an antenna including multiple slots corresponding to arteries and veins in the human leg to continuously and non-invasively detect the concentration of blood components in the human bloodstream via electromagnetic wave radiation. In other embodiments, the antenna design may include multiple slots corresponding to arteries and veins in other anatomical structures such as the foot, arm, leg, neck, etc. The correspondence between the slots and the underlying venous structures allows the antenna to focus / enhance the sensing mechanism on multiple key vascular structures while minimizing direct interaction with non-critical areas. Therefore, the sensor's sensitivity to changes in blood components in the underlying vessels is increased. The sensor 100 includes a first slotted arc portion 110 and a second slotted arc portion 120. The first slotted arc portion 110 and the second slotted arc portion 120 are directly connected via a top slot 102. The first slotted arc portion 110 corresponds to the shape of the peroneal parallel vein, and the second slotted arc portion 120 corresponds to the shape of the posterior tibial parallel vein. The first slotted arc portion 110 includes a long slotted main branch 112 connected to a distal curved branch 114. The distal curved branch 114 may include a curvature angle between approximately 55 degrees and approximately 120 degrees. The long, slotted main branch 112 connects to the top slot 102, which is generally V-shaped and entirely corresponds to the shape of the peroneal parallel vein or lateral perforating vein, such as… Figure 2 As shown in the diagram. The second slotted arc 120 includes a second long main branch 122 corresponding to the posterior or anterior tibial parallel vein. The second long main branch 122 includes a second distal tortuous branch 124. In one embodiment, the first slotted arc 110 is a fibular parallel vein groove including a length of about 25 mm and a groove width between about 0.5 mm and about 1 mm. In one embodiment, the second slotted arc 120 is a posterior tibial parallel vein groove including a length of about 21 mm and a groove width between about 0.5 mm and about 1 mm. In one embodiment, the antenna is used to transmit electromagnetic waves into human tissue adjacent to the vein region to better monitor and detect changes in blood component concentrations compared to other embodiments that do not track venous structures. Figure 1A The sensor 100 shown includes, for example, Figure 1B The dielectric constant ε is shown in the figure. r It is approximately 2.99. The dielectric constant (ε) r It is defined as the ratio of the electrical conductivity of a material to the electrical conductivity of free space (i.e., vacuum), and its value can be derived from a simplified capacitor model.

[0050] According to some implementations, the grooves may include a range of geometries, angles, and lengths for all different branches. If groove / design modifications are required, a range of groove widths and spacing between grooves can be provided. Stretching involves stretching the space between two grooves and / or the angle between two grooves to better overlap the grooves and the target underlying veins. Specific desired ranges of grooves / spacing will be grouped. Otherwise, if all desired ranges are covered, the design variations during stretching can be significant. Groove designs can be categorized into several size classes, such as extra-small, small, large, and extra-large, depending on the size of the target underlying anatomy. Flexibility in one implementation allows for matching between standard sizes. Flexibility in another implementation allows for matching based on visual and measurement calibration. In one implementation, the design can be customized and stretchable for children, where stretching enhances coverage of the veins. In this implementation, flexibility allows for stretching of the product as the child grows over a period of several months. Flexibility includes values ​​between about 0.1 GPa and about 10.0 GPa. Polydimethylsiloxane (PDMS), polyethylene terephthalate (PET), polyimide (PI), and parylene, which have excellent flexibility and malleability, can be used as substrates for flexible sensors.

[0051] The parallel peroneal vein and the parallel posterior tibial vein are located in Figure 2 As shown in the diagram. The groove width may correspond to the diameter of the corresponding parallel fibular vein, posterior tibial vein, or anterior tibial vein. The groove width for the parallel fibular vein ranges from about 0.5 mm to about 1.5 mm. The groove width for the posterior tibial vein ranges from about 0.5 mm to about 1.5 mm.

[0052] In one embodiment, the sensor includes an antenna array 200 having a group of a number of elements or antenna elements 100, the elements corresponding to a sensor diameter Ds in the range of about 10.0 mm to about 17.0 mm and a sensor length Ls between about 25.0 mm and about 35 mm, to appropriately cover veins, such as... Figure 3A As shown. In one embodiment, the antenna array 200 has an array diameter Da ranging from about 45.0 mm to about 65.0 mm, and an array length La ranging from about 155 mm to about 190 mm, which may be close to that of a typical small adult woman. In this embodiment, the sensor array 200 includes a first slotted sensor 210, a second slotted sensor 220, a third slotted sensor 230, and a fourth slotted sensor 240. The first slotted sensor 210, the second slotted sensor 220, the third slotted sensor 230, and the fourth slotted sensor 240 may be identical, uniform, or heterogeneous.

[0053] The first slotted sensor 210, the second slotted sensor 220, the third slotted sensor 230, and the fourth slotted sensor 240 may include a slot width of approximately 1.6 mm. Each of these sensors includes a first slotted arc portion 110 and a second slotted arc portion 120 directly connected to the first slotted arc portion 110 via a top slot 102. The first slotted arc portion 110 corresponds to the shape of the fibular parallel vein, and the second slotted arc portion 120 corresponds to the shape of the posterior tibial parallel vein. Further modifications to the first slotted sensor 210, the second slotted sensor 220, the third slotted sensor 230, and the fourth slotted sensor 240 can be obtained from human measurements to define the standard sizes of the fibular parallel vein and the posterior tibial parallel vein. Figure 3A The sensor array 200 shown includes, for example, Figure 3B ε is shown in r It is approximately 2.99.

