KR102892160B1 - Micro Flow Sensor Comprising Sensor Electrode Formed on Wire, Method for Preparing Same and Device for Measuring Blood Flow Comprising Same - Google Patents

Abstract

The present invention relates to an ultra-small flow sensor having a sensor electrode in the form of a micro-pattern formed on a guide wire, a method for manufacturing the same, and a blood flow meter including the same.
According to the present invention, an ultra-miniature thermal flow sensor can be manufactured by forming a microelectrode pattern on the surface of a medical guide wire through laser sintering patterning, and reliability can be significantly improved through minute design changes to the electrode structure. Accordingly, when the ultra-miniature flow sensor of the present invention is inserted into a cardiovascular system and used for blood flow measurement, blood flow velocity within the blood vessel can be accurately and conveniently measured.

Description

Micro flow sensor comprising sensor electrode formed on wire, method for preparing same and device for measuring blood flow comprising same

The present invention relates to an ultra-small flow sensor including a sensor electrode formed on a wire, a method for manufacturing the same, and a blood flow meter including the same, and more particularly, to an ultra-small flow sensor including a sensor electrode formed in a micro-pattern shape on a guide wire, a method for manufacturing the same, and a blood flow meter including the same.

According to a 2019 World Health Organization (WHO) survey, cardiovascular disease (CVD) is a leading cause of death worldwide, posing a significant socioeconomic burden. CVD is caused by narrowing or occlusion of the coronary arteries that supply blood to the heart, reducing blood flow to the heart and ultimately leading to heart failure, leading to high morbidity and mortality. To prevent these serious cardiovascular diseases, diagnostic technologies that can directly and accurately detect abnormal blood flow, such as changes in coronary artery blood flow, are needed.

Representative blood flow measurement methods for diagnosing cardiovascular disease include blood pressure-based fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR). For example, Korean Patent Publication No. 10-2011-0063667 discloses an intravascular transport sensor device for measuring fractional flow reserve across a stenotic lesion. However, pressure-sensing methods indirectly estimate blood flow changes based on the pressure difference between the aorta and the area passing through the lesion, which limits their accuracy. These errors can lead to misdiagnosis and medical errors.

Another method used to measure blood flow is thermal dilution. This method involves injecting saline solution into the coronary artery and measuring the time it takes for temperature to return to normal. Blood flow velocity is then determined using coronary flow reserve (CFR), defined as the ratio of the time between resting and hyperemic states. However, thermal dilution is not only complex to measure, but is also susceptible to the dose and timing of indicator injection, leading to unreliable results.

To overcome the limitations of conventional diagnostic methods, technology for medical guide wires or catheters equipped with sensors has recently been developed. For example, Republic of Korea Patent Publication No. 10-2018-0050275 discloses that intravascular catheters can be equipped with sensors to detect blood flow.

Guide wires or catheters equipped with flow sensors, as described above, allow for direct and accurate measurement of blood flow at lesion sites within blood vessels, without being influenced by the operator's subjective interpretation or individual patient characteristics. However, the difficulty of precisely forming microsensor circuits on ultra-small guide wires and the difficulty of making subtle design changes to improve performance necessitate the development of highly accurate, ultra-small sensors capable of directly measuring flow rate.

An object of the present invention is to provide an ultra-small flow sensor having a sensor electrode formed in a micro-pattern shape on a wire.

Another object of the present invention is to provide a method for manufacturing the above flow sensor.

Another object of the present invention is to provide a blood flow meter capable of accurately measuring blood flow velocity, including the above-described flow sensor.

In order to achieve the above-described object, the present invention provides a flow sensor including: a hollow guide wire; a sensor electrode positioned on the guide wire and including a micro heater and two thermistors positioned on both sides of the micro heater; an electrode pad connected to each end of the sensor electrode; and a wiring wire connected to the electrode pad and inserted into the hollow through a slot formed in the guide wire.

In the present invention, the diameter of the guide wire may be 200 to 500 μm.

In the present invention, the thickness of the guide wire may be 10 to 100 μm.

In the sensor electrode of the present invention, the gap between the micro heater and the thermistor may be 10 to 50 μm.

The flow sensor of the present invention may further include a Teflon coating layer between the guide wire and the sensor electrode.

The flow sensor of the present invention may further include a parylene coating layer formed to cover the sensor electrode and guide wire.

In the present invention, the thickness of the parylene coating layer may be 1 to 30 μm.

In the present invention, the diameter of the wiring wire may be 10 to 50 μm.

The present invention can also provide a method for manufacturing a flow sensor, comprising the following steps:

A step of forming a sensor electrode including a micro heater and two thermistors positioned on both sides of the micro heater and electrode pads connected to each end of the sensor electrode using laser patterning on a hollow guide wire;

A step of connecting a wiring wire to the above sensor electrode pad; and

A step of inserting the above wiring wire into the hollow space through the slot of the guide wire.

In the present invention, before forming the sensor electrode on the guide wire, a step of forming a Teflon coating layer can be further performed.

In the present invention, the step of forming the Teflon coating layer may include the step of coating a Teflon solution on the guide wire; and the step of forming the Teflon coating layer by heat-treating and hardening the coated Teflon solution.

In the present invention, the Teflon solution coating can be performed by dipping the guide wire into the Teflon solution at a coating speed of 0.1 to 10 mm/s.

In the present invention, the heat treatment when forming the Teflon coating layer can be performed at 200 to 400°C for 10 to 60 minutes.

In the present invention, before forming a Teflon coating layer on the guide wire, a step of plasma treating the guide wire may be further performed.

In the present invention, the plasma treatment can be performed at 10 to 1,000 W for 1 to 20 minutes.

In the present invention, the output of the laser beam in the laser patterning step may be 0.1 to 10 W.

In the present invention, the laser patterning of the sensor electrode can be performed by a step of forming a nanoparticle solution layer by applying a nanoparticle solution onto a guide wire; and a step of forming a micro pattern on the surface of the guide wire by irradiating the nanoparticle solution layer with a Bessel beam laser to induce sintering of the nanoparticles.

