Hemodynamic monitoring system

Abstract

A hemodynamic monitoring system comprising an endovascular catheter configured to measure hemodynamic parameters and a monitoring system configured to receive the measurements from the endovascular catheter and provide hemodynamic information based on the measurement. The endovascular catheter comprises a pressure sensors arrangement comprising a plurality of pressure sensors (10), the pressure sensors arrangement being mounted to a core-wire of the endovascular catheter, wherein said pressure sensors are distributed spaced apart along the core-wire.

Description

[0001] P2950PC00

[0002] Hemodynamic monitoring system

[0003] Technical field

[0004] The present invention relates to a hemodynamic monitoring system.

[0005] Background

[0006] Hemodynamic monitoring is used to assess cardiovascular function and health. Various hemodynamic parameters, such as pressure gradients and blood flow, help evaluate vascular conditions and guide interventional procedures.

[0007] When high precision in assessing coronary blood flow and pressure is required, catheter-based monitoring methods are often used. Conventional catheters are mostly optimized for measuring blood pressure and rely on fluid-filled lumens to transmit pressure from the blood vessel to an external transducer; however, these systems suffer from delayed response times and fluid-induced artifacts. At the clinical level, there is currently no solution to monitor the pressure distribution in an investigated vessel without avoiding the repositioning of a single-sensor endovascular catheter. Additionally, blood flow is typically measured separately using either Doppler ultrasound or thermodilution techniques. Doppler ultrasound assesses blood velocity but requires precise alignment with the blood flow and is highly susceptible to interference from turbulence or vessel calcification. In contrast, thermodilution calculates blood flow by injecting a thermal indicator and analyzing downstream temperature changes; its accuracy, however, depends on proper mixing of the indicator and is sensitive to variations in injection technique and temperature conditions.

[0008] Micro-Electro-Mechanical Systems (MEMS) based pressure sensors having diaphragms combined with piezoresistive or capacitive elements are known. However, achieving high precision at ultra-small sizes of less than 500 pm for MEMS based sensors is challenging. Implementation of MEMS based sensors for monitoring microcirculation in coronary arteries, which can have diameters of less than 400 pm, is thus not viable in practice with current conventional systems.

[0009] Summary

[0010] In view of the foregoing, it is an object of the invention to provide a hemodynamic monitoring system comprising an endovascular catheter that is very compact yet very precise.

[0011] It is advantageous to provide a hemodynamic monitoring system comprising an endovascular catheter that provides multiple hemodynamic information.P2950PC00

[0012] It is advantageous to provide a hemodynamic monitoring system comprising an endovascular catheter that can measure hemodynamic parameters in very small coronary arteries.

[0013] It is advantageous to provide a hemodynamic monitoring system comprising an endovascular catheter that is economical to implement and operate.

[0014] It is advantageous to provide an endovascular catheter of a hemodynamic monitoring system that is minimally invasive.

[0015] It is advantageous to provide a pressure sensor for an endovascular catheter of a hemodynamic monitoring system that is economical to manufacture.

[0016] It is advantageous to provide a pressure sensor for an endovascular catheter of a hemodynamic monitoring system that is very compact yet very precise.

[0017] Objects of the invention have been achieved by providing the system and methods according to the independent claims. Dependent claims set out various advantageous features of embodiments of the invention.

[0018] Disclosed herein is a hemodynamic monitoring system comprising an endovascular catheter configured to measure hemodynamic parameters and a monitoring system configured to receive the measurements from the endovascular catheter and provide hemodynamic information based on the measurement.

[0019] The endovascular catheter comprises a solid non-hollow core-wire and a pressure sensors arrangement comprising a plurality of pressure sensors, the pressure sensors arrangement being mounted to the core-wire of the endovascular catheter, wherein said pressure sensors are distributed in a spaced apart manner along the core-wire and configured to measure blood pressure at corresponding position at the core-wire. The core-wire is configured for providing a mechanical support for the pressure sensors arrangement and maintaining mechanical stability of the endovascular catheter in a blood vessel. The monitoring system is configured to provide a pressure gradient and flow rate using the measured blood pressures along the core-wire, wherein each pressure sensor is mounted to a sensor support comprising an orifice through which the core-wire is inserted.

[0020] The mounting of pressure sensors on a core-wire allows to provide a very compact, smallP2950PC00

[0021] diameter catheter with a high bending flexibility which is easy to guide, yet offering a high tensile strength and robust catheter despite the very small diameter. Another important advantage of the core-wire is that it simplifies manufacturing, in particular the assembly of the pressure sensors in a distributed manner along the catheter by mounting over, e.g. by sliding over, the core-wire.

[0022] In an advantageous embodiment, the monitoring system further is further configured to display the hemodynamics.

[0023] In an advantageous embodiment, the catheter further comprises an outer tube having a distal end and a proximal end, wherein the core-wire extends inside the outer tube, the outer tube comprising at least one opening adjacent each said pressure sensor.

[0024] In an advantageous embodiment, the sensor support comprises a flexible polymer film.

[0025] In an advantageous embodiment, the pressure sensor comprises:

[0026] - a substrate having a recess formed therein;

[0027] - a membrane on the substrate covering the recess;

[0028] - a membrane deformation sensor on the membrane; and

[0029] - electrical connection terminals connected to said membrane deformation sensor.

[0030] In an advantageous embodiment, said membrane deformation sensor comprises an active sensing element positioned at least partially over the recess and a passive sensing element that is not over the recess.

[0031] In an advantageous embodiment, the active sensing element and the passive sensing element are electrically coupled.