[0054] In one embodiment, the antenna is a microstrip antenna consisting of a mesh of slots representing veins in a human leg. The antenna is designed using a flexible dielectric substrate for easy insertion into leg coverings. In another embodiment, the antenna slots can be designed behind the foot veins and can be constructed on a flexible substrate to fit into a sock. The antenna includes a helical feed transmission line positioned at the bottom layer of the antenna, having three turns in a helical configuration, thus isolating the transmission line from the sensing surface. The helical feed line enhances the connection between the feed line and the top slot of the antenna. The antenna resonates when loaded with typical human leg tissue to improve its sensitivity to changes in blood composition. Human leg tissue includes layers of skin, fat, blood, muscle, and bone. The antenna operates at multiple frequencies within the microwave region. Specifically, the antenna is designed to operate in the UHF, L-band, and lower S-band range above or below approximately 500 MHz and approximately 3 GHz; alternatively, in the microwave region, examples could be the mm-wave region.

[0055] In one embodiment, the antenna is designed to be multi-band, wherein each component of the antenna is positioned behind the fibular parallel vein and the posterior tibial parallel vein. The helical feed allows activation of different slots and thus enhances the multi-band performance of the antenna. In another embodiment, the antenna is designed to be reconfigurable to cover multiple frequencies within a band ranging from approximately 500 MHz to approximately 3 GHz. Reconfiguration of the antenna is limited to its operating frequency by employing various reconfiguration components such as pin diodes, RF MEMs, varactor diodes, and / or digitally adjustable capacitors. The reconfiguration components are placed in strategic locations along the slots or feeds of the antenna. In another embodiment, mechanical reconfiguration techniques can also be used to reconfigure the operating frequency of the antenna. Such techniques include actuators, piezoelectric transducers, and other techniques to change the spacing between the ground plane and the slots or to alter the length of the slot mesh or feeds by stretching the material constituting the antenna and other means.

[0056] In other implementations, the design can be tailored to accommodate the physiological functions of multiple users by relying on a stretchable antenna material. In one implementation, the sock, along with the embedded stretchable antenna, can stretch to fit the topology of the parallel peroneal and posterior tibial veins of a particular user. Additionally, the sock can be equipped with electromechanical peripheral circuitry to assist in stretching or bending the antenna topology to match human anatomy. Adaptive stretching can be performed by the human eye, with the assistance of medical experts, or automatically via feedback from vein detection circuitry. Vein detection will be based on optical sensors, the vein image will be processed, and the electromechanical circuitry will automatically adjust the stretchable antenna to match the underlying image.

[0057] In one implementation, a stretchable antenna material similar to [1] TY - JOURAU - Chen, ZhiboAU - Xi, JingtianAU - Huang, WeiAU - Yuen, Matthew MFPY - 2017DA - 2017 / 09 / 08TI -Stretchable conductive elastomer for wireless wearable communication applications JO - Scientific Reports SP - 10958VL - 71S - 1Ab] can be used in one implementation.

[0058] The above implementation method allows for random customer design adjustments, thus making the design better suited to different groups of people. The changes in materials under tension can be analyzed and expanded.

[0059] In one implementation, stretching is limited to 10% of the width and length of the slot because stretching both the dielectric and conductive materials affects the device's efficiency, resonant frequency, and matching. Therefore, stretching in either the width or length of the slot does not exceed 10%. Based on TY - JOURAU - Chen, ZhiboAU - Xi, JingtianAU - Huang, WeiAU - Yuen, Matthew MFPY - 2017DA - 2017 / 09 / 08TI - Stretchable conductive elastomer for wireless wearable communication applications JO - Scientific Reports SP -10958VL - 71S - 1AB, as the percentage of stretching increases, the radiation efficiency near the initial resonant frequency shifts monotonically. With increasing strain, the resonant frequency shifts to lower frequencies due to the increase in effective electrical length. Ag-PDMS conductors can be considered hyperelastic materials; therefore, when the antenna is stretched in the longitudinal direction, the width and height shrink proportionally to maintain a constant overall volume during deformation, resulting in reduced impedance matching and thus lower radiation efficiency.

[0060] In some implementations, the design tolerance for stretching can be modified as follows: (a) Tolerance for reduced impedance matching: This can be tolerated as long as the stretched antenna maintains a resonant level moderately below -10 dB. Therefore, the design is configured to maintain a resonant level below -10 dB under maximum stretching conditions. (b) Tolerance for lower radiation efficiency during stretching: This is tolerable to some extent and can be addressed by increasing the input power. (c) Tolerance for changes in the response of the stretched design: This has no impact on sensitivity measurements or glucose level tracking, as the stretched design will be used to measure reference glucose levels and changes. This model was developed independently for the stretched design.

[0061] In another embodiment, such as Figures 4A-4B As shown, according to one embodiment, antenna 100 includes an element corresponding to an artery and vein in a human leg to continuously and non-invasively detect the concentration of blood components in the human bloodstream via electromagnetic wave radiation. The antenna including an element has an εr range of approximately 2.99 to approximately 2.33.

[0062] In another implementation, such as Figure 5As shown, the antenna array 200 includes at least four sensor elements corresponding to arteries and veins in a human leg, for continuously and non-invasively detecting the concentration of blood components in human bloodstream via electromagnetic radiation. The antenna array 200, including at least four elements, has a sensitivity of approximately εr of approximately 2.33.

