Patent Application
20200173898
The present invention generally to the field of biosensors, and more specifically to an ultrasensitive high Q-factor AT-cut quartz crystal microbalance (QCM) femtograms (fg or 10−15g) mass sensor and a method of using such a sensor to detect electrolyte and biomarker levels and femtogram frequency noises in ionic solutions such as blood or urine.
A number of medical conditions including electrolyte imbalance and cardiovascular or neurological events can be detected by sampling and testing bodily fluids such as urine and blood. Measuring levels of electrolytes and/or biomarkers, such as troponins, present in bodily fluids play a key role is diagnosis, prognosis, and risk stratification of patients.
Currently, many of these tests are done by taking a fluid sample from a patient and sending it to a laboratory for testing. Results from these laboratory tests often take many hours to obtain given the test equipment and procedures used and/or the backlog of samples waiting to be tested, prolonging diagnosis and treatment of potentially life-threatening medical conditions. Additionally, these laboratory tests cannot provide real time information, making it difficult to assess whether a patient is responding to a course of treatment as intended.
Point of care (POC) tests can drastically increase patients' chances of, fast diagnosis, successful treatment, survival because they can be administered much more quickly than the, lab tests. However, existing POC devices do not have the ability to monitor the rise and fall of electrolyte or troponin levels of a patient in real time. Additionally, most diagnostic POC devices are limited to picogram sensitivity, failing to detect medical conditions in their early stages, and generally they also take hours to provide results.
Ultrasensitive mass sensing devices, such as nanoelectromechanical systems (NEMS) and micro cantilevers that include a family of quartz crystal microbalance (QCM) and carbon nanotube (CNT), have shown a higher mass sensitivity and high throughput analysis capable of detecting a specific bioreceptor to which a target antibody or antigen binds. Upon binding of antigen/antibody targets on the sensor, the change in mass is related to a measurable output frequency in relation to the binding species such as a single cell, a molecule, a virus, a troponin, or a bacterium. These micro-organisms are in the pg to fg scale weight regime and can easily be detected by matching their masses with frequency change using devices with high mass resolutions in the pg to fg regimes. Although many patents based on CNT, micro-cantilevers, MEMS, NEMS and QCM have claimed to measure pg, fg, attogram (10−18 g or ag), and zeptogram (zg or 10−21 g), the technology to measure mass beyond pg in real time does not exist due to difficulty in fabrication and reproduction of the same vices and results.
A QCM mass sensor is a simple, cost-effective, high-resolution mass-sensing technique used to study properties of monolayer surfaces deposited on quartz wafers such as molecules, bacteria, antibody-antigen interaction, single cells, proteins, and thin films of polymers. A QCM sensors use a phenomenon in which when the mass of the electrode increases due to corrosion or mass deposited, the oscillation frequency of the quartz oscillator is reduced according to the amount of corrosion. The QCM sensor is capable of detecting a change in oscillation frequency of a quartz oscillator with a very high degree of sensitivity, and is capable of performing measurement in a short period of time compared to that of a sensor that uses other measuring methods, such as a coupon method. Therefore, QCM sensors are often adopted as an environment measuring device. QCM sensors are comparatively inexpensive, easy to fabricate and manufacture, and commercially available in the market. Commercial QCM sensors have the ability to measure mass to approximately 1×10−9 to 10−12 g/cm2.
QCM sensors are also capable of measuring mass and energy dissipation properties of surface functionalized bio materials while simultaneously carrying out electrochemistry studies on solution species. Sauerbrey was the first to recognize the potential usefulness of the QCM technology and demonstrated the mass sensitivity nature towards frequency changes at the surface at QCM electrodes. Sauerbrey derived the equation which relates the mass change per unit area at the QCM electrode surface to the observed change in oscillation frequency of the crystal as shown in the following equation:
K=2*f2/√{square root over (ρμ)}=2.26*10−6f2Hz·cm2/g,
where K is the mass sensitivity coefficient, ρ=2.648g/cm3, is the density of quartz crystal, and μ=2.947*1011 g/cm·s2, is the shear modulus of quartz crystal. By using the Sauerbrey's mass sensitivity coefficient, it has been shown that it is possible to use AT-cut QCM to measure mass of thin film functionalized on quartz disk to 2.7 fg/cm2 (L. Rodriguez-Pardo, J. F. Rodriguez, C. Gabrielli, H. Perrot. Sensitivity, noise, and resolution in QCM sensors in liquid media. IEEE Sensors Journal. 5, 6 (2005)).