In the present invention, after forming the sensor electrode, a step of forming a parylene coating layer can be further performed.

The present invention can also provide a blood flow meter including the flow sensor.

According to the present invention, an ultra-miniature thermal flow sensor can be manufactured by forming a microelectrode pattern on the surface of a medical guide wire through laser sintering patterning, and reliability can be significantly improved through minute design changes to the electrode structure. Accordingly, when the ultra-miniature flow sensor of the present invention is inserted into a cardiovascular system and used for blood flow measurement, blood flow velocity within the blood vessel can be accurately and conveniently measured.

Figure 1 schematically illustrates the structure of a flow sensor according to one embodiment of the present invention.
Figure 2 shows a cross-sectional view of a flow sensor according to one embodiment of the present invention.
FIG. 3 illustrates a method for measuring blood flow in a blood vessel using a flow sensor according to one embodiment of the present invention.
Figure 4 shows a process photograph of manufacturing a sensor-on-wire type flow sensor in one embodiment of the present invention.
Figure 5 illustrates a process of preprocessing a guide wire in a process for manufacturing a flow sensor according to one embodiment of the present invention.
FIG. 6 illustrates the design of an optical system for transforming a Gaussian laser beam into a Bessel beam during electrode patterning in a process for manufacturing a flow sensor according to one embodiment of the present invention.
FIG. 7 illustrates a step of forming a micro-patterned electrode through laser filament sintering in a flow sensor manufacturing process according to one embodiment of the present invention.
Figure 8 illustrates a design diagram of an electrode in the form of a micro-pattern formed in a process for manufacturing a flow sensor according to one embodiment of the present invention.
Figure 9 shows a high-resolution scanning electron microscope (SEM) photograph of a microelectrode formed in a process for manufacturing a flow sensor according to one embodiment of the present invention.
Figure 10 schematically illustrates the design of a flow sensor device manufactured in one embodiment of the present invention.
Figure 11 shows the change in line width and linear resistance of an electrode according to laser output in one embodiment of the present invention.
Figure 12 shows a confocal microscope photograph of an electrode fabricated on a guide wire in one embodiment of the present invention.
Figure 13 shows the results of a peeling test of an electrode manufactured on a guide wire in one embodiment of the present invention.
Figure 14 shows a sensor layout diagram in a suitability test of a sensor manufactured in one embodiment of the present invention.
Figure 15 shows the linear correlation between the average voltage amplitude of a flow sensor manufactured in one embodiment of the present invention and the actual flow rate of a commercial flow sensor.
Figure 16 shows the linearity and consistency of flow data between a flow sensor manufactured in one embodiment of the present invention and a commercial flow sensor based on ultrasonic technology.
Figure 17 illustrates a flow sensor manufactured by adjusting the distance between electrodes in one embodiment of the present invention.
Fig. 18 is a graph showing the difference in data reliability according to adjusting the distance between electrodes to 20 μm (a), 30 μm (b), and 40 μm (c) in a flow sensor manufactured in one embodiment of the present invention.
Figure 19 shows a photograph of an X-ray image monitored after inserting a sensor manufactured in one embodiment of the present invention into a coronary artery.
Figure 20 shows transient voltage signals corresponding to blood pressure and flow rate during an in-vivo animal experiment using a flow sensor manufactured in one embodiment of the present invention.
Figure 21 shows the change in voltage signal of blood flow (normal state and congested state) depending on whether a vasodilator is injected in an experiment using a flow sensor manufactured in one embodiment of the present invention.
Figure 22 shows the change in average voltage amplitude measured in the first animal experiment (a) and the second animal experiment (b) for the flow sensor manufactured in one embodiment of the present invention.

Hereinafter, specific implementations of the present invention will be described in more detail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which the present invention pertains. In general, the nomenclature used herein is well known and commonly used in the art.

The present invention relates to an ultra-small flow sensor including a sensor electrode formed on a guide wire, a method for manufacturing the same, and a blood flow meter including the same.

According to the present invention, a micro thermal flow sensor can be manufactured by forming a micro electrode pattern on the surface of a medical guide wire through laser sintering patterning. Furthermore, when applied to a blood flow meter, the micro thermal flow sensor can be inserted into a cardiovascular system to accurately and conveniently measure blood flow velocity within the blood vessel.

The ultra-small flow sensor of the present invention has a structure including a sensor electrode in the form of a micro-pattern on a medical guide wire.

FIG. 1 schematically illustrates the structure of a flow sensor according to one embodiment of the present invention. Referring to FIG. 1, the flow sensor (100) of the present invention may include a hollow guide wire (110); a sensor electrode (120) positioned on the guide wire (110) and including a micro heater (121) and two thermistors (122) positioned on both sides of the micro heater; an electrode pad (130) connected to each end of the sensor electrode (120); and a wiring wire (140) connected to the electrode pad (130) and inserted into the hollow through a slot (S) formed in the guide wire (110). At this time, the thermistors (122) positioned upstream and downstream of the micro heater (121) may be classified into an upstream thermistor (122a) and a downstream thermistor (122b), respectively.

A flow sensor having the above structure can be manufactured through a step of forming a sensor electrode (120) including a micro heater (121) and two thermistors (122) positioned on both sides of the micro heater using laser patterning on a hollow guide wire (110), and an electrode pad (130) connected to each end of the sensor electrode (120); a step of joining a wiring wire (140) to the electrode pad (130); and a step of inserting the wiring wire (140) into the hollow space through a slot (S) of the guide wire (110).

A guide wire is a medical wire used to insert medical devices into blood vessels in the human body. The present invention utilizes a hollow guide wire with a space formed within it. Typically, guide wires are made of stainless steel (SUS) to accommodate medical procedures and contact with the human body, but this is not a limitation; guide wires made of other biocompatible metals or new materials can also be applied to the present invention.

In the present invention, the diameter of the guide wire may be 200 to 500 μm, preferably 250 to 400 μm, and more preferably 300 to 380 μm. If the diameter is too small, it may be difficult to insert the wiring wire into the hollow portion of the guide wire, and if the diameter is too large, it may not be suitable for insertion into the body. In addition, the guide wire may have a thickness of 10 to 100 μm, preferably 20 to 80 μm, and more preferably 40 to 60 μm.