[0063] In another embodiment, the sensor 100 includes a longer configuration for a length Ls of the sensor 100, such as... Figure 6A As shown in the figure. The sensor includes a first slotted arc portion 110 and a second slotted arc portion 120 directly connected via a top slot 102. The first slotted arc portion 110 includes a longer slotted main branch 112 extending substantially along the length of the substrate 108. A distal curved branch 114 may include a curvature angle between approximately 55 degrees and approximately 120 degrees. The long slotted main branch 112 connects to the top slot 102, which is generally V-shaped and corresponds entirely to the shape of a peroneal parallel vein or a lateral perforating vein. The second slotted arc portion 120 includes a second long main branch 122 corresponding to a posterior tibial parallel vein or anterior tibial parallel vein. The second long main branch 122 includes a second distal curved branch 124. The sensor 100 has a sensitivity of approximately εr of approximately 2.33, such as Figure 6B As shown in the image.

[0064] like Figure 7A As shown, in the third embodiment, the sensor array 200 has a longer length Ls configuration. In this embodiment, the sensor array 200 includes a first slotted sensor 210, a second slotted sensor 220, a third slotted sensor 230, and a fourth slotted sensor 240. The first slotted sensor 210, the second slotted sensor 220, the third slotted sensor 230, and the fourth slotted sensor 240 can be identical, uniform, or heterogeneous. The first slotted sensor 210, the second slotted sensor 220, the third slotted sensor 230, and the fourth slotted sensor 240 can include a slot width of approximately 1.6 mm. The first slotted sensor 210, the second slotted sensor 220, the third slotted sensor 230, and the fourth slotted sensor 240 include a first slotted arc portion 110 and a second slotted arc portion 120 directly connected to the first slotted arc portion 110 via a top slot 102. The first slotted arc portion 110 corresponds to the shape of the fibular parallel vein, and the second slotted arc portion 120 corresponds to the shape of the posterior tibial parallel vein. Further modifications to the first slotted sensor 210, the second slotted sensor 220, the third slotted sensor 230, and the fourth slotted sensor 240 can be obtained from human measurements to define the standard sizes of the parallel fibular veins and the parallel posterior tibial veins. For example... Figure 7A The sensor array 200 shown includes, for example, Figure 7B The value of εr is shown to be approximately 2.33.

[0065] Figure 8A It shows Figure 8BThe sensor array implementation shown in the figure has a power value of 1W.

[0066] like Figure 9A As shown, in a fourth embodiment, the sensor array 300 is configured to include different sensors. In this embodiment, the sensor array 300 includes a first slotted sensor 310, a second slotted sensor 320, a third slotted sensor 330, and a fourth slotted sensor 340. The first slotted sensor 310, the second slotted sensor 320, the third slotted sensor 330, and the fourth slotted sensor 340 are heterogeneous, wherein the first slotted sensor 310 includes a substantially V-shaped configuration applied to the top portions of the fibular parallel veins and the posterior parallel veins. The second slotted sensor 320 includes a substantially parallel slot configuration applied to the top middle portions of the fibular parallel veins and the posterior parallel veins. The third slotted sensor 330 includes a substantially non-parallel slot configuration applied to the bottom middle portions of the fibular parallel veins and the posterior parallel veins. The fourth slotted sensor 340 includes a V-shaped curved slot configuration applied to the bottom portions of the fibular parallel veins and the posterior parallel veins. The fibular parallel vein slot includes a length Ls: between approximately 25 mm for the fourth slotted sensor 340 and approximately 30 mm for the first slotted sensor 310. The fibular parallel vein groove includes a groove width between approximately 1.0 mm and approximately 1.5 mm. The posterior tibial parallel vein groove includes a length Ls between approximately 20 mm of the fourth slotted sensor 340 and approximately 30 mm of the first slotted sensor 310. The posterior tibial parallel vein groove includes a groove width between approximately 1.0 mm and approximately 1.5 mm. Further modifications to the first slotted sensor 310, second slotted sensor 320, third slotted sensor 330, and fourth slotted sensor 340 can be obtained from human measurements to define the standard sizes of the fibular parallel vein and the posterior tibial parallel vein. Figure 9A The sensor array 200 shown includes, for example, Figure 9B The value of εr is shown to be approximately 2.33.

[0067] like Figure 10AAs shown, in a fifth embodiment, the sensor 400 is configured to include different sensor slot portions operatively connected to a single substrate. In this embodiment, the sensor 400 includes a first slotted sensor portion 410, a second slotted sensor portion 420, a third slotted sensor portion 430, and a fourth slotted sensor portion 440. The first slotted sensor portion 410, the second slotted sensor portion 420, the third slotted sensor portion 430, and the fourth slotted sensor portion 440 are heterogeneous, wherein the first slotted sensor portion 410 includes a substantially V-shaped configuration applied to the top portions of the fibular parallel veins and the posterior parallel veins. The second slotted sensor portion 420 includes a substantially parallel slot configuration applied to the top middle portions of the fibular parallel veins and the posterior parallel veins. The third slotted sensor portion 430 includes a substantially non-parallel slot configuration applied to the bottom middle portions of the fibular parallel veins and the posterior parallel veins. The fourth slotted sensor portion 440 includes a V-shaped curved slot configuration applied to the bottom portions of the fibular parallel veins and the posterior parallel veins. The parallel fibular vein groove includes a length Ls between approximately 140 mm and approximately 152 mm. The parallel fibular vein groove includes a groove width between approximately 1.0 mm and approximately 1.5 mm. The parallel tibial vein groove includes a length Ls between 140 mm and approximately 147 mm. The parallel tibial vein groove width is between approximately 1.0 mm and approximately 1.5 mm. Further modifications to the first slotted sensor portion 410, the second slotted sensor portion 420, the third slotted sensor portion 430, and the fourth slotted sensor portion 440 can be obtained from human measurements to define the standard sizes of the parallel fibular and parallel tibial veins.