After Sauerbrey derived an important equation which relates mass of a substrate added on a quartz disk to frequency shift, Allan was the next to derive an equation which represented frequency stability and noise arising from the driving oscillator circuit in the time domain in less than 10 seconds (M. J. Moure, P. Rodiz, D. Valdes, L. F. Rodriguez-Padro, and J. Farina. An FPGA based system for the measurement of frequency noise and resolution of QCM sensors. Latin American Applied Research. 37, 30 (2007)).
The institute of Electrical and Electronics Engineers (IEEE) has recognized Allan's equation and called it the Allan variance (IEEE Std. 1139, 1999) with the expression: σ=(1*10−7)/Q, where σ is the Allan variance and Q is the Q-factor of an AT-cut quartz disk. In embodiments of this invention, both Sauerbrey and Allan deviation equation is applied, and it has been shown that if the mass sensitivity coefficient of AT-cut quartz disk is known, it is possible to estimate mass resolution using as measured Q-factors. Since the Allan deviation σ(τ), can be estimated using σ=10−7/Q; then, the detection limit Δf(τ) can be calculated using the equation, σ(τ)*f(τ)=Δf(τ). The mass resolution on the surface of the active electrode area can be calculated by taking the ratio of detection limit Δf(τ) to mass sensitivity coefficient (K). It has also been reported in the literature that the typical absolute dissipation (ΔD) values of crystals oscillating in air and water are about 1*10−5 and 3.5*10−4, respectively, the ΔD reported in literature upon exchange of the protein on a gold electrode is approximately 1*10−6 (F. Hook, M. Rodahl, P. Brzezinski, and B. Kasemo. Energy dissipation kinetics for protein and antibody-antigen adsorption under shear oscillation on a quartz crystal microbalance. Langmuir 14, (2998), 729-734).
One of the current challenges is to make a portable diagnostic point of care device to detect not only femtogram mass, antigen, antibody, but also salt level, before cardiovascular or neurological infections. POC devices that are able to detect levels below single pg levels could open up new business opportunities globally in material sciences, life sciences, and in medical and diagnostic point of care, and could save the lives of many people by detecting the potentially life-threatening medical conditions and events early. Such POC devices require improved analytical sensitivity to detect the lower clinically relevant concentrations of indicators of medical conditions or events. Research into increasingly sophisticated POC platforms potentially permits the development of more advanced systems using novel signal transduction platforms, modified surfaces, microfluidic and detection systems. The trend towards miniaturization (nano and micro) complicates the process in terms of the ancillary components required but also introduces challenges for the type and quality of sensors developed for such applications. Therefore, the introduction of nanoscale mass sensing devices such as QCM, micro-cantilevers, carbon nanotube (CBN), and MEMS with higher mass sensitivity and detection of fewer than 10 seconds may provide a solution to the current problems. These devices depend only on the frequency shift and no photodetector or microcentrifuge is needed; because the change in frequency is directly proportional to the mass of molecules present.