[0032] In an advantageous embodiment, the pressure sensor further comprises an insulation layer over the membrane.

[0033] In an advantageous embodiment, said membrane deformation sensor comprises a piezoresistive material.

[0034] Also disclosed herein is a method for fabricating a pressure sensor, the method comprising: - providing a substrate;

[0035] - depositing a membrane on the substrate;P2950PC00

[0036] - forming orifices in the membrane;

[0037] - forming a recess in the substrate below the membrane by an etching process employing chemicals passing through the orifices to the substrate below the membrane; and

[0038] - sealing the orifices by an additive process to re-form the membrane.

[0039] In an advantageous embodiment, forming the orifices comprises

[0040] - providing an etching mask on the membrane, the etching mask defining an area of the recess and comprising a submicron etching pattern; and

[0041] - etching the membrane according to the etching mask.

[0042] In an advantageous embodiment, the method further comprises forming an insulation layer on the membrane layer, said membrane deformation sensor, and electrical connection terminals.

[0043] In an advantageous embodiment, the method further comprises providing at least one electrical contact point by removing a portion of the insulation layer covering the electrical connection terminals.

[0044] Also disclosed herein is a method for assembling an endovascular catheter, the method comprising:

[0045] - providing a sacrificial layer;

[0046] - mounting a plurality of sensor supports on the sacrificial layer, and a plurality of MEMS pressure sensors on the sensor supports;

[0047] - connecting interconnection leads to each pressure sensor;

[0048] - detaching said sensor supports from the sacrificial layer; and

[0049] - mounting said sensor supports to a core-wire in a distributed spaced apart manner.

[0050] In an advantageous embodiment, the method further comprises mounting the core-wire inside an outer tube.

[0051] In an advantageous embodiment, the method further comprises slidably mounting the sensor supports along the core-wire.

[0052] In an advantageous embodiment, the detaching of said sensor supports is performed by electrochemical etching of the sacrificial layer.

[0053] Further advantageous features of the invention will be apparent from the following detailed description of embodiments of the invention and the accompanying illustrations.P2950PC00

[0054] Brief description of the figures

[0055] Figures 1 a-c show schematic illustrations of embodiments of a hemodynamic monitoring system according to the invention;

[0056] Figure 2 illustrates a schematic illustration of an endovascular catheter of a hemodynamic monitoring system according to an embodiment of the invention;

[0057] Figure 3a illustrates another schematic illustration of an endovascular catheter of a hemodynamic monitoring system according to an embodiment of the invention;

[0058] Figures 3b to 3f illustrate enlarged schematic illustrations of various segments of the endovascular catheter illustrated in Figure 3a;

[0059] Figures 4a to 4c illustrate cross-sectional views though lines A-A, B-B, C-C respective of the endovascular catheter illustrated in Figures 3b, 3c, 3e;

[0060] Figure 5a is a perspective view with transparency of a portion of an endovascular catheter showing a core-wire and a pressure sensor according to an embodiment of the invention; Figure 5b is a perspective view of a pressure sensor mounted to a core-wire of an endovascular catheter according to an embodiment of the invention;

[0061] Figures 6a-c illustrate perspective views of several variations of a sensor support of an endovascular catheter according to an embodiment of the invention;

[0062] Figure 7a is a perspective view of a pressure sensor of an endovascular catheter of a hemodynamic monitor system according to an embodiment of the invention;

[0063] Figure 7b is a cross-sectional view of a pressure sensor of an endovascular catheter of a hemodynamic monitor system according to an embodiment of the invention;

[0064] Figures 8a to 8g show schematic illustrations of an assembly process of an endovascular catheter according to an embodiment of the invention;

[0065] Figure 9 illustrates steps a to j of a fabrication process of a pressure sensor of an endovascular catheter of a hemodynamic monitor system according to an embodiment of the invention; Figure 10a is a schematic illustration of microarteries of a coronary artery and an endovascular catheter according to an embodiment of the invention;

[0066] Figure 10b is a schematic illustration of microarteries of a coronary artery and an endovascular catheter according to an embodiment of the invention;

[0067] Figure 10c is a diagram of pressure measurements over time by different pressure sensors of an endovascular catheter of a hemodynamic monitoring system according to an embodiment of the invention;

[0068] Figure 10d is a schematic diagram of positioning of a plurality of pressure sensors mounted to a core-wire of an endovascular catheter of a hemodynamic monitoring system according to an embodiment of the invention;

[0069] Figure 10e is a diagram of a flow rate measured by a hemodynamic monitoring system accordingP2950PC00

[0070] to an embodiment of the invention;

[0071] Figure 11a is an electron microscope image showing a top view of multiple pressure sensors according to an embodiment of the invention;

[0072] Figure 11b is an electron microscope image showing a top view of a first layer of a pressure sensor according to an embodiment of the invention after etching the first layer according to a porous pattern of an etching mask according to a method of the invention;

[0073] Figure 11 c is an electron microscope image showing a cross-sectional view of a pressure sensor in forming a recess within a substrate of the pressure sensor according to for fabricating a pressure sensor of invention;

[0074] Figure 11 d is an electron microscope image showing an enlarged cross-sectional view of the pressure sensor in Figure 11c;

[0075] Figure 12 shows an electron microscope image of pressure sensors during a fabrication process before release and integration on the core wire with its different components, according to an embodiment of the invention;

[0076] Figure 13a is a perspective view of an endovascular catheter of a hemodynamic monitoring system according to an embodiment of the invention;

