KR101751813B1 - Bioresorbable and Biodegradable Flow Sensor - Google Patents

Abstract

The present invention relates to a bioabsorbable and biodegradable flow rate sensor. More particularly, the present invention relates to a biocompatible metal oxide layer that can be hydrolyzed into a bioabsorbable material, and a bioabsorbable metal oxide layer that is bioabsorbable, comprising a metal layer that is hydrolyzable to a bioabsorbable material located between said metal oxide layers. For a flow sensor.

Description

Bioresorbable and Biodegradable Flow Sensor [0002]

The present invention relates to a bioabsorbable and biodegradable flow rate sensor. More particularly, the present invention relates to a biocompatible metal oxide layer that can be hydrolyzed into a bioabsorbable material, and a bioabsorbable metal oxide layer that is bioabsorbable, comprising a metal layer that is hydrolyzable to a bioabsorbable material located between said metal oxide layers. For a flow sensor.

Balloon angioplasty and stent placement procedures help patient care across a wide range of cardiovascular, neurovascular, and peripheral vascular diseases.

Approximately six million patients each year receive percutaneous coronary intervention (PCI) for the treatment of arterial occlusion and endothelial injury. Although PCI using bare metal restores blood flow, there is an important limitation that neointimal hyperplasia and smooth muscle cells accumulate around the stent, and blood vessels can be clogged again. This limitation is believed to occur due to the complex interactions of the turbulent blood flow and inflammatory reaction around the stent.

In vivo implantable medical devices, such as stents, need to measure the flow rate of the fluid because the fluid, or blood, flows around it. It becomes possible to judge whether the blood flows normally, for example, according to the flow rate.

Thus, when a sensor for measuring the flow rate of blood is attached to an implantable medical device in vivo, the blood flow is measured therefrom, so that the normal operation of the in-vivo implantable medical device can be confirmed.

The present inventors have found that a biocompatible metal oxide layer that can be hydrolyzed into a bioabsorbable material and a bioabsorbable flow rate sensor comprising a metal layer that is hydrolyzable with a bioabsorbable material located between the metal oxide layers, , Specifically confirming that the blood flow velocity can be measured in particular, thereby completing the present invention.
[Prior Art Literature]
Korean Patent Publication No. 10-2010-0020057

A basic object of the present invention is to provide a bioabsorbable flow rate sensor comprising biocompatible metal oxide layers that can be hydrolyzed with a bioabsorbable material and a metal layer that is hydrolyzable with a bioabsorbable material located between the metal oxide layers, .

Another object of the present invention is to provide an implantable medical device in vivo equipped with a bioabsorbable flow rate sensor.

Still another object of the present invention is to provide a method of manufacturing a semiconductor device, comprising: (i) forming an adhesive layer on a substrate; (ii) forming a metal layer that is hydrolyzable as a bioabsorbable material on the adherent layer; (iii) forming a sealing layer on the metal layer; And (iv) attaching the substrate on which the adhesive layer, metal layer and encapsulation layer are formed to the surface of the implantable medical device in vivo.

A basic object of the present invention is to provide a bioabsorbable flow rate sensor comprising biocompatible metal oxide layers that can be hydrolyzed with a bioabsorbable material and a metal layer that is hydrolyzable with a bioabsorbable material located between the metal oxide layers, . ≪ / RTI >

The metal oxide used in the bioabsorbable flow rate sensor of the present invention may be selected from magnesium oxide, zinc oxide or molybdenum oxide. Moreover, the thickness of the metal oxide layer may be between 10 nm and 1 mm.

In one embodiment of the present invention, the metal oxide layer can be made of magnesium oxide, and the magnesium oxide becomes a material which can be absorbed in vivo by the following hydrolysis reaction.

_{MgO + H 2 O → Mg (} OH) 2

In addition, the metal layer used in the bioabsorbable flux sensor of the present invention may be magnesium (Mg), zinc (Zn), or iron (Fe). The thickness of the metal layer may be between 10 nm and 1 mm.

In one embodiment of the present invention, the electrode can be made of magnesium, zinc or iron. In this case, the magnesium is decomposed by the following hydrolysis reaction and absorbed in vivo.

Mg + 2H ₂ O - > Mg (OH) ₂ + H ₂

Another object of the present invention can be achieved by providing an in-vivo implantable medical device equipped with a bioabsorbable flow rate sensor.