In one embodiment of the present invention, a Teflon (PTFE) coating may be applied to the guide wire to enhance the coating effect of metal nanoparticles when forming the sensor electrode. That is, a Teflon coating layer may be formed between the guide wire and the sensor electrode.

The above Teflon coating layer can be formed through a step of coating a Teflon solution on the guide wire; and a step of hardening the coated Teflon solution by heat treatment.

Preferably, the coating of the Teflon solution can be performed through a dipping method. Specifically, the coating can be performed by dipping the guide wire into the Teflon solution at a speed of 0.1 to 10 mm/s, preferably 0.5 to 2 mm/s. The coating speed is a process condition that affects the thickness of the Teflon coating layer and the quality of the coating surface. If the coating speed is too fast or slow, the coating surface may become irregular and thick. However, in the present invention, by controlling the coating speed within the above range, a Teflon coating layer having a uniform and appropriate thickness can be formed. The thickness of the Teflon coating layer formed through the coating process may be 1 to 20 μm, preferably 3 to 10 μm, and more preferably 5 to 8 μm.

In a preferred embodiment of the present invention, a plasma treatment process can be performed before forming the Teflon coating layer.

Plasma treatment is a surface treatment technology that induces a physical/chemical reaction by delivering gaseous particles to the surface. In the present invention, a Teflon solution can be uniformly coated by subjecting the guide wire surface to plasma treatment.

The above plasma treatment can be performed for 1 to 20 minutes, preferably 2 to 10 minutes, under conditions of 10 to 1,000 W, preferably 50 to 200 W. If the plasma treatment conditions are outside the above range, there are problems such as poor yield, such as the Teflon coating layer not being homogeneous and the electrodes breaking during electrode patterning using a laser. However, if the plasma treatment is performed under the conditions of the above range, the Teflon coating layer is formed uniformly, which is preferable.

In the present invention, it is preferable to perform heat treatment to harden the coating surface after coating the Teflon solution.

Specifically, a Teflon coating layer can be formed by coating a Teflon solution and then heat-treating at a temperature of 200 to 400°C, preferably 250 to 350°C, to harden it. If the heat treatment temperature exceeds the above range, the coating surface becomes hard, but the surface becomes irregular, making it difficult to pattern the sensor electrode, which is a subsequent process. In addition, if the temperature is too low, a problem may occur in which the coating layer is not sufficiently hardened. Therefore, it is preferable to perform the heat treatment within the above temperature range. In addition, the heat treatment can be performed for 10 to 60 minutes, preferably 20 to 40 minutes.

In the present invention, the sensor electrode formed on the guide wire has a fine pattern shape, and in the present invention, a laser patterning method is used to form the pattern-shaped electrode on an ultra-small guide wire with a small diameter.

Specifically, the laser patterning of the sensor electrode according to the present invention can be performed by a step of forming a nanoparticle solution layer by applying a nanoparticle solution; and a step of forming a micro pattern on the surface of the wire by irradiating the nanoparticle solution layer with a Bessel beam laser to induce sintering of the nanoparticles.

The above nanoparticle solution refers to a solution in which nanoparticles of various sizes ranging from several nanometers (nm) to hundreds of micrometers (㎛) are dissolved or dispersed in a solvent. The size of the nanoparticles may vary depending on the type of material to be coated, but an average particle size of 10 to 500 nm is preferable, and an average particle size of 50 to 100 nm is more preferable when considering the uniformity of the coating.

The above nanoparticles are particles of a material for forming a micro-pattern on a wire. Preferably, the nanoparticles may be metal nanoparticles, which are mainly used as electrode materials. Considering compatibility with the human body, metal nanoparticles such as silver (Ag), gold (Au), platinum (Pt), or mixtures thereof may be used, but are not limited thereto.

The solvent used in the above nanoparticle solution may be an inorganic solvent such as distilled water or deionized water, or an organic solvent such as isopropanol, ethanol, methanol, butanol, propanol, glycol ether, acetone, toluene, dichloromethane, tetrahydrofuran (THF), or dimethylformamide.

The above nanoparticles may exist in a state dispersed or dissolved in a solvent, and when the nanoparticles are dissolved in a solvent, they exist in the form of ions.

In the above nanoparticle solution, the content of nanoparticles is preferably 5 to 50 wt%, preferably 30 to 40 wt%. If the content of nanoparticles is too low, it is difficult to form a fine pattern, and if the content of nanoparticles is too high, the coating of the fine pattern may be uneven or excessive time may be required for growth sintering.

In addition, it is preferred that the nanoparticle solution have a viscosity of 10 to 200 cP. If the viscosity of the nanoparticle solution is too low, the coating is not well maintained on the wire, making the process difficult. If the viscosity is too high, workability is poor. The nanoparticle solution layer can be applied to a thickness of 10 nm to 1 mm, and is preferably applied to a thickness of 100 to 500 nm.

As a method for applying (coating) the above nanoparticle solution to the wire, a known process capable of uniformly applying the solution to the wire can be used, for example, dip coating, spray coating, inkjet coating, etc. In the present invention, it is preferable to use a dip coating method to uniformly coat the nanoparticle solution on the guide wire, and at this time, the coating speed can be adjusted to 0.1 to 10 mm/s, and preferably, the coating can be performed at a speed of 0.5 to 2 mm/s.

During the above coating process, a step of drying the nanoparticle solution may be performed, if necessary. The drying step can evaporate the solvent in the nanoparticle solution, and the coating and drying of the nanoparticle solution can also be repeated multiple times.

In a preferred embodiment of the present invention, the order of the guide wire fixing steps can be determined depending on the process of applying a nanoparticle solution layer to the surface of the guide wire. In the case of dip coating, in which the guide wire is immersed in a nanoparticle solution and then removed, it is preferable to fix the wire after coating the nanoparticle solution. In the case of spray coating or inkjet coating, it is more preferable to fix the guide wire and then perform the coating. For example, the guide wire can be first fixed and then operated to pass through a nozzle to coat the nanoparticle solution.