[0077] Figures 13b to 13e are perspective views of a pressure sensors arrangement of a endovascular catheter according to embodiments of the invention, the pressure sensors arrangement comprising a plurality of pressure sensors mounted to a sensor support, where the sensor support comprises electrical connection terminals, electrically connecting interconnection leads to each electrical connection terminals of the pressure sensor, and the pressure sensors are connected to the electrical connection terminals of the sensor support using various methods, whereby:

[0078] Figure 13b illustrates that the pressure sensors are connected to the electrical connection terminals of the sensor support by solder balls and gluing;

[0079] Figure 13c illustrates that the pressure sensors are connected to the electrical connection terminals of the sensor support by wire bonding and gluing;

[0080] Figure 13d illustrates that the pressure sensors are connected to the electrical connection terminals of the sensor support by gold bumps and flip chip bonding; and Figure 13e illustrates that the pressure sensors are connected to the electrical connection terminals of the sensor support by patterned conductive glue and flip chip bonding.

[0081] Descriptions

[0082] Referring to the figures, a hemodynamic monitoring system 20 according to embodiments of the invention comprises an endovascular catheter 1, as an endovascular measurement unit, and monitoring unit 30.P2950PC00

[0083] The endovascular catheter 1 is configured to measure hemodynamic parameters. The monitoring unit 30 is configured to receive the measurements from the endovascular catheter 1 and to provide hemodynamic information.

[0084] The endovascular catheter 1 comprises a pressure sensors arrangement 4 comprising a plurality of pressure sensors 10 and a solid non-hollow core-wire 3. The pressure sensors arrangement 4 is mounted to the core-wire 3 of the endovascular catheter 1. The pressure sensors 10 are distributed along the core-wire 3 configured to acquire simultaneous multi-point pressure measurements along the core-wire 3. This avoids the need for repositioning the endovascular catheter 1 along a blood vessel to acquire blood pressures at different positions within the blood vessel sequentially.

[0085] The sensors are preferably equally spaced within a range of 10 to 15 cm along the distal part of the catheter. The distance between them may be calculated by the total spacing divided by number of sensors, of which there are at least three.

[0086] The monitoring unit 30 comprises a data acquisition system (DAQ) including a receiving section 31 to receive the measurements from the pressure sensors 10 and a processing section 32 to process the measurement signals. The pressure sensors arrangement 4 may output a digital signal or alternatively an analog signal, in which case the receiving section 31 may be configured to convert the analog outputs of the pressure sensors 10 into a digital signal. The monitoring unit may further comprise a displaying section 33 configured to display the hemodynamic information received from the processing section 32. For instance, the displaying section 33 may display blood pressures and / or blood flow rates at different points within the blood vessel punctually or as a continuous monitoring process over a certain time period.

[0087] In an embodiment, the endovascular catheter 1 may comprise an outer tube 2 extending from a distal end 7 to a proximal end 8, the core-wire 3 mounted inside the outer tube 2. The outer tube 2 comprises at least one opening 9 for each pressure sensor, such that the pressure sensor is in fluid communication with the environment around the tube, in particular with the blood in an artery.

[0088] An example of preferred dimensions are as follows:

[0089] • Target Blood Vessel Diameter: 0.2 mm - 30 mm (suitable for a wide range of blood vessels, including major vessels such as the aorta, vena cava, as well as peripheral vessels).

[0090] • Outer Tube Diameter: Approximately 0.18 mm - 0.36 mm (comparable with standard 0.007”P2950PC00

[0091] and 0.014” guidewire profiles).

[0092] Core-Wire Diameter: Ranges between 0.05 mm - 0.09 mm to ensure flexibility yet sufficient mechanical support for sensor integration.

[0093] The proximal end 8 of the outer tube 2 comprises a connector 8 which is electrically coupled to the pressure sensors of the pressure sensors arrangement 18 via one or more interconnection lead(s) 6. The connector 8 is configured to connect to a wireless transmitter or to a wired connection, for transmission of the pressure measurement signals to the monitoring system 30.

[0094] The pressure sensors may be mounted on one or more sensor supports 5 assembled to the core-wire 3.

[0095] In advantageous embodiments, for instance as illustrated in figures 5b, 6b, 6c and 8d, the sensor support 5 may be slidably mountable along the core-wire 3 during assembly of the endovascular catheter 1. After assembly, the position of the sensor support 5 is fixed such that the position of the pressure sensors are maintained and the spacing between each pressure sensors remains unchanged.

[0096] The sensor support 5 may comprise a sensor mounting portion 23 and a core-wire mounting portion 25. The pressure sensors are mounted to the sensor mounting portion 23 and the corewire mounting portion 25 is coupled to the core-wire 3. The core mounting portion may comprise an orifice or passage through which the core wire may be inserted, or may comprise latches, clips, or other mechanical means to fix the sensor support to the core-wire. The core mounting portion may also be configured for bonding to the core-wire by an adhesive or by a weld or solder connection. In certain embodiments, the sensor support comprises a passage or orifice and is movable slidably along the core-wire 3 during assembly.

[0097] In an embodiment, as illustrated in figures 8a, 8b and 8d, the sensor support 5 is in the form of a thin flexible film, for instance a polymer film, comprising at least one orifice configured to allow the core-wire 3 to pass through.

[0098] In advantageous embodiments, the sensor support 5 may further comprise electrical connection terminals configured to connect the interconnection leads to the electrical connection terminals of the pressure sensors. The electrical connection terminals are preferably positioned adjacent to a distal end of the sensor support 5. The interconnection leads 6 are connected to the electrical connection terminals of the sensor support by welding or by thermocompression bonding. The pressure sensors are electrically connected to the electrical connection terminalsP2950PC00

[0099] of the sensor support by solder balls and gluing, wire bonding and gluing, gold bumps and flip chip bonding, or patterned conductive glue and flip chip bonding (see Figures 13a-13e).