[0068] like Figure 10A The sensor array 400 shown includes, for example, Figure 10B The value of εr is shown to be approximately 2.33.

[0069] For all the above embodiments, the substrate may be polyethylene terephthalate (PET) with a thickness t = 136 μm, dielectric constant = 2.33, and tangent δ = 5.79e-3. Dimensions may include, but are not limited to, a length of 17.3 cm and a width of 5.6 cm; the frequency range of interest is 0.5–4 GHz. The sensor embodiment includes measurement parameters of the reflectance coefficient (S11): amplitude and phase.

[0070] For all the above embodiments, antenna performance changes when the design topology is altered or reconfigured; however, additional circuitry of the device can detect the response of different frequency scans within a predefined operating range based on the expected stretching distance. The responses from different frequency ranges are then used to develop models to predict glucose or component levels.

[0071] A computer program is used to convert signals measured from an antenna, which allows the amplitude and phase of reflected and / or transmitted signals to the concentration of blood components via a trained model.

[0072] Non-invasive electromagnetic sensors continuously detect the concentration of certain blood components in human bloodstream. The sensors emit electromagnetic waves into human tissue to monitor and detect changes in blood component concentration. The sensor device converts the detected energy into amplitude and phase.

[0073] The sensor device processes the detected amplitude and phase and converts them into concentration. The sensor includes a slot antenna as shown in Figures 1-10. The sensor operates at multiple frequencies within a band ranging from approximately 500 MHz to approximately 1 GHz. The sensor includes a transmission line separate from the sensing surface. The sensor is reconfigurable to cover more frequencies within the band range of approximately 500 MHz to approximately 1 GHz. In one embodiment, the sensor includes slots corresponding to arteries and veins in the human hand. The sensor includes slots corresponding to the shapes of the parallel peroneal vein and the parallel posterior tibial vein, such as... Figure 11 As shown in the image.

[0074] In one implementation, the sensor is designed onto a dielectric substrate. For example... Figure 12 As shown, a sensor designed using a flexible substrate can be easily placed inside a sock. The sensor is connected to a network analyzer to convert the detected energy into amplitude and phase. The sensor is then connected to a signal processing system to convert the amplitude and / or phase into the concentration of blood components.

[0075] According to one embodiment, the sensor is designed to operate while a human leg model is loaded. This makes it more sensitive to changes in blood component levels. The human leg model consists of five layers: skin, fat, blood, muscle, and bone. Here, the design is to accommodate the topology of key regions / organs to enhance its sensitivity. The shape of the antenna corresponds to the veins and arteries of the leg. Specifically, the shape corresponds to the shape of the parallel peroneal veins and the parallel posterior tibial veins. This distribution increases the antenna's sensitivity to changes in blood component levels flowing in the veins and arteries of the lower leg. Multiple slots allow the antenna to operate at multiple frequencies within the UHF and microwave bands, ranging from approximately 500 Hz to approximately 3 GHz, providing a practical window for detecting changes in blood glucose levels in different patients at different frequencies.

[0076] Feeding Method: In one embodiment, the antenna is fed using transmission lines. Transmission lines of different shapes can be used to increase the number of slots connected. For one sensor embodiment, a spiral transmission line, as shown, covers as many slots as possible. This allows the antenna to operate at lower frequencies within the UHF band and introduces additional resonant frequencies. (This increases the simulation of spiral and periodic transmission lines as well as simple straight transmission lines.) According to one embodiment, a coaxial feeding method can be used to improve the sensor's feeding system.

[0077] Other implementations of the feeder can be designed to ensure matching while allowing crossovers between different slots and feeders.

[0078] Sensor substrate: In one embodiment, the antenna, along with various sensors (humidity, sweat, temperature, etc.), is mounted inside a sweat-proof / moisture-proof sock. The sensors are designed on a very thin dielectric substrate. The same sensors can be designed on a flexible substrate to accommodate the shape of each patient's hand. Flexible antennas can also be designed using adhesive flexible materials such as silicon layers, skin-mounted adhesives, and then directly fixed to the patient's hand. "Flexible" refers to the property of being easily bent without breaking, and includes bending radii between approximately 5 mm and approximately 1000 mm. Flexible plastic substrates, such as polyimide, PEEK, polyester (PET), polyimide (PI), polyethylene naphthalate (PEN), and polyetherimide (PEI), along with various fluoropolymers (FEP) and copolymers or transparent conductive polyester films, allow the antenna and sensor to conform to the desired shape or bend during use. An alternative to flexible substrates is to thin conventional silicon substrates to tens of micrometers using various etching techniques to achieve reasonable flexibility, known as flexible silicon (-5 mm bending radius).

[0079] Adjustments for different patients: The response of the antenna is expected to depend on many criteria changing from one patient to another, including but not limited to: skin thickness, color, type (hairy and hairless skin); skin perfusion, hydration; sweating; patient's metabolic rate and body mass index; and other medical conditions such as cholesterol, diabetes.