The ability to measure frequency noises equivalent to femtogram mass and Na+ ions from 0.100 M/L to 0.155 M/L in the clear urine or saline solution (NaCl), would make it possible to develop the technology to detect normal and abnormal salt level, a single virus, a bacterium or blood Cardiac Troponin level. Technology like this needs a device to generate stable frequency noises approximately from 10−8 to 10−12 through the electrolyte solution in contact with the surface of the mass sensor without using a mechanical force, a phenomenon which uses AC-electrodynamic force to move fluids and charged ions in microfluidic devices1, 2, 3. The potential advantages include the nom-moving mechanical parts, precise high velocity fluid flow on the electrode layer4,5,6, ease to fabricate, and low power consumption. Recent studies using NaCl7,8,9 solution have shown that several electrolytes stabilize the velocity of ions on the electrode surface, from non-linear (when the frequency is between 1 to 100 KHz) to approximately linear curve as the frequency increases (above 1.0 MHz). Following those studies, it has also been reported that blood components such as serum have an impedance that steadily decreases with the increase of frequency up to 100 kHz and flatten10 out after 1.0 MHz to produce stable frequency between 1 and 10 MHz. The same effect has been reported from analysis of normal and diabetic blood where the relaxation time11 dropped from 2.1*10−5 s, and flattened rapidly at 1.26*10−7 s, after 1.25 MHz. This effect was also observed by measuring output voltage in between 1 and 2 MHz using 2 M and 5 M of NaCl solution12. The results showed that the output voltage signals increased as NaCl concentrations increased and the frequency started to flatterns and stabilizes slowly after transitioning from 1 to 2 MHz.
Therefore, there is a need for cost-effective and sensitive diagnostic equipment and a process to detect electrolyte and analytes, such as troponin at femtogram levels in ionic solutions such as blood or urine for more rapid interventions. There further exists a need for such detection to be continuous so as to detect changes in patient condition without resort sending samples for laboratory testing and then awaiting results.
A measurement probe system is provided that includes a housing, a Quartz Crystal Microbalance (QCM) mass sensor disposed within the housing, a first cover and a second cover attached to the housing at the ends of the housing. A chamber that is configured to receive a fluid sample is defined between the housing, the mass sensor, and the second cover. The measurement probe system also includes an electrical input in electrical communication the mass sensor and an electrical output in electrical communication with the second cover.
A method of using the measurement probe system to detect nanoparticle levels in an ionic solution is also provided. The method includes inputting a sample of the ionic solution into the chamber, applying a frequency from a signal generator connected to the QCM mass sensor via the electrical input when the mass sensor is in contact with the sample in the chamber, detecting frequency noises with the second cover and transmitting those frequency noises from the second cover to a frequency counter via the electrical output, and assessing the level of nanoparticles present in the sample of ionic solution based on the frequency measured by the frequency counter.
The subject matter that is regarded as the invention is particularly pointed out and distinctly claimed in the claims at the conclusion of the specification. The foregoing and other objects, features, and advantages of the invention are apparent from the following detailed description taken in conjunction with the accompanying drawings in which:
The present invention has utility as a probe and a process of using such a probe to detect electrolyte and biomarker levels and femtogram frequency noises in ionic solutions such as blood or urine. Embodiments of the probe include an ultrasensitive high Q-factor Quartz Crystal Microbalance (QCM) femtogram mass sensor. The QCM mass sensor generates frequency noises capable of detecting abnormal and normal electrolyte and biomarker levels in ionic solutions. The probe is used to measure frequency noises arising from nanoparticles suspended in ionic solutions. The nanoparticles may be electrolytes, bacteria, virus, antivirus, molecules, or cardiac troponin.
Electrolyte velocity, relaxation time, and frequency noises tend to stabilize between 1 and 2 MHz when electrolyte ions move on the surface of the electrode. Accordingly, the ultrasensitive QCM mass sensor13 is designed to resonate at 1.694 MHz. This sensor is very sensitive and is used to produce and detect very tiny frequency noises between 10−8 and 10−10 MHz. According to embodiments, electrolyte and biomarker concentrations are determined using measured frequency noises with the best aging rates14 of 10−10 MHz. Thus, an extension of QCM mass sensor technology15-20 to measure frequency noises equivalent to femtogram or electrolyte or biomarker level in ionic solutions is provided. This AT-cut QCM mass sensor is significantly more sensitive than any available system in the market. Here a QCM mass sensor is used over Microelectromechanical Systems (MEMS), Micro-Cantilevers, and Carbon Nanotube (CNT)21-34 because it is cost-effective, easy to fabricate and reproduce, and has the limitation to measure mass from 10−9 to 10−10 gm/cm2, however it will be understood that the other sensor types can also be used. The present invention has the capability to measure frequency noises equivalent to femtogram; thus being able to measure normal and abnormal electrolyte and up to 10−13 gm/1000 mL of Cardiac Troponin in ionic solutions.