In one embodiment of the invention, the in-vivo implantable medical device may be a stent. Furthermore, the stent may be a bioabsorbable stent that is degraded into a bioabsorbable material through a hydrolysis reaction. In one embodiment of the invention, the bioabsorbable stent may be made of magnesium, zinc, iron, calcium, sodium and alloys thereof. The bioabsorbable stent may also be doped with manganese. Preferably, the bioabsorbable stent may be composed of magnesium, zinc, iron, calcium, sodium and alloys thereof.

The in vivo implantable medical device of the present invention may further comprise a bioabsorbable nonvolatile resistive memory element. The nonvolatile resistance memory element may comprise biocompatible electrodes that can be hydrolyzed into a bioabsorbable material and a resistive layer that can be hydrolyzed to bioabsorbable material located between the electrode layers.

The electrode may be magnesium or zinc, and the resistive layer may be selected from magnesium oxide, zinc oxide or molybdenum oxide.

The thickness of the resistive layer may be 5 nm to 500 nm, and the thickness of the electrode layer may be 10 nm to 1 mm.

Still another object of the present invention is to provide a method of manufacturing a semiconductor device, comprising: (i) forming an adhesive layer on a substrate; (ii) forming a metal layer that is hydrolyzable as a bioabsorbable material on the adherent layer; (iii) forming a sealing layer on the metal layer; And (iv) attaching the substrate on which the adhesive layer, metal layer and encapsulating layer are formed to the surface of the implantable medical device in vivo.

In one embodiment of the invention, the substrate is a synthetic polymer such as biodegradable polyesters such as polylactic acid (PLA), polyglycolic acid (PGA), polyglycerol sebacate (PGS) silk, chitosan, starch, hyaluronic acid, gelatin, cellulose, and the like.

The adhesion layer may also be a biocompatible metal oxide layer that can be hydrolyzed into a bioabsorbable material. Specifically, the metal oxide layer may be selected from magnesium oxide, zinc oxide or molybdenum oxide. Further, the thickness of the adhesion layer may be from 5 nm to 500 nm.

In one embodiment of the invention, the metal layer can be magnesium, zinc or iron. In addition, the thickness of the metal layer may be 5 nm to 500 nm.

In one embodiment of the present invention, the encapsulating layer may be a biocompatible metal oxide layer that can be hydrolyzed into a bioabsorbable material. Further, the metal oxide layer may be selected from magnesium oxide, zinc oxide or molybdenum oxide.

In the method of the present invention, the step (iv) may be carried out by a transfer printing method by solvent-vapor annealing.

In the method of the present invention, the in-vivo implantable medical device may be a stent, and the stent may be made of magnesium, zinc, iron, calcium, sodium and alloys thereof. The bioabsorbable stent may also be doped with manganese. Preferably, the stent may be made of an alloy of 97% magnesium, 2% zinc and 1% manganese.

Since the bioabsorbable flow rate sensor of the present invention is made of biodegradable, biocompatible and bioabsorbable water-soluble materials, it is suitable for application to medical devices.

The bioabsorbable flow sensor of the present invention can be mounted on a medical device, for example, a stent, which can be implanted in a living body together with an information storage element. Thus, the bioabsorbable stent according to the present invention can measure the velocity of the blood flow passing through the stent and store the measured blood flow velocity information.

1 is a schematic view of a stent equipped with the bioabsorbable Mg / MgO / Mg nanomembrane resistance memory element prepared in Example 1. FIG.
FIG. 2 is a graph showing current-voltage (IV) characteristics of a bipolar resistance memory of a resistance memory element mounted on a stent manufactured in Example 1, (b) TEM (transmission electron microscope) (d) a plot of the cumulative probability as a function of the set / reset resistance, (e) retention characteristics, and (f) Show durability characteristics.
FIG. 3 shows a stent having a bioabsorbable Mg / MgO / Mg nanomembrane resistance memory device manufactured in Example 1 installed in a balloon catheter. 3 is an enlarged photograph of the resistance memory element.
4 shows the current-voltage characteristics of the resistance memory element (RRAM) manufactured in Example 1, which is provided in the balloon catheter, in the new state (red) and the deformed state (blue).
5 is a plot of percent resistance change versus temperature change for an estimate of the modified linear correlation of the sensor made in Example 4 of the present invention.
6a is a photograph of the stents in the aorta for three different current levels of the flow sensor, FIG. 6b is a plot of the percent resistance change versus flow rate of the flow sensor at the three different current levels of the flow sensor, and c is a plot of the percent resistance change of the flow sensor (measured at a constant current of 50 mA).