[0080] To adjust the antenna's response, signal processing techniques are first used to detect the linear region, and then the antenna's resonant frequency is adjusted to cover that region. The reconfigurable resonant frequency improves the sensor's sensitivity and makes it more personalized for each patient.

[0081] Possible alternative implementations of the design: Since the sensor can detect changes in dielectric constant, it can be used in various applications such as: blood glucose detection and any other blood biomarkers, hydration monitoring / blood flow monitoring, cholesterol, fracture healing monitoring, cardiac activity: heart rate, blood pressure, and material / liquid properties. A similar design could be used for radiation-based localized application of drugs, in combination or without combination, to specific potential patterns / structures.

[0082] Measurement metrics: The sensor is connected to a network analyzer to convert the detected energy into amplitude and phase. For the antenna, S11 parameters are detected, including but not limited to amplitude, phase, or impedance, and the power level is determined.

[0083] Predictive modeling for selecting key features: Sensors are connected to a signal processing system to convert amplitude and / or phase into the concentration of blood components. Predictive modeling for selecting key features includes: 1) measuring S11 parameters using sensors; 2) preprocessing data outliers and removing noise using different techniques (wavelet, moving average filter, or other types of filters); 3) extracting features; 4) modeling, calibration, and tuning; and 5) recalibrating the model to improve accuracy.

[0084] Data preprocessing includes outlier and noise removal using various techniques (wavelet, moving average filter, or other types of filters); extracted features, including S11 amplitude, S11 phase, and / or impedance, are sampled into different frequency components. The features are then normalized (between -1 and 1): reference values ​​are removed (e.g., values ​​corresponding to a glucose concentration of 80 mg / dL); the average of each metric is removed; and the data is divided by the maximum value of each metric.

[0085] Modeling, calibration, and tuning include regularized regression, used in one implementation to predict glucose concentration (Lasso, PLS, mixed models, etc.). Single-feature and multi-feature models can be used in some implementations. Time-based models can also be used.

[0086] In one embodiment, the antenna is a rigid antenna with the following substrate parameters: Rogers RO3203, thickness t = 0.51 mm, dielectric fa = 3.02; (due to the manufacturing method of this type of substrate, the thickness and dielectric value may vary by + / - 5%.) Therefore, the thickness t can be between about 0.45 mm and about 0.54 mm; and the dielectric fa is between about 2.80 and about 3.20. In one embodiment, the dimensions are: 70 * 70 * 0.51 mm³; the feed is helical; the frequency range of interest is about 0.5 GHz to about 3 GHz; the measured parameters are: reflection coefficient (S11): amplitude and phase. The dimensions can range from about 50-100 mm in width and length, and about 0.2 mm to 1.0 mm in thickness. According to one embodiment, alternative substrate materials can be used and the antenna components need to be redesigned.

[0087] The specific substrate RO3203 is available in four different standard thicknesses: (0.25 mm), 0.020" (0.50 mm), 0.030" (0.75 mm), and 0.060" (1.52 mm). In other embodiments, this thickness may be from another substrate from a different supplier or from the same supplier but with a different production number (potentially with different dielectric constants or materials), accordingly requiring a redesign of the antenna components.

[0088] In another embodiment, the antenna includes a flexible substrate with the following parameters: substrate: PET (polyethylene terephthalate); thickness t = 136 μm; dielectric constant εr of approximately 2.99; tangent δ = 5.79e-3; (thickness, dielectric constant, and tangent δ values ​​may vary due to manufacturing variations in specific substrate series.) Substrate suppliers offer different substrate materials and thicknesses. Kapton® polyimide is the most popular. https: / / v- / \V\v.dupont.com / electronic-materials / kapton-polvimide-film.html Therefore, for example, for a specific substrate, the thickness t can be between approximately 129 µm and approximately 143 µm; the dielectric constant may also be affected by variations in the manufacturing process; so too may the tangent δ. Dimensions: 70*80*0.5 l mm 3Feed: Helical; Frequency range of interest: approximately 0.5 GHz - 3 GHz; Parameters measured: Reflectance coefficient (SI 1): amplitude and phase. PET is used as a polymer in one embodiment; other types of flexible materials exist, such as paper substrates [9], and other flexible substrates require a complete redesign of the entire antenna component. While a wide range of thicknesses can be incorporated into the embodiments, most flexible films are provided in a narrow range of relatively thin dimensions of approximately 12 μm to approximately 125 μm (1 / 2 mil to 5 mil), while thinner and thicker materials are possible in other embodiments. [9] Kirn, Sangkil, and Manos M. Tentzeris. 'Parylene coated waterproofwashable inkjet-printed dual-band antenna on paper substrate.' International Journal of microwave and Wireless Technologies 10.7 (2018): 814-818.

[0089] Modeling techniques

[0090] According to one implementation, the phase and amplitude measurements of the reflection coefficient S11 obtained for a given antenna (rigid or flexible) at multiple frequencies are used for the estimation of glucose levels.

[0091] Different regression techniques were tested to best identify the most suitable model for capturing potential variations in glucose levels. Radial basis functions (RBF), Gaussian processes (GP), and locally weighted partial least squares (LW_PLS) can achieve several desired properties, including but not limited to: sparsity, reduced variance, and more accurate capture of local behavior. In particular, local model coverage is needed to enhance accuracy corresponding to regions with low glucose levels. Other regression techniques include partial least squares (PLS) and least absolute convergence and selection operator (LASSO).