In the present invention, "fixing" means maintaining a constant tension by pulling both ends of the area where the micro-pattern will be formed to prevent the guide wire from bending or otherwise changing shape during the coating process. A guide wire fixed in this manner can be moved while maintaining tension for laser irradiation, as described below. This does not mean that the guide wire is fixed in a specific location.

The “ends” of the above guide wire refer to both ends of the area where the micro pattern is to be formed, and are not necessarily limited to the ends of the entire length of the guide wire.

In the present invention, after coating a nanoparticle solution layer on a guide wire and fixing the wire (or vice versa), a laser is irradiated on the nanoparticle solution layer to induce sintering of the nanoparticles, thereby forming an electrode in the form of a micro-pattern on the guide wire.

Typically, to obtain a uniformly sintered thin film on a three-dimensional substrate using a laser, the sintering process must be performed while precisely focusing on the curved surface of the substrate. However, focusing the laser on a curved three-dimensional substrate, such as a guide wire, requires considerable technical difficulty. Since the length of the laser beam capable of stable sintering is within several times the focal point, the substrate or the focal point must be moved in real time to ensure that the laser focus is precisely positioned on the sintering area of the substrate. This requires an additional precision positioning system, dramatically increasing the difficulty and cost of the process.

In the present invention, a micro pattern is formed on the surface of a wire having a curve by using a modified beam having a long focus using an optical system.

Specifically, the present invention can form a fine pattern on the surface of a wire by constructing an optical system having a long depth of focus using a Bessel beam. The Bessel beam reduces energy consumption by focusing the beam on a narrow area, increases concentration, and reduces the focal size of the beam, thereby enabling the formation of a pattern the size of an optical wavelength. In addition, the beam is focused using interference and has a long depth of focus, enabling the formation of a fine pattern on the surface of a wire.

The specific principle of the above Bessel beam and the optical system for implementing it are described with reference to the inventor's registered patent No. 10-2181868.

When a laser beam is irradiated onto a nanoparticle solution layer coated on a guide wire, the nanoparticles heat up and grow, increasing in size and bonding to each other, resulting in sintering. When the laser beam's focus is adjusted to 1 μm, the nanoparticle sintering can form a pattern with a resolution of approximately 1 μm. This allows for the precise formation of microscopic patterns on the surface of the guide wire.

Because the Bessel beam has a long depth of focus, the nanoparticle solution applied to the upper and side surfaces of the guide wire can be heated and sintered without adjusting the height of the focus. Therefore, the method of the present invention can form a micropattern up to a central angle of 180°, preferably up to a central angle of 160°, based on the cross-section of the guide wire in a single operation without rotating the guide wire. This means that approximately 40 to 50% of the entire 360° area can be processed in a single operation.

The wavelength of the laser that can be used in the present invention may be ultraviolet light, visible light, or infrared light, and the type of laser may include, for example, a CW (continuous wave) laser, a QCW (quasi-continuous wave) laser, a pulse laser, etc., ranging from fs (femtoseconds) to ms (milliseconds). In the present invention, a CW (continuous wave) laser can be used to easily perform microelectrode patterning on a guide wire.

In the present invention, the laser irradiation can be configured to form a fine pattern over a wider area more quickly by processing the line beam in parallel rather than by a single device, or by irradiating multiple beams using an array lens or the like.

In addition, since a sintered micro-pattern is formed only in the area irradiated with the laser, it is possible to form a pattern of a free shape by moving the laser focus. For example, the method of moving the laser focus can be used by moving the laser while fixing the guide wire, or by moving the guide wire while fixing the laser. In this case, since the guide wire is placed on a moving means, the wire can be moved by moving the moving means. In addition to this method of moving the laser or wire using a moving means and irradiating the laser to the patterning area, a method of moving and irradiating the Bessel beam using a galvano scanner, or a method of combining these two methods can be used.

After moving the laser to the micro-pattern formation area, the focus of the Bessel beam is adjusted. For example, the focus can be adjusted using an objective lens, a scanner, etc. In addition, the process temperature, the laser beam movement speed (scan rate), the laser beam output, the pulse width, the repetition rate, etc., which can affect the area or thickness of the micro-pattern to be formed, can be adjusted.

In the laser patterning step of the present invention, the output of the laser beam may be 0.1 to 10 W. When a laser beam within the above output range is irradiated, the nanoparticles are heated to 100 to 2,000°C, thereby allowing the nanoparticles to grow and sinter in a short period of time.

In a preferred embodiment of the present invention, the output of the laser beam can be adjusted to 0.4 to 1.0 W, preferably 0.6 to 0.8 W. Within this range, the line width and linear resistance of the electrode are optimized, thereby enabling the production of a sensor with excellent performance.

The process of the present invention utilizes a laser beam, enabling patterning at extremely high speeds. Specifically, micro-patterns can be formed on the surface of a wire at speeds ranging from 1 mm/s to 10 m/s, and preferably at speeds of approximately 3 m/s.

The depth of focus of the above Bessel beam can be adjusted differently depending on the configuration of the optical system, and a depth of focus of 100 μm or more can be realized by using a beam expander, and thus, even on the curved surface of the guide wire, the focus can be moved only horizontally without moving up and down, thereby forming a fine pattern due to sintering of nanoparticles.

The micro-pattern formation process of the present invention can form micro-patterns by coating a nano-particle solution layer over a wider area or the entire surface of the wire and then irradiating the laser only to the required area, without the need for precisely forming a nano-particle solution layer only on the surface of the guide wire where the micro-pattern is to be formed. Therefore, a precise process is not required for coating the nano-particle solution layer, and conventional coating processes such as dip coating or spray coating are sufficient.

The method of the present invention may further include a step of forming a micro-pattern on a guide wire and then removing the remaining nanoparticle solution.

The above nanoparticle solution removal process or washing process may use a method using ultrasonic waves or sprays, or a method using a washing solution such as ethanol or acetone, but is not particularly limited thereto.