[0100] The pressure sensor 10 comprises a substrate 11 with a recess 12 formed within the substrate 11, and a membrane 13 on the substrate 11 covering the recess 12. The substrate may for instance comprise or consist of silicon Si or polymers such as polyimide or liquid crystal polymer (LCP). The recess 12 covered by the membrane may form a reference chamber for pressure sensing. The pressure sensor 10 further comprises a membrane deformation sensor 14 on the membrane 13. The membrane deformation sensor 14 comprises electrical connection terminals 17 for electrical connection to an interconnection lead 6 that extends to the connector 18 such that the measurements by the pressure sensor arrangement 4 is transmitted to the monitoring unit 30. In an embodiment, the electrical connection terminals 17 comprise gold (Au).

[0101] In an embodiment, the membrane 13 comprises or consists of a low-stress silicon nitride (Sisl^ ) or silicon (Si), polysilicon, silicon oxide (SiC>2), silicon oxynitride (SiON), silicon carbide (SiC), aluminum oxide (AI2O3), aluminum nitride (AIN), graphene, titanium nitride (TiN), polyimide, parylene-C, polydimethylsiloxane (PDMS).

[0102] In an embodiment, the membrane deformation sensor 15 comprises a piezoresistive material. In an example, the membrane deformation sensor 15 comprises a p-type boron-doped polysilicon. N-type phosphorus-doped polysilicon could also be used. In terms of doping techniques, diffusion doping, ion implantation and in-situ doping could be used.

[0103] In an embodiment, the membrane deformation sensor 15 comprises an active sensing element 15a positioned at least partially over the recess 12 and a passive sensing element 15b that is not positioned over the recess. The active sensing element and the passive sensing element are electrically coupled.

[0104] In an embodiment, the pressure sensor 10 comprises an insulation cover layer 19 made of a biocompatible material, for instance an aluminum oxide (AI2O3).

[0105] A method for producing the endovascular catheter 1 according to an embodiment includes providing a sacrificial layer 28, mounting the sensor supports 5 on the sacrificial layer and the pressure sensors 10 on the sensor supports, and connecting the interconnection leads 6 to the terminals 17 of each pressure sensor 10, for instance by welding or soldering. The sensor supports 5 may then be detached from the sacrificial layer 28, for instance by etching away the sacrificial layer, or by debonding the sensor supports from the sacrificial layer by electro-erosion,P2950PC00

[0106] ultrasonic or thermal means. The sensor supports, in a variant, may also be formed from the material of the sacrificial layer and the parts of the sacrificial layer to be removed may be removed mechanically, thermally (e.g. laser cutting), or chemically (e.g. by etching, using a photomask that protects the sensor supports and exposes the surrounding material for chemical etching). In an embodiment, the sacrificial layer 28 may be a tungsten-aluminum (WAI) layer or other sacrificial layers such as glucose-based, salt-based, polymer-based.

[0107] In an embodiment, mounting the pressure sensors 10 to corresponding sensor support 5 comprises is performed by gluing the pressure sensors 10 to each sensor support 5 using micro dispensing of cyanoacrylate or epoxy glue.

[0108] The interconnection leads 6 can be coupled to the pressure sensors 10 by bonding using the thermo-compression. The thermo-compression bonding enables to couple the interconnection leads 6 to the pressure sensors 10 without removing an insulation layer of the interconnection leads 6 before coupling.

[0109] The interconnection leads 6 may further be encapsulated in an insulating material, to protect the bonding of the interconnection leads 6.

[0110] After detaching, the pressure sensors 10 mounted to corresponding sensor supports 5 and connected to interconnection leads 6 may be assembled to the core-wire 3. Assembly of the sensor supports 5 to the core-wire 3 may be by sliding each sensor support 5 along the corewire or by or by latching, clipping or other mechanical means to fix the sensor support to the core-wire, or by bonding the sensor support to the core-wire by an adhesive or by a weld or solder connection.

[0111] The sensor supports 5 are distributed along the core-wire 3 with a predefined spacing between them configured to obtain a measurable pressure difference in an artery. The core-wire 3 may then be inserted into the outer tube 2, or the outer tube may be formed around the core wire and pressure sensor arrangement 4, for instance by wrapping around a flat sheet into a tube and welding the longitudinal seam to form the outer tube. The outer tube may also be formed by coating or depositing the outer tube material around and along the core wire.

[0112] In an embodiment, the method further comprises aligning the interconnection leads 6 at the proximal end and connecting the interconnection leads to terminals of the connector 18.

[0113] In the illustrated embodiment, the connector terminals are in the form of contact sleeves throughP2950PC00

[0114] which the interconnection leads may be inserted, one of the interconnection leads being electrically connected to one corresponding contact sleeve by welding, or particularly by thermos-compression bonding.

[0115] In an embodiment, the method further comprises mounting a distal tip 16 to the distal end 7, for instance by bonding or soldering the distal tip 16 to the distal end 7.

[0116] Figures 8a-8g show schematic illustration of the method to assemble the endovascular catheter 1 according to an embodiment of the invention.

[0117] Figure 8a shows that a plurality of the sensor supports 5 are mounted to the sacrificial layer 28 and an enlarged schematic illustration demonstrates the sensor supports 5 and one pressure sensor 10 mounted on corresponding sensor support 5.

[0118] Figure 8b shows coupling the interconnection leads 6 connected to terminals of the pressure sensor 10.