It is to be understood that in instances where a range of values are provided that the range is intended to encompass not only the end point values of the range but also intermediate values of the range as explicitly being included within the range and varying by the last significant figure of the range. By way of example, a recited range of from 1 to 4 is intended to include 1-2, 1-3, 2-4, 3-4, and 1-4.
Referring again to
As shown in
Disposed on the outside of the first cover 111 is a first base support 109, which is attached to the first cover 111 and/or the housing 110 by screws 117, 118, or any other suitable fasteners. A male part 116 of a coaxial cable is connected to the first base support 109. A wire 126 electrically connects the male part 116 of the coaxial cable to the brass electrode 119. According to embodiments, the wire 126 is copper.
Disposed on the outside of the second cover 106 us a second base support 112, which is attached to the second end of the housing 110 by screws 113, 114, or any other suitable fasteners. An output coaxial cable 115 is connected to the second base support 112. A wire 128 electrically connects the output coaxial cable 115 to the second cover 106. According to embodiments, the wire 128 is copper,
In operation, the QCM mass sensor is placed at the top of chamber 108 where the full coated gold electrode 105 sits on the surface of the ionic solution that is fed into the chamber 108 through the input 120. The circular ring electrode 119 of the QCM mass sensor is exposed on the top side. Input signals are applied from a female terminal coaxial cable from a signal generator, such as a Tektronix AFG2021 (not shown), to the input male coaxial cable terminal 116 connected directly to the QCM mass sensor. The coaxial cable 116 receives the input signal from the signal generator via the wire 126 which connects directly to the QCM mass sensor through the brass ring electrode 119. The QCM mass sensor produces frequency noises via the ionic solution, and the suspended nanoparticles, or molecules, are measured as output frequency noises from the second cover 106, which may be a brass disk. The output signal from the output coaxial cable 115, which is connected to the second cover 106 via wire 128, is measured using a frequency counter, such as Tektronix FCA3000 (not shown) via a female coaxial cable terminal.
By using the invented probe system, a frequency counter and a signal generator, it is possible to measurer signal noises related to electrolyte and biomarker levels in ionic solutions, such as bodily fluids, over the course of extended periods of time, for example 24 hours. Also, it is possible to measure other metabolic products seen in unclear urine and whole blood such as urea, blood cells, antigens, antibodies, and lipids by using special concentrated sodium chloride solution where the measurable parameters are the rise time pulses.
According to embodiments, the probe system can be miniaturized to neglect the use of the signal generator and frequency counter, thus being able to develop a portable system which can be used in Doctors' office, hospitals, laboratories, home care, and long-term care facilities. The probe system can be easily miniaturized using Field Programmable Get Array (FPGA). The FPGA can be programmed to translate the measured frequency noises to their equivalent electrolyte or biomarker level measured in ionic solutions. The presently disclosed probe system is capable of measuring pulses related to frequency noises from 10−8 to 10−12 MHz, thereby enabling users to analyze individual molecules, electrolytes, biomarkers, hormones, antibodies, bacterial, virus, Cardiac Troponin, and blood cells in concentrated ionic solutions, and determine their corresponding selectivity noises depending on the measurable rise time pulses.
An initial part of the measurement includes the Q-factors measurements of the QCM. The highest -factor is 765682 and the calculated mass in the air at the same resonance frequency (1.694 MHz), is 1.25*10−15 gm/cm2. Next, the frequency noises are related to the electrolytes in concentrated saline solution using the probe. The measured frequency noises from 10−8 to 10−10 MHz, represent the concentrations of electrolyte level and femtogram mass or (10−15 gm) in an ionic solution. This probe can also detect frequency noises equivalent to Cardiac Troponin to 2.268*1.0−13 gm/1000 mL.