Hereinafter, the present invention will be described in more detail with reference to the following examples or drawings. It is to be understood, however, that the following description of the embodiments or drawings is intended to illustrate specific embodiments of the invention and is not intended to be exhaustive or to limit the scope of the invention to the precise forms disclosed.

Example  One. Mg  alloy Stent  On Mg / MgO / Mg  Manufacture of memory

To fabricate the Mg alloy stent, the ZM21 Mg alloy ingot was laser-cut and polished first. AZ4620 photoresist (Clariant, USA) was spin coated on both sides of the ZM21 Mg alloy substrate (~ 200 μm) at 3000 rpm (30 seconds). The Mg alloy substrate was then patterned using a wet etching process using photolithography and an Mg etchant (70% ethylene glycol, 20% deionized water, 10% nitric acid). After the etching process, the Mg alloy mesh was immersed in boiling acetone to remove the AZ4620 photoresist. Thereafter, an insulating MgO layer (~50 nm) (adhesion layer) was deposited on the stent by an electron beam evaporation method. Subsequently, the lower electrode (Mg, 60 nm) was formed by thermal evaporation of Mg. A switching layer (MgO, 12 nm) was deposited by a sputtering process (base pressure 5 × 10 ^-6 Torr, Ar 20 sccm, 5 mTorr, 150 W RF power). Next, an upper electrode (Mg, ~ 60 nm) was deposited on the MgO film through another thermal evaporation process step. Another MgO encapsulation layer (~80 nm) was added to the upper surface of the Mg / MgO / Mg (RRAM) structure using electron beam evaporation (see FIG. 1).

Example  2. RRAM Reliability test

In the set / reset retention measurements, each resistance state was programmed and the current level was measured at a read voltage of 0.2 V. The bipolar IV curve for the bioabsorbable Mg / MgO / Mg nanomembrane resistance memory device prepared in Example 1 shows how the device switches between the low resistance state (LRS) and the high resistance state (HRS) (Fig. 2a). The resistive switching is accomplished by applying a positive voltage (reset of 0.7 V) or a negative voltage (a set of -0.8 V). Low-power operation of the storage element is possible by a low reset and set voltage. The inset of FIG. 2A shows the switching order. FIG. 2B shows a transmission electron microscope (TEM) photograph of the storage element module, showing in detail the interface to the MgO nanomembrane switch layer (~ 12 nm) and the Mg electrode. The current values independent of the area of the LRS and HRS suggest that the conduction mechanism is by filamentary connection (FIG. 2C). Figure 2D shows uniform resistance switching in the RRAM array, both HRS and LRS being stable. The retention properties of these devices can be extrapolated to several years by a switching cycle (Fig. 2f) in excess of 1,000 cycles (Fig. 2e). Maintained well for 10 ³ s in both the high resistance state (HRS) and the low resistance state (LRS) (Fig. 2E). The read / write endurance was measured by consecutive DC voltage sweeping from -2V to 2V. The HRS and LRS current values measured at a contact pressure of 0.2 V were stable (Figure 2f).

Example  3. RRAM Characterization of

A current-voltage analysis of the RRAM of the bioresorbable Mg / MgO / Mg nanomembrane resistance memory element (made in Example 1) in the pristine state and the deformed state (expanded state) on the balloon catheter was performed (Fig. 3). Electrical measurements were performed using a probe station and parameter analyzer (B1500A, Agilent, USA). IV characteristics, no significant changes were seen when the stent was expanded, i.e., when the RRAM was deformed (Fig. 4).

Example  4. Magnesium alloy In the stent  Manufacture of flow rate / temperature sensor

The Mg temperature and flow sensor consists of an adhesion layer, a long filament Mg resistor, and an outer encapsulation layer (MgO and PLA). First, the adhesion layer (~ 60 nm thick ZnO) was sputtered on a PLA film of about 15 μm thickness (base pressure of 5 × 10 ^-6 Torr, Ar 20 sccm, 5 mTorr, 150 W RF power). The metal wiring (Mg, ~ 100 nm) was thermally evaporated through a shadow mask. For encapsulation, an electron beam evaporation method was used to grow about 400 nm thick MgO. An additional two PLA layers (~ 15 μm) were laminated on top by a solvent-vapor-annealing process. Finally, the sensor film was transferred and printed on the stent by a solvent-vapor-annealing process.