[0119] Figure 8c shows electrochemical etching of the sacrificial layer 28.

[0120] Figure 8d shows mounting the sensor supports 5 to the core-wire 3 by sliding each sensor support 5 along the core-wire 3.

[0121] Figure 8e shows inserting the core-wire 3 into the outer tube 2. An arrow shown in Figure 8e indicates the direction of the insertion of the core-wire 3 from the proximal and to the distal end.

[0122] Figure 8f shows connection of one interconnection lead 6 to a corresponding contact sleeve 18.

[0123] Figure 8g shows a mold to create the proximal connector 18. The mold comprises two parts: a top transparent cover and a base that may be fixed together, for instance using screws. On the base the proximal contact rings are equally placed and between the contact rings, elastomer or polymeric molding tubes are inserted. The arrow shown in Figure 8g indicates the injection inlet. After the molding process, the molding tubes are disposed.

[0124] A method for fabricating the pressure sensor 10, according to an embodiment of the invention illustrated in figure 9a to 9j, comprises providing the substrate 11, forming a membrane layer over a surface of the substrate, etching orifices in the membrane over an area that covers the area in which the recess 12 is to be formed, forming the recess 12 within the substrate 11 byP2950PC00

[0125] accessing the substrate through the orifices in the membrane, and reforming the membrane by filling in the orifices.

[0126] Figure 9a illustrates the membrane 13 on the substrate 11 after depositing the membrane 13 on the substrate.

[0127] In an embodiment, the membrane 13 can be deposited on the substrate 11 using a low-pressure chemical vapor deposition (LPCVD) method. A typical thickness of the membrane may be in a range of 150 to 300 nm, for instance around 200nm. The footprint (surface area) of the pressure sensor may be less than 700 pm x 700 pm with a height less than 200 pm, preferably around 500 pm x 500 pm or less, with a height around 100 pm or less.

[0128] The manufacturing process steps according to embodiments of the invention, with a single photolithography process, enables the fabrication of a MEMS pressure sensor with a remarkably small footprint (under 500 pm x 500 pm x 100 pm) while maintaining the desired sensitivity and temperature compensation for low-pressure measurements, while achieving precise control over all critical parameters.

[0129] Figure 9b illustrates the etching mask 27 deposited on the membrane 13. In Figure 9b the length L of the area of the recess and a width m of a geometrical element of the etching pattern corresponding to an orifice and spacing n between the orifices are shown (e.g. dots with diameter m with spacing n between each dot within the length L). Figure 9c illustrates the membrane on the substrate after etching the membrane 13 according to the etching mask 27. The orifices may have a size for instance in a range of 100 to 400 nm, for instance between 200nm and 300nm, for instance around 250nm.

[0130] In an embodiment, forming the orifices within the membranes comprises providing an etching mask 27 with a submicron etching pattern with orifices distributed over areas of the recesses 12. The etching mask can be provided using various methods such as photolithography-based methods, electron beam lithography, nanoimprint lithography or other per se known methods. Providing the etching mask can be performed using a deep ultraviolet photolithography. Various known dry or wet etching methods can be used. For instance, a plasma dry etching process using fluorine chemistry (CH2F2) can be applied to the substrate with the previously deposited photoresist acting as the etching mask.

[0131] In an embodiment, the submicron etching pattern comprises a geometrical pattern. Dimensions of structures of the geometrical pattern and spacing defining orifices between structures areP2950PC00

[0132] predefined within the area of the recess. For instance, a deep ultraviolet photolithography can be utilized and submicron dot patterns with a dot of radius in a range of 100nm to 500nm are patterned across a predetermined length L and width Won the membrane 13. A typical chamber length L or width W may be in a range of 50um to 200um, for instance in a range of 80um to 150um, for instance around 100um.

[0133] In an example, the Bosch process or deep reactive ion etching (DRIE) can be used to etch the substrate 11 to a predefined depth of 0.5 urn to 3 urn by employing alternating cycles of sulfur hexafluoride (SFe) and octafluorocyclobutane (C4F8) according to perse known Bosch process, to precisely define the depth of the recess 12. Then, the photoresist etching mask is subsequently removed.

[0134] Figure 9d illustrates the recess 12 formed within the substrate 11 after further etching the substrate 11 under the membrane 13. In order to form the recess 12, a triple bath wet etching sequence can be used.

[0135] Figure 9e illustrates the membrane 13 covering the recess 12 reformed thus sealing the etched orifices of the membrane. The etched portion of the membrane 13 can be sealed by depositing an additional low stress silicon nitride layer (Si3N4) layer deposited for instance via LPCVD. Thereby, the recess 12 is sealed directly by the membrane 13 and under a vacuum.

[0136] In an embodiment, the method further comprises providing the membrane deformation sensor 15 on the membrane 13. In an example, a layer of boron-doped polysilicon, a piezoresistive material may be deposited and subsequently patterned using a photolithography to provide the membrane deformation sensor 15.

[0137] Figure 9f illustrates the membrane deformation sensor 15 mounted (e.g. deposited) on the membrane 13 and figure 9b illustrates the electrical connection terminals 17 formed on the substrate in contact with the deformation sensor. The electrical connection terminals 17 can be formed for instance by depositing gold (Au) on the membrane 13 through a perse known metal evaporation process.