The probe equipped with an ultrasensitive QCM mass sensor is capable of measuring normal and abnormal electrolyte and biomarker levels in deionized water same as that in clear urine by measuring the frequency noises related to Potassium, Calcium, Magnesium and Sodium. The probe also detects different concentrations of cardiac troponin level in a standardized saline solution with other blood electrolytes having Na+ ions, approximately 0.155 M/L.
The probe measures the frequency change, Δf, as the concentrations of electrolytes in ionic solutions change. An applied AC electric field from the signal generator to QCM mass sensor is used to move charged ions and fluid contents back and forth, causing, Δf, and mass change, Δm, on the surface of the sensor as discussed by Sauerbrey35. Other factors which affect, Δf, in the solution medium are the compression effect due to changes in pressure, Δfp, the interaction of the smooth surface of a vibrating QCM mass sensor with a viscous medium, Δfγ, the roughness effect due to the interaction of the rough surface with the fluid36, Δfr, and the change due to viscosity and density variations of the immersion solution Δf72 . Therefore, the measured frequency noises in the solution medium are: Δf=Δfm+Δfp+Δfη+Δfr+Δfγ. The following are the basic symbols used in equations which show the relationship between the measured, Δf, resonant frequency (f0), the viscosity of fluid medium (η), density of fluid (ρ1), the density of blank quartz disk (ρq) and the shear modulus of the crystal (μq).
Starting with Sauerbrey, the measured frequency change, Δf, as a function of the mass change, Δm, is shown as:
where, A, is the area of the Gold electrode surface. Equation (1) reduces to a linear sensitivity factor, Cf, as shown in equation (2):
The Cf is a fundamental property of the QCM crystal, which is equal to 56.6 Hz μg−1 cm2, and can be solved by equation (3):
The equations 1, 2, and 3, are strictly applicable to uniform, rigid, thin-film deposits on the crystal surface. Another valid form of mass adsorption related to frequency change and mass change is shown in equation (4):
where, m, is the known mass gold electrode layer. From this relationship it can be seen that the change in frequency, Δf, is proportional to the change in mass, Δm, on the crystal surface. Kanazawa and Gordon37 used this concept in liquid solutions and related the mass deposited to the liquid viscosity and density as shown in equation (5):
The mass effect, Δfm, and the viscous effect, Δfη, are the primary variable factors considered measured as a function of Δf during our experimentation. Since the measurable Δf using equation 5 includes all five factors, equation (4) can be used to estimate Δm of interacting particles with an electrode layer having a known mass (m). Therefore, if the Δf is measured in presence of solution medium, the effects from other factors encountered in equation (5) are also measured collectively and, equation (4) can be used to calculate Δm if the mass (m) of the Gold electrode on the surface of the crystal is known. To achieve these goals, we have designed a cylindrical chamber which uses NaCl solution to conduct an AC electrical signal noises from the QCM mass sensor to the probe's output male coaxial cable connected to a brass electrode.
Before doing the Q-factor measurements using impedance meter, the frequency counter and the signal generator are calibrated using different input voltage to find the maximum input voltage where the frequency noises stable. The input parameters from the signal generator (Tekronix AFG2021) are varied from 1.0 V, 5.0 V and 10.0 V at 1.694 MHz, and the output frequency noises are then measured using a frequency counter (Tektronic FCA3000) as shown in
The Q-factors are then measured as a function of frequencies from 1.60 to 1.75 MHz at 10.0V. The highest Q-factor is 765682 at 1.697 MHz, and the lowest Q-factors are around 30,000 at both 1.68 MHz and 1.73 MHz, as shown in
Table 1 is the equivalent Sodium ions concentration (Na+) in clear urine prepared from deionized water. The samples for frequency noise measurements are prepared from NaCl crystals dissolved in deionized water. The concentration of Na+ (0.00345 M) remains constant and the amount of deionized water is varied from 34 mL to 22.25 mL to make the concentration of Na+ ions in deionized water the same as the normal Na+ ions in urine or blood; which is equivalent to 0.100 M/L to 0.155 M/L, respectively, For sample number 1, the moles (M) of NaCl dissolved in deionized water are calculated as 0.5 g/58 gm=0.0086 M. Since the 0.0086 M is for both Na+ and Cl− ions in the solution, a mole ratio for each ion is used to obtain the exact moles of Na+ and Cl− ions. For Na+ ions, the mole ratio is (23/58)*0.0086=0.00345 M. The urine equivalent Na+ ions concentration (say 0.100 M/L=0.100 M/1000 mL) is known, so the equivalent volume of deionized water for (0.00345) is calculated as (1000 mL*0.00345 M)/0.100 M=34 mL. The same process is repeated for samples number 2 to 9. The results are depicted in Table 1.