[0092] PLS is a regression technique based on sparsity and maximizing correlation. It generates new regressors, called PLS directions, which are formed by linearly combining the original variables and depend on their univariate effects on the target. Therefore, the importance of this technique lies in its ability to generate PLS directions by maximizing the variance of the new regressor variables (similar to principal components) and the correlation between the regressor variables and the output variable.

[0093] Radial basis functions (RBFs) are nonlinear regression techniques that utilize basis functions (radial basis functions): for the ID case, y = f(x) = LK wkbk(x). Radial functions are radially symmetric functions about a point xc called the function center. Different RBFs can be used. Optimization methods are employed to find the optimal function center and parameters.

[0094] Gaussian processes (GP) are a modeling technique that also provides information about the uncertainty of the estimate at a given point xq. This technique associates point xq with different training points x using a covariance function k(x, xq) based on the distances of point xq to different training points x, thus again highlighting the local influence of training points that depends on the model parameters.

[0095] In locally weighted PLS, PLS is used to build a local linear regression model specific to each new point x0 of the performance to be predicted. This model provides distance-based weights for each training point based on the distance between x0 and different training points. This process is iterative, and the underlying model uses linear regression in the form of PLS ​​(unlike RBF and GP). Therefore, it takes the PLS direction as the new regressor.

[0096] For each x0, the newly generated local model strongly depends on the similarity / proximity between x0 and the training samples. In the model, the Euclidean distance is the distance between x0 and the training samples.

[0097] Example

[0098] The following embodiments are provided to provide those skilled in the art with a complete disclosure and description of how to prepare and evaluate the compounds, compositions, articles, apparatus, and / or methods claimed herein, and are intended purely as examples of the invention and not to limit the scope of what the inventors consider to be their invention. However, those skilled in the art will understand from this disclosure that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtaining the same or similar results.

[0099] Efforts have been made to ensure the accuracy of figures (e.g., quantities, temperatures, etc.), but some errors and deviations should be taken into account. Unless otherwise stated, parts are parts by weight, temperatures are °C or ambient temperature, and pressures are atmospheric pressure or close to atmospheric pressure.

[0100] Example 1: In vitro experiments with serum

[0101] The experimental setup for in vitro experiments includes a foam container filled with 30 ml of fetal bovine serum-PBS / glucose solution, which is very similar in composition to blood. Foam size: same as the antenna size (70*70 mm).2 And the thickness is 0.5 cm.

[0102] The container remained stationary throughout the experiment.

[0103] The initial measurement was completed. A reference glucose level was obtained using a Glucotrack blood glucose meter from Roche. For each measurement, 10 repeated readings of the S11 amplitude and phase were obtained using a vector network analyzer (VNA). This was to average out any measurement errors. S11 values ​​were recorded across the entire desired frequency range.

[0104] After each measurement, the glucose level was slightly increased for the next measurement. A small amount of glucose, equivalent to 10 mg / dl, was added to the FBS solution. After each addition of glucose, the FBS solution was mixed and allowed to stand for 10 minutes to ensure homogeneity. The same procedure was repeated until the glucose level in the FBS reached approximately 500 mg / dl. The same experiment was performed on both the rigid and flexible antennas: a total of 41 measurements were performed on the rigid antenna, and a total of 38 measurements were performed on the flexible antenna.

[0105] Individual OGTT models were developed. Normalization was performed in each OGTT. Ten randomized replicates (splits of test and training data) were performed for each OGTT to better understand the error. Only GP (Gaussian process) was used. The glucose concentration of the FBS solution varied from 50 mg / dL to 445 mg / dL in very small steps. The normalized S11 was compared with a reference glucose level obtained through a commercially available invasive glucometer.

[0106] Example 2: Sensitivity Test

[0107] A foam-based, vessel-shaped container was filled with 14 ml of FBS. Two experiments were conducted to demonstrate the importance of focusing the EM wave onto the vein. Initial measurements were performed. Reference glucose levels were obtained using a Roche Glucotrack glucometer. Ten storage measurements of S11 amplitude and phase were taken using a VNA. After each measurement, a small amount of glucose, equivalent to 100 mg / dL, was added to the FBS solution.

[0108] After each addition of glucose, the FBS solution was mixed and allowed to stand for 10 minutes to ensure homogeneity. The same procedure was repeated until the glucose level in the FBS reached approximately 500 mg / dL. This experiment was conducted using a rigid antenna: a total of 7 data points were collected across two experiments.

[0109] Example 3: In vitro experiment on rat skin

[0110] Fresh rat abdominal skin was dissected and cut into 70 × 70 mm pieces, then preserved in phosphate-buffered saline (PBS) solution. The skin containing PBS was placed in a foam container. The foam size was the same as the antenna size (70 × 70 mm) and 0.5 cm thick. The container remained fixed throughout the experiment. A thin nylon container was filled with 14 ml of fetal bovine serum PBS / glucose solution, which was very close to blood in composition. Initial measurements were performed, and reference glucose levels were obtained using a Roche Glucotrack glucometer. Ten S11 amplitude and phase measurements were stored using a VNA.

[0111] After each measurement, a small amount of glucose, equivalent to 100 mg / dl, was added to the FBS solution. After each addition of glucose, the FBS solution was mixed and allowed to stand for 10 minutes to ensure homogeneity. The same procedure was repeated until the glucose level in the FBS reached approximately 500 mg / dl. The same experiment was performed on both antennas: a total of 14 measurements were taken for both the rigid and flexible antennas.