According to the above laser patterning method, a micro-pattern measuring several to several tens of micrometers can be formed on the surface of a guide wire having a diameter on the micrometer scale. Therefore, the flow sensor of the present invention can be inserted into extremely small locations within the body, such as inside blood vessels.

The sensor electrode of the present invention has a calorimetric sensor structure, including a micro heater and two thermistors positioned on both sides of the micro heater.

The micro heater generates heat based on ambient temperature changes, and the thermistors located on both sides are divided into an upstream thermistor located upstream of the heater and a downstream thermistor located downstream of the heater, which can detect the temperature generated by the fluid flow. In this structure, an electrical signal is generated due to the temperature difference according to the fluid flow, and the flow rate (flow velocity) can be measured.

Under constant flow conditions, the time it takes for heat to transfer from the microheater on the sensor electrode to the downstream thermistor varies with distance, and the heat transfer time is a factor affecting the linearity of the sensor response. In the present invention, the gap between the microheater on the sensor electrode and the thermistor can be adjusted to provide the most effective heat transfer time within a specific flow rate range.

In the sensor electrode of the present invention, the gap between the micro heater and the thermistor may be 10 to 50 μm, preferably 20 to 40 μm, and more preferably 25 to 35 μm. When the gap is adjusted to an optimal distance according to the present invention, the linearity of the response between the blood flow rate and the sensor output voltage can be corrected.

If the gap between the sensor electrodes is too narrow, the stability of the sensor may be significantly reduced when the flow rate exceeds a certain level, and if the gap is too wide, the problem of inconsistent results may occur at low flow rates. However, in the present invention, by optimizing the gap between the micro heater and the thermistor, a sensor with excellent actual flow rate and linearity in all sections of the flow rate can be manufactured.

In relation to this, in the embodiment of the present invention, when the gap between the sensor electrodes was 20 μm, an unstable result was confirmed at a flow rate of 200 mL/min or more, and when the gap was 40 μm, the result value at high flow rate was stable, but the consistency was reduced at low flow rate, whereas in the 30 μm sample, it was confirmed that the linearity with the actual flow rate was excellent at the flow rate of all sections.

In the sensor electrode of the present invention, the width of the thermistor may be 5 to 25 μm, preferably 10 to 20 μm. Within the above range, the design may be such that the heating temperature of the metal does not exceed 4°C.

In one embodiment of the present invention, the flow sensor may include a parylene coating layer formed to cover the guide wire and the sensor electrode.

Parylene is a general term for para-xylene ( p -xylene) polymers, and parylene coating is a chemical vapor deposition (CVD) coating technology that vaporizes powdered raw materials in a vacuum to form a polymer film.

The above parylene coating enables a coating having a uniform thickness and no pinholes, and can be designed to avoid thermal deformation and mechanical deformation. In the present invention, the thickness of the parylene coating layer may be 1 to 30 μm, preferably 5 to 20 μm, and more preferably 8 to 15 μm.

In the present invention, the upstream thermistor, micro heater, and downstream thermistor of the sensor electrode each have two terminals, and each terminal has a structure in which an electrode pad is connected. That is, a total of six electrode pads can be formed in the flow sensor of the present invention.

The width of the electrode pads may be 10 to 1,000 μm, preferably 50 to 200 μm, and the spacing between the electrode pads may be 10 to 1,000 μm, preferably 50 to 200 μm.

A wiring wire is connected to each electrode pad, and the wiring wire is inserted into the hollow portion of the guide wire through a slot formed in the guide wire. At this time, the diameter of the wiring wire may be 10 to 50 μm, preferably 20 to 30 μm.

The above electrode pad and wiring wire can be connected using a 1:1 individual attachment method or a simultaneous bonding method.

According to one embodiment of the present invention, when using a 1:1 individual attachment method, a probe station is used to align the guide wire pattern and the wiring wire so as to be perpendicular to each other, and a heating film is attached to the lower part of the guide wire to apply heat of 70℃ or higher. Next, a method may be used in which the pad of the sensor electrode pattern and the wiring wire are fixed using the fine adjustment arm of the probe station, and conductive epoxy is applied thereon and then fixed by heat for 10 minutes. After completing the bonding of the electrode pad and the wiring wire, the upper part of the bonding portion of the wiring wire can be cut off and conductive epoxy can be applied again to design an electrical signal connection.

When utilizing the above 1:1 individual attachment method, the process can be performed without removing the insulation film from the wiring wire, eliminating the need for additional processing steps to remove the ultra-thin insulation film. Furthermore, since no portion of the wiring wire's insulation is stripped, there is no risk of electrical short-circuiting.

In another embodiment of the present invention, a simultaneous bonding method can be utilized. In this case, simultaneous bonding is performed using the flip chip bonding technique. Specifically, a wiring fPCB is manufactured using a polyimide (PI) film that is separated from each wiring wire using a metal mold and fixed at the same interval as the electrode pads. A laser is then used to expose the cross-sections of the film and the wiring wires at the bonding site.

After that, a wiring bonding system is manufactured using a 3-axis stage, a 2-axis stage, and a rotation stage. Guide wires are mounted on the upper stage of the bonding system, and a wiring fPCB containing wiring wires is mounted on the lower stage. Then, the positions of the sensor electrode pads and signal lines of the guide wires are observed through a monitor from below and aligned so that they are orthogonal to each other. After applying conductive epoxy to the sensor electrode pads, they are attached to the wiring wire fPCB and heat is applied to harden the conductive epoxy.

When using the above simultaneous bonding method, the accuracy and efficiency of wiring can be improved, and repetitive wiring work can be reduced, which has the advantage of enabling high-throughput work.

FIG. 2 is a cross-sectional view of a sensor according to a preferred embodiment of the present invention. Referring to FIG. 2, a hollow guide wire (110), a Teflon coating layer (111) formed on the hollow guide wire (110), a microelectrode (120) formed on the Teflon coating layer (111), a parylene coating layer (112) formed to cover both the area where the microelectrode (120) is formed and the area where it is not formed, and a wiring wire (140) inserted into the hollow interior of the guide wire (110) can be confirmed.