As shown in
In
Table 5 shows three samples of Cardiac Troponin prepared from 200 μg diluted three times from its original open container. The vial with 200 μg is opened, filled with at least 0.2 mL of deionized water, covered and shaken for 3 minutes, the Cardiac Troponin contents are then removed and dissolved in 10 mL of deionized water and put in another container with a magnetic stirrer. The solution with Cardiac Troponin is stirred for 3 minutes and then poured into another container marked sample 1. About 0.1 mL of sample 1 was put into the probe's chamber a few seconds after stopping the magnetic stirring for frequency noise measurement before the contents in the solution precipitate or separate. The left over contents in the container with Cardiac Troponin is mixed with 0.2 mL of deionized water, shaken for 3 minutes, and then washed again with 100 mL of deionized water. The solution is then stirred using a magnetic stirrer for 3 minutes and then poured into the container marked sample 2. In less than 20 seconds, a 0.1 mL of sample 2 is poured into the probe's chamber for frequency noise measurement. The leftover of the contents of Cardiac Troponin in the original container with its container is poured into 1000 mL of deionized water and stirred for 3 minutes using a magnetic stirrer. The solution is then poured into another container labelled sample 3. A small portion (2 drops) of sample 3 is poured into 0.1 mL of the probe's chamber for frequency noise measurement.
7*10−8
2*10−8
7*10−9
3*10−9
3*10−5
1*10−5
In order to convert the measured frequency noises, Δf, shown in Table 6 to femtogram, the detectable frequency noises on the bottom electrode (with 0.4 cm radius) of QCM are assumed to be the same as the frequency applied on the ring electrode. Thus, considering the mass (m) of the electrode layer, the tiny volume (V) of the Gold layer must be known. This volume is estimated using the equation πr2t where the thickness (t) is 3*10−5 cm and the radius (r) of the bottom layer of the Gold electrode is 0.4 cm. The mass (m) of the Gold layer is then calculated by multiplying the density of Gold (ρ=19.3 gm/cm3) to the volume it occupies. Therefore, the mass of Gold electrode layer in contact with solution or air is given by multiplying πr2t*ρ=(3.14*0.4 cm*0.4 cm*3*10−5 cm)*(19.3 gm/cm3)=9.6*10−5 gm. The measured frequency shift (Δf) in the presence of air is 3*10−10 MHz when the applied resonant frequency (f) is 1.694 MHz. The frequency ratio (Δf/f) is 1.7*10−10, and the Δm due to frequency noises applied on the ring electrode and bottom brass electrode when the chamber is filled with air, is given by the expression: Δf/f*m=1.7*10−10*9.6*10−5 gm=16*10−15 gm.