[0112] Example 3: In vivo experiments in rats

[0113] Rats: Sprague Dawley rats. Animals were housed at the American University of Beirut's Animal Care Facility, in rack-mounted wire cages with a maximum of five rats per cage, in a room with controlled temperature and humidity and a 12-hour light / dark cycle. Standard laboratory pellet formula and tap water were provided as needed. The experiment was conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of the American University of Beirut. [l][l]Gerges, Alice & Rizzo, M & Eid, Assaad & Hajj Hussein, Inaya & Zgheib, Z & N Zeenny, M & Jurjus, Rosalyn & Uzzo, Maria & Spatola, Giovanni & Bonaventura, Giuseppe & Leone, Angelo & Massaad-Massade, Liliane & Jurjus, Abdo. (2017). Tea catechins induce crosstalk between signaling pathways and stabilize mast cells in ulcerativecolitis. Journal of biological regulators and homeostatic agents. 31. 865-877.

[0114] Animals weighed approximately 700g. Rats were studied after an 8-hour overnight fast. Thirty minutes before the test, rats were anesthetized with the inhaled anesthetic Forane. The rats were anesthetized only during antenna placement on their backs; they remained awake throughout the experiment. The measurement area of ​​hairy rats was shaved before antenna placement to avoid potential external influences on the measurements. The antenna was secured to the rat's back with 0.5 cm foam spacing and connected to a portable VNA. The animal was then placed in a restraint to limit its movement during the experiment.

[0115] Intraperitoneal glucose tolerance test (IPGTT) was performed. At time 0, rats received an intraperitoneal injection of 0.2 ml of saturated glucose solution. Measurements were taken every 5 minutes using a ventilator and a blood glucose meter. A reference glucose level was used with the ventilator, and for each measurement, 10 repeated readings of the S11 amplitude and phase were obtained using a ventilator. This was to average out any measurement errors. S11 values ​​were recorded across the entire desired frequency range.

[0116] Example 3: In vivo experiments on human subjects

[0117] Subjects were asked not to eat or drink anything for 8 hours before each visit.

[0118] 1. Sensor System Fixation: Subjects are required to sit in a chair to restrict body movement. Rigid and flexible antennas are placed on both hands, and measurements are taken simultaneously from both antennas. The antennas are secured to the hands using Gauze Wrap and connected to a portable VNA. The antennas do not directly contact the skin; they are separated by 0.5 cm of foam.

[0119] 2. Fasting glucose blood test: After the sensor system is fixed, the first reference measurement is performed using an invasive blood glucose meter, and 10 measurements are stored from the VNA at the same time.

[0120] 3. Glucose intake: Subjects were required to ingest 75 grams of sugar by eating 500 ml of ice cream within 10-15 minutes.

[0121] Glucose test: The same procedure described in step 3 (fasting blood glucose test) was repeated every 15 minutes for two hours. VNA storage was obtained every 5 minutes. The oral glucose tolerance test takes about 2 hours to complete. This procedure was repeated a total of 3 times for each subject on 3 different days. Data were provided for a cohort of healthy individuals aged 25 to 60 years. All participants were from a healthy control group.

[117]

[0122] Example: Detection of different glucose levels

[0123] The free-space multi-band characteristics enable analysis of the antenna's response at different frequencies, allowing for more comprehensive non-contact characterization of blood components with improved sensitivity. Foam containers filled with FBS glucose solution were placed above the sensing layer of the slot antenna. The antenna was connected to a vector network analyzer (VNA) to measure its S11 coefficient over a scan width of 0.5–1.5 GHz. The antenna was stationary throughout the experiment, and the glucose concentration of the FBS solution was varied in 50 mg / dL steps to cover a broad concentration range representing blood glucose variations from 28 to 471 mg / dL. Actual glucose levels were measured using an invasive glucometer (Accu Chek from ROCHER). A significant shift in the S11 amplitude was observed when the antenna was loaded with FBS solution.

[0124] system

[0125] As used in this application, the terms "component" and "system" are intended to refer to a computer-related entity, or hardware, a combination of hardware and software, software, or software in execution. For example, a component can be, but is not limited to, a process running on a processor, a processor, an object, an executable file, an execution thread, a program, and / or a computer. For illustration, both an application running on a server and the server itself can be components. One or more components may reside within a process and / or an execution thread, and components may be located on a single computer and / or distributed across two or more computers.

[0126] Typically, program modules include routines, programs, components, data structures, etc., that perform specific tasks or implement specific abstract data types. Furthermore, those skilled in the art will understand that the methods of this invention can be practiced with other computer system configurations, including single-processor or multi-processor computer systems, minicomputers, mainframe computers, personal computers, handheld computing devices, microprocessor-based or programmable consumer electronics, each of which can be operatively coupled to one or more related devices.

[0127] The aspects illustrated in this invention can also be practiced in a distributed computing environment, where certain tasks are performed by remote processing devices linked via a communication network. In a distributed computing environment, program modules can reside in both local and remote memory storage devices.

[0128] Computers typically include a variety of computer-readable media. Computer-readable media can be any available medium that can be accessed by a computer and includes volatile and non-volatile media, removable and non-removable media. By way of example and not limitation, computer-readable media can include computer storage media and communication media. Computer storage media includes volatile and non-volatile, removable and non-removable media implemented in any method or technology for storing information such as computer-readable instructions, data structures, program modules, or other data. Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other storage technologies, CD-ROM, Digital Universal Optical Disc (DVD) or other optical disc storage, magnetic cartridges, magnetic tape, disk storage or other magnetic storage devices, or any other medium that can be used to store desired information and can be accessed by a computer.