[0138] In an embodiment, the method further comprises forming the insulation layer 19 on the pressure sensor 10, which is configured to provide biocompatible insulation for the pressure sensor 10. The insulation layer 19 may for instance comprise an aluminum oxide (AI2O3) layer deposited on the pressure sensor 10, for instance using a perse known atomic layer deposition process.P2950PC00

[0139] Figure 9h illustrates an insulation layer 19 formed over the pressure sensor 10, thereby on the membrane 13, the membrane deformation sensor 15, and the electrical connection terminals 17. Figure 9h illustrates a portion of insulation layer 19 removed to expose a contact point 23 on the electrical connection terminal 17 for connection to an interconnection lead 6 as shown in figure 9j.

[0140] A bottom layer of the substrate may further be removed e.g. by grinding to achieve a desired defined thickness of the pressure sensor 10.

[0141] The above processes are performed on a wafer having a plurality of pressure sensors, which at the end of the process is then diced into individual chips for each pressure sensor.

[0142] Quantification of absolute flow within arterial vessels is essential for the assessment and treatment of coronary circulation. The flow rate can be calculated using the measurements of the pressure sensing arrangement 4 to assess the pressure gradient according to Womersley’s theory.

[0143] Womersley’s theory extends the classic Poiseuille’s law, which describes steady, laminar flow through a circular pipe, to account for pulsatile flow — the rhythmic, intermittent propagation of fluid through a blood vessel or piping system. Unlike constant, smooth propagation that produces purely laminar flow, pulsatile flow is more representative of physiological conditions found in arterial blood flow. The theory introduces a complex relationship between the pressure gradient and the flow rate v(r, t), accounting for the frequency-dependent nature of the pulsatile flow. The flow rate v(r, t) at any radial position r within the vessel and at any time t can be expressed through a Fourier series that accommodates the oscillatory nature of pulsatile blood flow as follows:

[0144] I dP 1 / YoC^r^ / v)1 / 2) \

[0145] v(r, t) = IR

[0146]

[0147] r] dx ia> V YoG^^C^ / v)1 / 2)) /

[0148] , where

[0149] IR denotes the real part of the complex expression;

[0150] r] is dynamic viscosity of fluid or blood;

[0151] dP

[0152] — represents the pressure gradient along the vessel;

[0153] ay is the angular frequency of the pulsatile flow;

[0154] v is the kinematic viscosity of fluid or blood;

[0155] Jois the zero-order Bessel function; and

[0156] r and R are the local and total radius of the vessel, respectively.P2950PC00

[0157] Properties such as viscosity and density of blood of a patient can be either directly measured or estimation from standard physiological values can be used. During a coronary intervention, a frequency of a cardiac pulsation can be recorded with an electro-cardiogram. A diameter of a blood vessel can be assessed using x-ray angiography images acquired during a coronary intervention using the hemodynamic monitoring system 20.

[0158] A plurality of pressure sensors 10 within the pressure sensors arrangement 4 are positioned with spacing between them. Therefore, the pressure sensors arrangement 4 can measure the pressure gradient (dP) across a known distance (dx) between two adjacent pressure sensors 10.

[0159] By integrating the flow rate across the vessel’s cross-sectional area yields the volumetric flow rate Q(t), which is be given as follows:

[0160] cR

[0161] Q(t) = I 2nrv(r, t)dr

[0162]

[0163] Jo

[0164] Doppler-based flow rate measurement methods are sensitive to precise location of sensors within the vessel. On the other hand, as the hemodynamic monitoring system 20 enables to measure pressure gradients using the pressure sensors arrangement 4, the predetermined distance between sensors improve the accuracy of the pressure gradient and therefore the flow rate calculation. Additionally, the capability to perform simultaneous multi-point measurements allows for a comprehensive analysis of flow patterns, accommodating the complexity of coronary anatomy and the presence of side branches, which is limited in continuous thermodilution.

[0165] Figure 10a show a schematic illustration of a heart and coronary arteries and the endovascular catheter 1 according to an embodiment of the invention. For illustrative purposes, the pressure sensors arrangement 4 mounted to the core-wire 3 and a portion of the outer tube 2 are shown in Figure 10a. In the embodiment, the pressure sensors arrangement 4 comprises n pressure sensors 10, in which n is a natural number larger than 1. Pressure sensors are denoted as Pi, ...,Pn. Pkrepresents th pressure sensor 10 of the pressure sensors arrangement 4. Each pressure sensor can detect blood pressure at corresponding position at the core-wire.

[0166] Figure 10b shows an enlarged schematic illustration of coronary arteries and the endovascular catheter 1 being inserted into a branch of the coronary arteries. Flow rate between two adjacent pressure sensors Pk, Pk+1is denoted as Qk(t).

[0167] Using a multi-sensor pressure guidewire, the pressure distribution along the main artery can be continuously measured at multiple points. This enables the estimation of branch pressuresP2950PC00

[0168] without the need to for direct probing. By monitoring the pressures before and after the branch, the flow can be inferred using the principle of conservation (Qmain,in= Qmain.out + Qbranch) ■

[0169] Figure 10c shows a diagram of measured blood pressures by the pressure sensors 10. For descriptive purposes, blood pressures overtime measured by a first, second, and nth pressure sensors are denoted as PltP2, and Pnin solid, dotted, and dashed lines, respectively.

[0170] Figures 10d, 10e shows a schematic of the guidewire with the pressure sensors 10 inserted into an investigated vessel and the resulting diagram of measured flow rate using the pressure gradient. The distance dx represents the distance between P1and Pn. It can denote the distance between any two pressure sensors and does not represent necessarily the distance between each sensor. The flow rate can be computed between any two points of the guidewire.