The measured Δf when the chamber was filled with deionized water was 0.75 KHz and Δm is calculated using the same expression: Δf/f*m =4.4*10−4*9.6*10−5 gm=1.13*10−9 gm. The frequency noises, Δf, related to concentrations of Ca++, Mg++, and K+ ions in deionized water are between 10−1 and 10−6 MHz (Table 6) showing that, the Na+ ions are the dominant electrolyte in urine or blood; because, the measured Δf for Na+ ions is between10−8 and 10−10 MHz. The measured Δf when the chamber is filled with 0.10M of Na+ ions was 7*10−8 MHz and the Δm was calculated using Δf/f*m=4.13*10−8*9.6*1.0−5 gm=3.96*10−12 gm. When the Na+ ions concentration increases to 0.120 M, the frequency shift, Δf, is 2*10−8 MHz and the calculated Δm is f/f*m=1.18*10−8*9.6*10−5 gm=1.13*10−12 gm. When the concentration of Na+ ions increases to 0.130 M the measured frequency shift, Δf, was 7*10−9 MHz and the Δm is calculated using Δf/f*m=4.13*10−9*9.6*10−5 gm=3.9*10−13 gm. When the concentration of Na+ ions is 0.140 M, the measured frequency shift, Δf, is 3*10−9 MHz and Δm is calculated as Δf/f*m=1.77*10−9*9.6*10−5 gm=1.7*10−13 gm. When the Na+ ions concentration is 0.150 M, the frequency shift, Δf, is 4*10−10 MHz and the Δf is calculated as Δf/f*m=2.36*10−10*9.6*10−5 gm=2.26*10−14 gm. When the Na+ concentration is increased to 0.155 M, the measured frequency noises stabilized to 2*10−10 MHz, and the Δm is calculated using the same expression; Δf/f*m=1.18*10−10*9.6*10−5 gm=1.13*10−14 gm.
Therefore, when the frequency change, Δf, is from 10−8 to 10−10 MHz, the detected concentration is related to that of normal and abnormal Na+ ions level equivalent to that seen in urine or blood. The frequency change, Δf, from 0.1 to 10−6 MHz belongs to other electrolytes (K+, Ca++, and Mg++) as shown in Table 6. The normal concentration of salt in the urine may be between 0.135 and 0.145 M/L of Na+ ions. Accordingly, the present invention detects not only abnormal salt level below 0.135 M/L but also, a higher salt level above 0.145 M/L. It also detects Cardiac Troponin in deionized water, that is, the measured frequency change, Δf, is 3.3*10−7 MHz when 2 drops of Cardiac troponin in 10 mL are added to the 0.1 mL chamber filled with the standardized electrolytes. The calculated Δm is Δf/f*m=1.94*10−7*9.6*10−5 gm=1.87*10−11 gm. The measured frequency change, Δf, is 1.1*10−8 MHz when the 2 drops of Cardiac Troponin in 100 mL are added in 0.1 mL chamber filled with the standardized electrolytes.
The Δm is then calculated using Δf/f*m=0.649*10−8*9.6*10−5 gm=6.23*10−13 gm. The measured frequency change, Δf, is 4*10−9 MHz when the 2 drops of Cardiac Troponin in 1000 mL are added to 0.1 mL chamber filled with the standardized electrolytes. The Δm is then calculated using Δf/f*m=2.362*10−9*9.6*10−5 gm=2.268*10−13 gm. Given the results of these experiments, the present invention is 100,000 times more sensitive than the current QCM mass sensor technology and, has a mass resolution capable to measure mass from 3.76*10−14 to 1.25*10−15 gm/cm2 in the air. Additionally, when 1.694 MHz is applied to a solution with 0.155 M/L of Na+ ions, the frequency noises stabilize to approximately 2*10−10 MHz, which is sensitive enough to detect nanoparticles suspended in the solution to 1.13*10−14 gm. Accordingly, the present disclosure provides a QCM mass sensor capable of detecting normal and abnormal electrolyte level, virus, bacteria, or blood Troponin level before major infection can cause cardiovascular diseases, heart failure, or neurological diseases.
While at least one exemplary embodiment has been presented in the foregoing detailed description, it should be, appreciated that a vast number of variations exist. It should also be appreciated that the exemplary embodiment or exemplary embodiments are only examples, and are not intended to limit the scope, applicability, or configuration of the described embodiments in any way. Rather, the foregoing detailed description will provide those skilled in the art with a convenient road map for implementing the exemplary embodiment or exemplary embodiments. It should be understood that various changes can be made in the function and arrangement of elements without departing from the scope as set forth in the appended claims and the legal equivalents thereof.
The references listed below and all references cited herein are hereby incorporated by reference in their entireties.
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