KR102494035B1 - Artificial skin phantom model for evaluation of sensor insertion ability of continuous glucose measurement system and a process for the preparation thereof - Google Patents

Abstract

The present invention relates to an artificial skin phantom that can be used to evaluate the ability of a continuous blood glucose monitor to insert a sensor into the body and manage product quality, and a method for manufacturing the same.

Description

Artificial skin phantom model for evaluation of sensor insertion ability of continuous glucose measurement system and a process for the preparation thereof}

The present invention relates to an artificial skin phantom that can be used to evaluate the ability of a continuous blood glucose monitor to insert a sensor into the body and manage product quality, and a method for manufacturing the same.

Unlike conventional self-monitoring blood glucose meters using blood sampling, the continuous glucose measurement system directly inserts a sensor into the subcutaneous area such as the abdomen or upper arm and places it for a long time to obtain blood glucose levels in the intercellular fluid within the subcutaneous fat. It is a real-time blood glucose monitoring system capable of periodically measuring values. This continuous blood glucose measurement system is used for 24-hour monitoring of blood glucose trends in diabetic patients who need proper blood sugar maintenance and acute hypoglycemia in patients with type 1 diabetes, diabetic patients with large fluctuations in blood sugar, hypoglycemic insensitivity, and patients who change insulin therapy. It is effectively applied to effective self-glycemic management and doctor's treatment plan establishment by notifying emergency situations such as Due to the effectiveness of this continuous blood glucose measurement system and the possibility of entering the medical market, it was first developed by Medtronic in June 1999 and received FDA approval. As of 2018, the global market size has been reported to exceed 2 trillion won. Three American companies, Dexcom, Abbott, and Medtronic, are leading the global market, and some Chinese products have begun to be sold in China, and companies such as i-Sense Co., Ltd. are competitively developing and launching products in Korea.

Such a continuous blood glucose measurement system commonly uses a common sensor insertion system in which a sensor is inserted into the subcutaneous fat at a depth of about 3 to 18 mm using an induction needle equipped with a blood glucose sensor therein, and then the induction needle departs from the subcutaneous tissue. are doing Such joint sensor implantation may be affected by the patient's age, skin thickness, and skin tissue condition, and these conditions may affect the development and lifespan of the sensor and the measurement accuracy of the sensor.

However, an artificial skin phantom dedicated to a continuous blood glucose measurement system for the development and evaluation of such skin implantation is currently undeveloped, and the need for an artificial skin phantom for physical evaluation as a scale material for product development and evaluation is emerging.

Therefore, it is necessary to develop an artificial skin phantom dedicated to the continuous blood glucose measurement system required for research and development related to sensor insertion technology of the continuous blood glucose measurement system and quality control in the production stage of the product.

Guerci, B., et. al. Diabetes care., 26 (2003) 582-589. Diabetes Research in Children Network (DirecNet) Study Group. Diabetes Technol. Ther., 5 (2003) 781. Tavris, D. R., et. al. Diabetes Technol. Ther, 6 (2004) 518-522. Bode, B. W., et. al. Diabetes Technol. Ther., 2 (2000) 43-48.

Accordingly, an object of the present invention is to indirectly evaluate the physical changes and characteristics of an induction needle and an inserted sensor when a sensor of a continuous blood glucose meter is inserted in vitro,

An artificial skin phantom having a double-layer structure having elasticity equivalent to a human body is provided.

Another object of the present invention is to provide a method for manufacturing the artificial skin phantom.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the above object of the present invention, the present invention is a skin layer composed of silicon (silicon); and a subcutaneous layer made of gelatin.

In one embodiment of the present invention. The artificial skin phantom may be used to indirectly evaluate the physical changes and characteristics of the induction needle and the inserted sensor outside the body when the sensor of the continuous blood glucose meter is inserted, but is not limited thereto.

In another embodiment of the present invention, the artificial skin phantom may have elasticity equivalent to a human body, but is not limited thereto.

In another embodiment of the present invention, the artificial skin phantom may have a double layer structure, but is not limited thereto.

In another embodiment of the present invention, the artificial skin phantom may be used for development and evaluation of skin implantation, but is not limited thereto.

In addition, the present invention provides a method for manufacturing an artificial skin phantom comprising the following steps:

Preparing a gelatin layer by dispensing and curing the gelatin solution;

Preparing a silicon layer by coating after dispensing a silicon solution; and

Mounting a silicone layer on top of the gelatin layer.

In addition, the present invention is an artificial skin phantom portion including a silicone skin layer and a gelatin subcutaneous fat layer; And it provides a measuring device comprising a measuring device structure.

In one embodiment of the present invention, the measuring device may be a continuous blood glucose meter, but is not limited thereto.

The artificial skin phantom according to the present invention can be used as an artificial skin phantom for evaluating the sensor insertion ability of the continuous blood glucose monitor according to the elasticity of the human body and the detection characteristics according to the geometric structure.

1 shows the degree of elasticity of main body attachment sites of a continuous blood glucose meter according to the patient's body mass index.
2 shows the degree of elasticity of main body attachment sites of the continuous blood glucose meter according to the patient's body position.
3 shows the configuration and structure of an artificial skin phantom.
4 shows the elasticity of the artificial skin phantom by mixing ratio and structure.

As used herein, the term "artificial skin phantom" refers to a model used as a substitute for skin among models used as substitutes for biological system research, such as investigation and analysis of the distribution of electromagnetic waves inside the human body and the specific absorption rate of human tissue.

As used herein, the term "silicon" refers to a polysiloxane-based compound among polymers in which silicon and oxygen are bonded.