[0171] Figures 11a-d shows electron microscope images of the pressure sensors 10 according to various embodiments of the invention. Each figure shows a scale bar displaying a segment representing 300 pm, 1 pm, 10 pm, and 1 pm, respectively. The pressure sensors 10 in different sizes, 200x200 pm2and 100x100 pm2are presented with a scale bar. Figure 11b shows an enlarged portion of the membrane 13 of the pressure sensor 10 after etching the membrane 13 according to the etching mask 27. Figure 11c shows a cross-sectional view of the pressure sensor 10 with the recess 12 formed within the pressure sensor 10. The etched portion of the membrane 13 is not sealed yet. Figure 11d shows an enlarged image of the recess 11 and one side wall of the substrate 11 forming the recess 11.

[0172] Figure 12 shows electron microscope image of the pressure sensors 10 with its different components at the late stage of fabrication before release and integration on the core wire: the two piezoresistors, the membrane and the electrical connections. The shape, size and positioning of the piezoresistor can vary depending on the configuration desired.P2950PC00

[0173] List of references

[0174] A hemodynamic monitoring system 20

[0175] Endovascular measurement unit (catheter) 1

[0176] Outer tube 2

[0177] Openings 9

[0178] Distal end 7

[0179] Spring coil 14

[0180] Distal tip 16

[0181] Proximal end 8

[0182] Connector 18

[0183] Connector sleeve 24

[0184] Core-wire 3

[0185] Pressure sensors arrangement 4

[0186] Pressure sensor 10

[0187] Substrate 11

[0188] Recess 12

[0189] Membrane 13

[0190] Diaphragm membrane portion 14 Membrane deformation sensor 15

[0191] Active sensing element 15a Passive sensing element 15b Electrical connection terminals 17

[0192] Contact points 23

[0193] First conducting element 17a Second conducting element 17b Third conducting element 17c Insulation layer 19

[0194] Sensor support 5

[0195] Sensor mounting portion 23

[0196] Core-wire mounting portion 25 Electrical connection terminals Interconnection leads 6

[0197] Monitoring unit 30

[0198] Receiving section 31

[0199] Processing section 32

[0200] Displaying section 33

Claims

P2950PC00Claims1. A hemodynamic monitoring system (20) comprising:an endovascular catheter (1) configured to measure hemodynamic parameters; and a monitoring system (30) configured to receive the measurements from the endovascular catheter and provide hemodynamic information based on the measurement, wherein the endovascular catheter (1) comprises a solid non-hollow core-wire (3), and a pressure sensors arrangement (4) comprising a plurality of pressure sensors (10), the pressure sensors arrangement being mounted to the core-wire (3) of the endovascular catheter, wherein said pressure sensors are distributed spaced apart along the core-wire and configured to measure blood pressure at corresponding position at the core-wire, the core-wire being configured for providing a mechanical support for the pressure sensors arrangement and guiding the endovascular catheter in a blood vessel, wherein the monitoring system is configured to provide a pressure gradient and flow rate using the measured blood pressures along the core-wire, wherein each pressure sensor is mounted to a sensor support comprising an orifice through which the core-wire is inserted.

2. The system according to claim 1, wherein the monitoring system further is further configured to display the hemodynamics.

3. The system according to any preceding claim, wherein the catheter further comprises an outer tube (2) having a distal end (7) and a proximal end (8), wherein the core-wire extends inside the outer tube, the outer tube comprising at least one opening adjacent each said pressure sensor.

4. The system according to any preceding claim, wherein the pressure sensor comprises:a substrate (11) having a recess (12) formed therein;a membrane (13) on the substrate covering the recess;a membrane deformation sensor (15) on the membrane; andelectrical connection terminals connected to said membrane deformation sensor.

5. The system according to the preceding claim, wherein said membrane deformation sensor comprises an active sensing element (15a), for instance comprising a piezoresistive material, positioned at least partially over the recess, and a passive sensing element (15b) not positioned over the recess.

6. The system according to the preceding claim, wherein the active sensing element and theP2950PC00passive sensing element are electrically coupled.

7. The system according to any one of the three directly preceding claims, wherein the pressure sensor further comprises an insulation layer (19) over the membrane.

8. The system according to any one of the four directly preceding claims, wherein the sensor support further comprises electrical connection terminals configured to electrically connect one or more interconnection leads (6) to the electrical connection terminals of the pressure sensor, wherein said one or more interconnection leads are connected to the electrical connection terminals of the sensor support and the pressure sensor is connected to the electrical connection terminals of the sensor support.

9. The system according to the preceding claim, wherein the pressure sensors are electrically connected to the electrical connection terminals of the sensor support by solder balls and gluing, wire bonding and gluing, gold bumps and flip chip bonding, or patterned conductive glue and flip chip bonding.

10. A method for fabricating the pressure sensor (10) according to any one of claims 4 to 9, the method comprising:providing the substrate;depositing the membrane on the substrate;forming orifices in the membrane;forming the recess in the substrate below the membrane by an etching process employing chemicals passing through the orifices to the substrate below the membrane; andsealing the orifices by an additive process to re-form the membrane.

11. The method according to the preceding claim, wherein forming the orifices comprises providing an etching mask on the membrane, the etching mask defining an area of the recess and comprising a submicron etching pattern; andetching the membrane according to the etching mask.

12. The method according to either of the two directly preceding claims, further comprising forming an insulation layer on the membrane layer, said membrane deformation sensor, and electrical connection terminals.

13. A method for assembling the endovascular catheter (1) according to any one of claims 1 to 9, the method comprising:providing a sacrificial layer (28);P2950PC00mounting a plurality of said sensor supports on the sacrificial layer, and a plurality of the pressure sensors on the sensor supports;connecting interconnection leads to each pressure sensor;detaching said sensor supports from the sacrificial layer; andmounting said sensor supports to the core-wire in a distributed spaced apart manner.