The flow sensor of the present invention is an ultra-small sensor in which a heat flow sensor is embedded in a guide wire, so-called sensor-on-wire (SoW). It is very small in size and made of a biocompatible material, so that it can be inserted into the body, and by using it, blood flow can be accurately measured in a simple manner. Accordingly, the flow sensor of the present invention can be used in a blood flow measurement device.

Figure 3 illustrates a method for measuring blood flow in a blood vessel using a flow sensor of the present invention.

Referring to Fig. 3, when a sensor is inserted into a blood vessel, blood sequentially passes through an upstream thermistor, a micro heater, and a downstream thermistor on the surface of a guide wire. At this time, the flow rate can be detected by measuring the temperature difference between the downstream thermistor and the upstream thermistor, and when the resistance between the two thermistors is unbalanced, the temperature difference between the resistances on both sides of the sensor electrodes generates a voltage signal. Accordingly, a blood flow meter can be manufactured by connecting software for monitoring the flow rate signal to the sensor to monitor the flow rate signal and store the data. In addition, since the sensor of the present invention can detect not only the flow rate of blood but also the flow direction, it is possible to determine local reflux as well.

In the present invention, the output voltage is measured using software connected to the sensor, the distance (time) between peaks of the sensor signal waveform is set, and then the amplitude (peak-to-peak) value of the signal waveform is calculated. Since the amplitude of the output signal decreases as the flow rate (velocity) increases, the flow rate (velocity) can be measured by plotting the average amplitude value of the signal derived when each flow rate occurs on a result graph.

Thus, the ultra-miniature flow sensor of the present invention can be used as a micro-blood flow sensor for in vivo diagnosis, enabling accurate measurements through a simple sensor structure. Therefore, the present invention is expected to be usefully applied in the medical field, including to patients with cardiovascular disease, and thereby contribute to advancements and cost reductions in the medical field.

Example

The present invention is described in more detail through the following examples. However, these examples are intended to illustrate some experimental methods and configurations of the present invention, and the scope of the present invention is not limited to these examples.

Manufacturing Example: Fabrication of a sensor-on-wire type flow sensor

A flow sensor in the form of a sensor-on-wire was manufactured by coating a silver nanoparticle solution on a stainless steel guide wire (SUS304) as shown in the process in Fig. 4 and forming a microelectrode through laser filament scanning sintering using a Bessel beam.

First, before forming electrodes on the guide wire, pretreatment of the guide wire was performed as shown in Fig. 5. A guide wire with a diameter of 340 μm was sonicated in an ethylene alcohol solution to remove contamination and then dried with nitrogen (N ₂ ) gas. Subsequently, the guide wire was air plasma treated for 5 minutes at a power of 100 W. A Teflon solution (PTFE, 320G-804, DuPont ^™ ) was stirred at 200 rpm for 2 hours and left in a vacuum for 20 minutes to remove internal pores. Then, the surface of the guide wire was uniformly coated by dipping it into the Teflon solution at a speed of 60 mm/min (1 mm/s). The Teflon-coated guide wire was baked at 300°C for 30 minutes to remove the solvent and harden it.

Afterwards, the silver nanoparticle solution was uniformly coated on the Teflon-coated wire using the dip coating method at a speed of 1 mm/s, and the coating was repeated three times to obtain a sufficient thickness. The nanoparticle solution used was a solution (WA-2, Winletech) containing 35 wt% silver nanoparticles with an average particle diameter of 80 nm dispersed in isopropyl alcohol (IPA).

Laser filament scanning sintering (LFSS) was performed using a continuous wave (CW) fiber laser (IPG Photonics Co., Ltd) with a maximum output of 10 W and a wavelength of 1070 nm in Gaussian spatial mode (M2=1.05) as a light source.

Figure 6 schematically illustrates the design of an optical system for transforming a Gaussian laser beam into a Bessel beam. A normalized laser beam was transmitted to a conical axicon lens with an angle of 2° using a beam expander and an iris, and a first Bessel beam was formed through a plano-convex lens with a focal length of 200 mm. The first Bessel beam was passed through a 2D galvanometer scanner (SCANLAB Gmbh) and focused with an F-theta lens with a focal length of 100 mm to form a laser filament spot (15 μm) with a Bessel profile.

A guide wire coated with a silver nanoparticle solution was placed perpendicular to the laser beam incidence axis and pulled by magnetic grippers located at both ends of the wire. The path of the laser filament beam spot was programmed using computer-aided design (CAD) software, and after irradiating the laser, the solution layer not exposed to the laser was removed with deionized water. The wire was post-baked at 200°C for 2 hours to remove residual organic substances and enhance the aggregation of the laser-sintered nanoparticles. Thus, an electrode having two thermistors (upstream and downstream) and a heater was formed through laser filament sintering, as shown in Fig. 7, and a micro-patterned electrode was formed according to the design of Fig. 8.

In order to evaluate the microstructural perfection of the above electrode pattern, the structure was confirmed using a high-resolution scanning electron microscope (SEM), and the results are shown in Fig. 9. As a result, no patterning defects such as peeling, microcracks, or short circuits were observed in the electrode.

In the sensor composed of the above micro heater, two thermistor circuits, six pads, and extension electrodes, six pads and 25 ㎛ diameter copper wires (6-filar polyimide, SANDVIK) were soldered to transmit signals from the thermistor and supply power to the heater. In addition, a parylene-C (DIX-C) coating with a thickness of approximately 10 ㎛ was formed to insulate and protect the circuit from blood. The six copper wires were connected to a flexible circuit film so that they could be connected to a Wheatstone bridge circuit board for sensor operation. The voltage signal generated by the fluid flow was obtained at a sampling rate of 100 Hz using a PCB and analysis software using Python. Accordingly, a prototype sensor device as shown in Fig. 10 was fabricated.

To test the sensor's operation, the sensor module was inserted into a water-filled, blood vessel-shaped tube. A 10 mA current was applied to a microheater via the connected pad. Heat generation was detected, and the resulting temperature change was observed using a thermal imaging camera. The temperature change was confirmed to be less than 4°C, confirming that the sensor system of the present invention can effectively operate within human coronary arteries.