[0129] Communication media typically contain computer-readable instructions, data structures, program modules, or other data in modulated data signals (such as carrier waves or other transmission mechanisms), and include any information transmission medium. The term "modulated data signal" means a signal having one or more characteristics that are set or altered in a manner that encodes information in the signal. By way of example and not limitation, communication media include wired media such as wired networks or direct wired connections, and wireless media such as acoustic, RF, infrared, and other wireless media. Any combination of the foregoing should also be included within the scope of computer-readable media.

[0130] Software includes applications and algorithms. Software can be implemented on smartphones, tablets or personal computers, the cloud, wearable devices, or other computing or processing devices. Software can include logs, diaries, spreadsheets, games, recordings, communications, SMS messages, websites, charts, interactive tools, social networks, VoIP (Voice over Internet Protocol), email, and video.

[0131] In some embodiments, some or all of the functions or processes described herein are executed by a computer program that is formed of computer-readable program code and contained in a computer-readable medium. The phrase "computer-readable program code" includes any type of computer code, including source code, object code, executable code, firmware, software, etc. The phrase "computer-readable medium" includes any type of medium that can be accessed by a computer, such as read-only memory (ROM), random access memory (RAM), hard disk drive, miniature optical disc (CD), digital video optical disc (DVD), or any other type of memory.

[0132] All publications and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication or patent application is specifically and individually indicated to be incorporated by reference.

[0133] While the invention has been described in conjunction with various embodiments, it should be understood that other modifications are possible. This application is intended to cover any variations, uses, or adaptations of the invention, generally following the principles of the invention and including deviations from this disclosure within the scope of known and customary practice in the field to which this invention pertains.

Claims

1. A non-invasive sensor for detecting the concentration of a biomarker, comprising: An antenna array configured to resemble the shape of parallel fibular and posterior tibial veins; wherein the antenna array includes a first slotted sensor, a second slotted sensor, a third slotted sensor, and a fourth slotted sensor; the first, second, third, and fourth slotted sensors each include a first slotted arc portion and a second slotted arc portion; the first and second slotted arc portions are directly connected by a top slot; wherein the first slotted arc portion corresponds to the shape of the parallel fibular veins, and the second slotted arc portion corresponds to the shape of the posterior tibial veins; the first slotted arc portion includes a long slotted main branch connected to a distal curved branch; the long slotted main branch is connected to the top slot, wherein the top slot is substantially V-shaped; the second slotted arc portion includes a second long main branch corresponding to the posterior tibial veins; the second long main branch includes a second distal curved branch; and the antenna array transmits electromagnetic waves into human tissue in a region adjacent to the veins to monitor and detect changes in blood component concentrations.

2. The sensor according to claim 1, wherein, The distal curve branch includes a curvature angle between approximately 55 degrees and approximately 120 degrees.

3. The sensor according to claim 2, wherein, The first slotted arc portion includes a fibular parallel vein groove with a length of approximately 25 mm and a groove width of approximately 0.5 mm and approximately 1 mm.

4. The sensor according to claim 3, wherein, The second slotted arc portion includes a posterior tibial parallel vein groove with a length of approximately 21 mm and a groove width of approximately 0.5 mm and approximately 1 mm.

5. The sensor according to claim 4, wherein, The antenna array has a dielectric constant ε of approximately 2.

99. r .

6. The sensor according to claim 1, wherein, The antenna array stimulates specific nerves for the treatment of muscle spasms, pain management of peripheral neuropathy, and other applications of non-invasive monitoring or non-invasive nerve stimulation at the same frequency and power level for glucose monitoring.

7. The sensor according to claim 1, wherein, The antenna array includes multiple antenna elements corresponding to a sensor diameter Ds ranging from about 10.0 mm to about 17.0 mm and a sensor length Ls between about 25.0 mm and about 35 mm to properly cover the vein.

8. The sensor according to claim 7, wherein, The antenna array includes an array diameter Da ranging from about 45.0 mm to about 65.0 mm and an array length La ranging from about 155 mm to about 190 mm.

9. The sensor according to claim 1, wherein, The first slotted sensor, the second slotted sensor, the third slotted sensor, and the fourth slotted sensor each have a slot width of approximately 1.6 mm.

10. The sensor according to claim 9, wherein, The dielectric constant ε of the antenna array is approximately 2.

99. r .

11. The sensor of claim 1, further comprising a three-turn helical feed transmission line positioned at the bottom layer of the antenna array, such that the transmission line is separated from the sensing surface; wherein, The antenna array resonates when loaded with typical human leg tissue to increase its sensitivity to changes in blood composition.

12. The sensor according to claim 11, wherein, The antenna array operates in the UHF band, L band, and lower S band in the range of approximately 500 MHz to approximately 3 GHz.

13. The sensor according to claim 12, wherein, The antenna array includes a stretching characteristic limited to 10% in both the width and length of the slot, wherein the stretched antenna array maintains a resonance level below -10 dB.

14. The sensor according to claim 13, wherein, The substrate is polyethylene terephthalate (PET) with a thickness t = 136 μm, dielectric constant = 2.33, and tangent δ = 5.79e-3.

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