14. The method according to the preceding claim further comprising mounting the core-wire inside an outer tube.

15. The method according to either of the two directly preceding claims further comprising slidably mounting the sensor supports along the core-wire.

16. A hemodynamic monitoring system (20) comprising:an endovascular catheter (1) configured to measure hemodynamic parameters; and a monitoring system (30) configured to receive the measurements from the endovascular catheter and provide hemodynamic information based on the measurement, wherein the endovascular catheter (1) comprises a solid non-hollow core-wire (3), and a pressure sensors arrangement (4) comprising a plurality of pressure sensors (10), the pressure sensors arrangement being mounted to the core-wire (3) of the endovascular catheter, wherein said pressure sensors are distributed spaced apart along the core-wire and configured to measure blood pressure at corresponding position at the core-wire, the core-wire being configured for providing a mechanical support for the pressure sensors arrangement and guiding the endovascular catheter in a blood vessel, wherein the monitoring system is configured to provide a pressure gradient and flow rate using the measured blood pressures along the core-wire.

17. The system according to the preceding claim, wherein the monitoring system further is further configured to display the hemodynamics.

18. The system according to either of the two directly preceding claims, wherein the catheter further comprises an outer tube (2) having a distal end (7) and a proximal end (8), wherein the core-wire extends inside the outer tube, the outer tube comprising at least one opening adjacent each said pressure sensor.

19. The system according to any one of the three directly preceding claims, wherein each pressure sensor is mounted to a sensor support comprising an orifice through which the corewire is inserted.21P2950PC0020. The system according to any one of the four directly preceding claims, wherein the pressure sensor comprises:a substrate (11) having a recess (12) formed therein;a membrane (13) on the substrate covering the recess;a membrane deformation sensor (15) on the membrane; andelectrical connection terminals connected to said membrane deformation sensor.

21. The system according to the preceding claim, wherein said membrane deformation sensor comprises an active sensing element (15a), for instance comprising a piezoresistive material, positioned at least partially over the recess, and a passive sensing element (15b) not positioned over the recess.

22. The system according to the preceding claim, wherein the active sensing element and the passive sensing element are electrically coupled.

23. The system according to any one of the three directly preceding claims, wherein the pressure sensor further comprises an insulation layer (19) over the membrane.

24. The system according to any one of the four directly preceding claims, wherein the sensor support further comprises electrical connection terminals configured to electrically connect one or more interconnection leads (6) to the electrical connection terminals of the pressure sensor, wherein said one or more interconnection leads are connected to the electrical connection terminals of the sensor support and the pressure sensor is connected to the electrical connection terminals of the sensor support.

25. The system according to the preceding claim, wherein the pressure sensors are electrically connected to the electrical connection terminals of the sensor support by solder balls and gluing, wire bonding and gluing, gold bumps and flip chip bonding, or patterned conductive glue and flip chip bonding.

26. A method for fabricating the pressure sensor (10) according to any one of claims 20 to 25, the method comprising:providing the substrate;depositing the membrane on the substrate;forming orifices in the membrane;forming the recess in the substrate below the membrane by an etching process employing chemicals passing through the orifices to the substrate below the membrane; andsealing the orifices by an additive process to re-form the membrane.22P2950PC0027. The method according to the preceding claim, wherein forming the orifices comprises providing an etching mask on the membrane, the etching mask defining an area of the recess and comprising a submicron etching pattern; andetching the membrane according to the etching mask.

28. The method according to either of the two directly preceding claims, further comprising forming an insulation layer on the membrane layer, said membrane deformation sensor, and electrical connection terminals.

29. A method for assembling the endovascular catheter (1) according to any one of claims 16 to 25, the method comprising:providing a sacrificial layer (28);mounting a plurality of said sensor supports on the sacrificial layer, and a plurality of the pressure sensors on the sensor supports;connecting interconnection leads to each pressure sensor;detaching said sensor supports from the sacrificial layer; andmounting said sensor supports to the core-wire in a distributed spaced apart manner.

30. The method according to the preceding claim further comprising mounting the core-wire inside an outer tube.The method according to either of the two directly preceding claims further comprising slidably mounting the sensor supports along the core-wire.

31. A method for fabricating a pressure sensor (10), the method comprising:providing a substrate;depositing a membrane on the substrate;forming orifices in the membrane;forming a recess in the substrate below the membrane by an etching process employing chemicals passing through the orifices to the substrate below the membrane; andsealing the orifices by an additive process to re-form the membrane.

32. The method according to the preceding claim, wherein forming the orifices comprises providing an etching mask on the membrane, the etching mask defining an area of the recess and comprising a submicron etching pattern; andetching the membrane according to the etching mask.23P2950PC0033. The method according to either of the two directly preceding claims further comprising forming an insulation layer on the membrane layer, said membrane deformation sensor, and electrical connection terminals.

34. A method for assembling an endovascular catheter (1), the method comprising: providing a sacrificial layer (28);mounting a plurality of sensor supports (5) on the sacrificial layer, and a plurality of pressure sensors (10) on the sensor supports;connecting interconnection leads (6) to each pressure sensor;detaching said sensor supports from the sacrificial layer; andmounting said sensor supports to a core-wire (3) of the endovascular catheter in a distributed spaced apart manner.

35. The method according to the preceding claim further comprising mounting the core-wire inside an outer tube (2).

36. The method according to either of the two directly preceding claims further comprising slidably mounting the sensor supports along the core-wire.

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