Experimental Example 1: Analysis of Electrode Characteristic Changes According to Laser Output

In the fabrication of the sensor in the manufacturing example, the laser output was changed to 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and 1.0 W when forming the microelectrode, and the characteristic changes accordingly were analyzed.

Figure 11 shows the changes in the electrode line width (㎛) and linear resistance (Ω/mm) according to the laser output. Referring to the experimental results, it can be confirmed that as the laser output increases, the electrode line width gradually increases due to heat diffusion in the peripheral area, and the linear resistance decreases inversely proportional to the line width.

As a result of the experiment, a pattern width of 15 μm could be formed at a laser power of 0.7 W and a scan speed of 50 mm/s, and the linear resistance was measured to be 85 Ω/mm. Therefore, 0.7 W was selected as the optimal laser power condition for designing an optimal pattern and optimizing electrical characteristics.

Experimental Example 2: Confirming the shape and durability of the electrode.

Figure 12 shows a confocal microscope photograph of an electrode fabricated on a guide wire, and it can be confirmed that an electrode with a thickness of approximately 270 nm was formed without defects on a guide wire with a radius of curvature of 170 μm.

In addition, since mechanical durability is very important for in-body medical sensors, the adhesive strength of the electrodes was tested by performing a peel test several times with Scotch tape (3M) on the manufactured sensor, and the resulting photo is shown in Fig. 13.

As can be seen from Fig. 13, the character electrode pattern (KMU) remained firmly bonded despite multiple peeling tests. Accordingly, it was confirmed that the electrode manufactured using the laser filament scanning sintering method possessed excellent durability.

Experimental Example 3: Determining the Suitability of a Heartbeat Simulation Device and Sensor

An artificial heartbeat simulator was developed that simulates the periodic fluid dynamic properties of cardiac blood flow.

The experiment was conducted by installing a commercial flow sensor (FD-XS1; Keyence, USA) of the Delta TOF type using ultrasound in the center of a tube to measure the real-time flow rate of water maintained at 35 to 40°C. The sensor was inserted into the tube through a medical Y connector, and the voltage signal obtained by the temperature difference between two thermistors was obtained in the range of 90 to 110 bpm and fluid flow velocity of 20 to 50 cm/s. An artificial blood vessel with an inner diameter of 3 mm, corresponding to the average size of a human coronary artery, was used as an artificial blood vessel in the heart rate simulator.

The fabricated sensor, commercial flow sensor, and pressure sensor were arranged as shown in Fig. 14, and the output voltage of the sensor was compared with the actual flow rate of the commercial flow sensor to derive a calibration curve, which was used as reference data for verifying accuracy. In addition, the internal pressure according to the flow rate change was detected by the pressure sensor. To verify the reliability of the device, the discharge amount according to the actual water pressure was measured with a scale, and the consistency with the values obtained from the commercial sensor was evaluated, and the result was confirmed to show 99% consistency.

In clinical studies, the average blood flow in patients with coronary artery stenosis was reported to be 170 to 400 mL/min, and even in cases of severe stenosis, it was reported to be 120 to 185 mL/min. Based on these results, the flow rate range for verifying the performance of the sensor-on-wire was set to 100 to 300 mL/min.

Additionally, the output voltage was used at 90 to 110 beats per minute (bpm) to mimic the normal human heart rate. Voltage signals based on flow rate were analyzed using commercial code (Matlab, MathWorks) to derive voltage values for each flow rate.

Figure 15 shows the linear correlation between the average voltage amplitude obtained from the sensor-on-wire and the actual flow rate (100–300 mL/min) of a commercial flow sensor. It can be seen that the amplitude decreases as the flow rate increases, and the average voltage amplitude decreases linearly with increasing flow rate. The evaluation of the measurement resolution of the sensor-on-wire showed that the average voltage amplitude decreased by approximately 4.2 μV as the flow rate increased by 5 cm/s.

Figure 16 demonstrates the linearity and consistency of flow data between a commercial ultrasonic flow sensor and a sensor-on-wire. The results show a slope of nearly 1, confirming that the sensor-on-wire offers accuracy comparable to that of the commercial sensor at flow rates up to 300 mL/min.

Experimental Example 4: Analysis of Sensor Performance According to the Distance Between Sensor Electrodes

To improve the accuracy of the flow sensor, the linearity of the response between the blood flow velocity and the sensor output voltage was compensated by adjusting the distance between the sensor electrodes.

The linearity of the sensor's response is affected by the separation distance (gap) between the heater and the thermistor, because the time required for heat to transfer from the heater to the downstream sensor varies with distance.

Based on the simulation results, the separation distance selected as 10 to 20 μm was changed to 20 to 40 μm, and the response linearity was analyzed. As shown in Fig. 17, three types of sensor samples with different separation distances of 20, 30, and 40 μm were manufactured, and then the fluid flow rate was measured under conditions of 100 to 300 mL/min with a pulse rate of 60 beats per minute, and the results are shown in Figs. 18a to 18c, respectively.

Experimental results show that samples with electrode spacings of 20 and 40 μm tend to deviate from linearity at certain flow rates, whereas samples with a spacing of 30 μm exhibit a constant negative slope across the entire flow rate range. Accordingly, it was confirmed that 30 μm is the optimal distance between electrodes for flow rates ranging from 100 to 300 mL/min.

Experimental Example 5: Animal Experiment for Coronary Blood Flow Measurement

Using the sensor system manufactured in the manufacturing example, blood flow was measured in the coronary artery of an experimental animal.

A Yorkshire mail pig weighing approximately 30 kg was used in the experiment, and a cylindrical hypotube (SMART-hypo01, Course Wire) with an inner diameter of 240 μm was used as the template wire. An alloy of nickel and platinum coil was attached to the tip of the wire for flexibility and X-ray detection.

The electrodes of the sensor were extended to a length of more than 80 cm so that they could reach the coronary artery of the animal through the carotid artery, and a copper wire strand for signal connection was placed inside the hypotube medical guide wire through a 90° cut, 0.8 mm long slot for gentle insertion into the blood vessel.