Example  5. Characterization of flow rate / temperature sensor

The percent resistance change of the flow rate / temperature sensor manufactured in Example 4 was measured using a DAQ (data-acquisition) board driven by LabView software (National Instruments, USA). The plot for the percent resistance change as a function of temperature change shows a linear function with a slope of 0.08% / DEG C (FIG. 5). Using a digital multimeter (DMM) driven by LabView software, resistance changes at constant currents induced by various flow rates were measured in extracted dog arteries. The flux / temperature sensor was sealed with MgO and PLA layers to prevent leakage current in the fluid.

A bioabsorbable RRAM was combined with the sensor module on the BES to store sensing data. Figure 6a shows an endovascular flow / perfusion model in vitro. Aortas (Fig. 6A) were resected and the BES was inserted into the path of the simulated blood flow. The fluid velocity sensor of the stent is activated by measuring the resistance change, and then correlates with the change in fluid velocity (Fig. 6B). The RRAM module stored this flow data based on a four-level data group corresponding to a flow rate change. These rate changes were saved via MLC operation (Figure 6c). Each fluid velocity was stored in different cells of the memory in real time using Lab-view software. Although the connection of the device is wired, the power and stored data can be wirelessly transmitted by integrating the wireless devices.

Claims (29)

An adhesion layer composed of a biocompatible metal oxide that can be hydrolyzed with a bioabsorbable material;
A metal resistor located on the adhesion layer, the metal resistor being hydrolyzable with a bioabsorbable material and in the form of a filament; And
And an encapsulation layer disposed on the metal resistor and composed of a biocompatible metal oxide that is hydrolyzable with a bioabsorbable material,
Wherein the bioabsorbable flow rate sensor senses the flow rate through a change in resistance of the metal resistor at a constant current induced by the flow rate. The bioabsorbable flow sensor according to claim 1, wherein the metal oxide of the adhesion layer or the sealing layer is selected from the group consisting of magnesium oxide, zinc oxide and molybdenum oxide. The bioabsorbable flow sensor of claim 1, wherein the metal of the metal resistor is selected from the group consisting of magnesium, iron, and zinc. The bioabsorbable flow sensor according to claim 1, wherein the thickness of the adhesive layer or the sealing layer is 5 nm to 500 nm. The bioabsorbable flow rate sensor according to claim 1, wherein the thickness of the metal resistor is 10 nm to 1 mm. Absorptive flow rate sensor and a bioabsorbable nonvolatile resistance storage element for storing flow rate sensing data generated from the bioabsorbable flow rate sensor,
Wherein the bioabsorbable flow rate sensor comprises:
An adhesion layer composed of a biocompatible metal oxide that can be hydrolyzed with a bioabsorbable material;
A metal resistor located on the adhesion layer, the metal resistor being hydrolyzable with a bioabsorbable material and in the form of a filament; And
And an encapsulation layer disposed on the metal resistor and composed of a biocompatible metal oxide that is hydrolyzable with a bioabsorbable material,
Wherein the bioabsorbable flow rate sensor is characterized by sensing a flow rate through a change in resistance of the metal resistor at a constant current induced by a flow rate,
Wherein the bioabsorbable nonvolatile resistance memory element comprises biocompatible electrode layers that can be hydrolyzed into a bioabsorbable material and a resistive layer that is hydrolyzable with a bioabsorbable material positioned between the electrode layers. Implantable medical devices. 7. The in vivo implantable medical device according to claim 6, wherein the in-vivo implantable medical device is a stent. The in vivo implantable medical device according to claim 7, wherein the stent is a bioabsorbable stent made of a material selected from the group consisting of magnesium, zinc, iron, calcium, sodium and alloys thereof. 9. The implantable medical device according to claim 8, wherein the bioabsorbable stent is doped with manganese. delete delete 7. The in vivo implantable medical device according to claim 6, wherein the biocompatible electrode layer of the non-volatile resistive memory element is selected from the group consisting of magnesium, zinc and iron. The in vivo implantable medical device according to claim 6, wherein the resistive layer of the nonvolatile resistance memory element is selected from the group consisting of magnesium oxide, zinc oxide and molybdenum oxide. 7. The in-vivo implantable medical device according to claim 6, wherein the thickness of the resistive layer of the nonvolatile resistance memory element is between 5 nm and 500 nm. 7. The in-vivo implantable medical device according to claim 6, wherein the thickness of the biocompatible electrode layer of the nonvolatile resistance memory element is 10 nm to 1 mm. delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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