The above animal experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC, Approval No. KBIO-IACUC-2021-189). A 7-cm incision was made in the skin to insert a catheter into the left and right coronary arteries, and a sensor-on-wire was inserted through the catheter. The tip position and direction of advancement of the sensor-on-wire were manipulated through in situ X-ray monitoring. After collecting data on normal blood flow, 1 to 2 mg of nitroglycerin (1 mg, Myungmoon Pharmaceutical) or nicorandil (48 mg, JW Pharmaceutical) vasodilators were administered to temporarily increase coronary blood flow.

Figure 19 shows an X-ray image monitoring photograph after inserting a sensor into a coronary artery, and in this way, the position and direction of the sensor tip in the coronary artery can be manipulated through real-time monitoring.

Figure 20 shows the transient voltage signals corresponding to blood pressure and flow rate during an in-vivo animal experiment, and the fluid dynamic characteristics and periodic waveform of the sensor-on-wire can be confirmed. In addition, Figure 21 shows the voltage signal changes in blood flow (normal state and hyperemic state) according to the injection of a vasodilator. In the hyperemic condition, the average amplitude was reduced by 8 to 40% compared to the normal state, and it was confirmed that the sensor can clearly detect the change in flow rate according to the actual blood flow change caused by the drug.

Figures 22a and 22b show the changes in the average voltage amplitude obtained by artificially controlling blood flow in the left coronary artery with a drug in two animal experiments, respectively.

Referring to Fig. 22a, in the first animal experiment, the amplitude (0.36 mV) in the resting state decreased to 0.31 mV in the hyperemic state, resulting in a 14% voltage decrease. Converting the flow rate using the regression equation derived from the heartbeat simulator experiment means that the blood velocity increases from 75.4 cm/s (377 mL/min) to 89.5 cm/s (447 mL/min). Referring to Fig. 22b, in the second animal experiment, the amplitude decreased by 8% from 0.37 mV to 0.35 mV, which means that the blood velocity increases from 62.5 cm/s (321 mL/min) to 76.2 cm/s (381 mL/min). Thus, a blood flow velocity of approximately 60 to 90 cm/s was detected in the left coronary artery of the pig through the animal experiment.

After completing data collection, the sensor was left in a blood vessel for 1 hour to evaluate its biocompatibility. After removal, the wire surface was checked for thrombosis. As a result, thrombosis formation was minimized even after long-term exposure to the blood vessel, confirming that the sensor is biocompatible.

From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical concept or essential characteristics. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as encompassing all changes or modifications derived from the meaning and scope of the following claims and their equivalent concepts, rather than the detailed description above.

110 Guide wire 111 Teflon coating layer
112 Parylene coating layer 120 Sensor electrode
121 Micro Heater 122 Thermistor
130 electrode pads 140 wiring wires
S slot

Claims (19)

hollow guide wire;
A sensor electrode positioned on the guide wire and including a micro heater and two thermistors positioned on both sides of the micro heater;
Electrode pads connected to each end of the sensor electrode; and
A wiring wire connected to the above electrode pad and inserted into the hollow through a slot formed in the guide wire
As a flow sensor, including:
A flow sensor having a gap between the micro heater and the thermistor of 25 to 35 μm.
In the first paragraph,
A flow sensor, wherein the diameter of the above guide wire is 200 to 500㎛.
In the first paragraph,
A flow sensor, wherein the thickness of the above guide wire is 10 to 100㎛.
delete In the first paragraph,
A flow sensor further comprising a Teflon coating layer between the guide wire and the sensor electrode.
In the first paragraph,
A flow sensor further comprising a parylene coating layer formed to cover the sensor electrode and guide wire.
In paragraph 6,
A flow sensor, wherein the thickness of the parylene coating layer is 1 to 30 μm.
In the first paragraph,
A flow sensor, wherein the diameter of the wiring wire is 10 to 50㎛.
A method for manufacturing a flow sensor, comprising the following steps:
A step of forming a sensor electrode including a micro heater and two thermistors positioned on both sides of the micro heater and an electrode pad connected to each end of the sensor electrode using laser patterning on a hollow guide wire, wherein the gap between the micro heater and the thermistor is 25 to 35 μm;
A step of connecting a wiring wire to the above sensor electrode pad; and
A step of inserting the above wiring wire into the hollow space through the slot of the guide wire.
In paragraph 9,
A method for manufacturing a flow sensor, further comprising a step of forming a Teflon coating layer before forming a sensor electrode on the guide wire.
In paragraph 10,
A method for manufacturing a flow sensor, wherein the step of forming the Teflon coating layer comprises the step of coating a Teflon solution on the guide wire; and the step of forming a Teflon coating layer by heat-treating and hardening the coated Teflon solution.
In paragraph 11,
A method for manufacturing a flow sensor, wherein the above Teflon solution coating is performed by dipping a guide wire into a Teflon solution at a coating speed of 0.1 to 10 mm/s.
In paragraph 11,
A method for manufacturing a flow sensor, wherein the above heat treatment is performed at 200 to 400°C for 10 to 60 minutes.
In paragraph 10,
A method for manufacturing a flow sensor, further comprising a step of plasma treating the guide wire before forming a Teflon coating layer on the guide wire.
In paragraph 14,
A method for manufacturing a flow sensor, wherein the above plasma treatment is performed at 10 to 1,000 W for 1 to 20 minutes.
In paragraph 9,
A method for manufacturing a flow sensor, wherein the output of the laser beam in the above laser patterning step is 0.1 to 10 W.
In paragraph 9,
Laser patterning of the above sensor electrodes,
A step of forming a nanoparticle solution layer by applying a nanoparticle solution on a guide wire; and
A step of forming a micro pattern on the surface of the guide wire by irradiating the nanoparticle solution layer with a Bessel beam laser to induce sintering of the nanoparticles.
A method for manufacturing a flow sensor, performed by.
In paragraph 9,
A method for manufacturing a flow sensor, further comprising a step of forming a parylene coating layer after forming the sensor electrode.
A blood flow meter comprising a flow sensor according to any one of claims 1 to 3 and claims 5 to 8.