As used herein, the term "skin layer" refers to a layer including both the epidermis layer and the dermis layer of the human body.

As used herein, the term "gelatin" is a kind of induced protein extracted from collagen constituting animal tissues, bones, ligaments and tendons.

As used herein, the term “subcutaneous layer” refers to a fat layer with a thickness of about 15 mm mainly composed of fat cells as a layer located between the dermis layer and fascia among human skin tissues.

As used herein, the term "elasticity" refers to the property of returning to its original shape after an external force is applied to a material.

As used herein, the term "elasticity" refers to the pressure value during elastic deformation that returns to its original shape after an external force is applied, and skin elevation induced by applying negative pressure to the skin surface phase) and the restoration movement distance of the skin retraction phase induced by negative pressure loss.

In one embodiment, the elasticity (elasticity) can be measured under the derivation formula below.

<Elasticity measurement derivation formula>

= 표면 중간에서 측정된 피부 팽창(m)

= Skin swelling measured in the middle of the surface (m)

= 정수

= integer

= 표면 압력(surface pressure ; Pa)

= surface pressure (Pa)

= 탄력성 계수(elasticity modulus ; MPa)

= elasticity modulus (MPa)

r = radius of the surface (0.005 m)

s = thickness of the surface (skin thickness, general default value is 1mm)

As used herein, the term "Shore hardness" refers to the size of the resistance to deformation of the object by measuring the height raised by repulsion when a falling object fixed to the tip of a small diamond is dropped from a certain height. .

As used herein, the term "silicone skin layer" means a Shore hardness of about 0.05 to 5, 0.05 to 4, 0.05 to 3, 0.05 to 1, 0.05 to 0.5, 0.05 to 0.05. Refers to an artificial skin layer composed of silicone having a value of 0.4, a value of 0.05 to 0.3, or a value of 0.05 to 0.2, and a thickness of about 0.1 to 10 mm, about 0.5 to 5 mm, about 0.5 to 4 mm, or about It can be configured in various ways within the range of 0.5 to 3.5 mm.

As used herein, the term "gelatin subcutaneous layer" refers to gelatin in a solvent composed of water at 1 to 30% (w/v), 2 to 20% (w/v), or 3 to 20% (w/v). v), 4 to 20% (w/v), 5 to 17% (w/v), 5 to 15% (w/v), 5 to 10% (w/v), 5 to 8% (w/v) v), 6 to 8% (w/v), 6 to 10% (w/v), 7 to 13% (w/v), 7 to 15% (w/v), 7 to 20% (w/v) v), 7 to 30% (w/v), 8 to 12% (w/v), 8 to 14% (w/v), 8 to 16% (w/v), 10 to 14% (w/v) v), 10 to 16% (w/v), 10 to 18% (w/v), 10 to 20% (w/v), 12 to 20% (w/v), 12 to 18% (w/v) v), 12 to 16% (w / v), 14 to 16% (w / v) refers to the artificial subcutaneous layer included. The gelatinous subcutaneous fat layer may have a thickness of about 0.1 to 30 mm, 0.5 to 25 mm, 1 to 25 mm, 1 to 20 mm, 2 to 20 mm, 2 to 18 mm, 2 to 16 mm, and the like. there is.

The artificial skin phantom according to one embodiment may be composed of a bilayer composed of a silicone skin layer and a gelatin subcutaneous layer.

In one embodiment, the skin component layer in the artificial skin phantom may include a silicone skin layer and a gelatin subcutaneous fat layer.

The artificial skin phantom measuring device of the present invention includes an artificial skin phantom part including a silicone skin layer and a gelatin subcutaneous fat layer; and a measuring device structure.

In one embodiment, silicon was used as a material for simulating the relatively high hardness of the human skin layer.

In one embodiment, gelatin was used as a material for simulating the hardness of relatively low fat in the subcutaneous fat layer of the human body.

The continuous blood glucose meter according to one embodiment may measure the level of glucose diffused and distributed in the subcutaneous fat layer in real time using a sensor inserted into the subcutaneous fat layer by an induction needle, but is not limited thereto.

An artificial skin phantom for evaluating sensor insertability of a continuous blood glucose meter according to an embodiment may be for evaluating physical changes of a needle and an implanted sensor according to the skin environment when an induction needle of a continuous blood glucose meter is inserted. Not limited.

Silicon constituting the skin layer of the artificial skin phantom according to one embodiment may have a shore hardness of about 0.1. When the silicone according to the present invention is greater than the Shore hardness, it may exhibit higher elasticity than that of human skin. In addition, when the hardness is smaller than the Shore hardness, elasticity may be higher than that of the skin.

According to one embodiment, the thickness of the silicone skin layer may be, for example, 1 mm, 2 mm, or 3 mm, similar to about 2 to 3 mm, which is the total thickness of the epidermal layer and the dermal layer of human skin. In the artificial skin phantom according to the present invention, as the thickness of the silicone increases, the elasticity may increase, and as the thickness decreases, the elasticity may decrease.

In one embodiment, the gelatin constituting the subcutaneous fat layer of the artificial skin phantom may be mixed in a solvent at about 7% (w / v), about 10% (w / v), or about 15% (w / v). there is. The gelatin according to the present invention may increase or decrease the elasticity of the artificial skin phantom according to the mixing ratio.

In one embodiment, the thickness of the gelatin subcutaneous fat layer may be 5 to 20 mm, 6 to 19 mm, 7 to 18 mm, 7 to 15 mm, 8 to 13 mm, 9 to 11 mm, preferably about 10 mm, similar to the thickness of the subcutaneous fat layer of human skin. there is.

In one embodiment, the artificial skin phantom may be composed of a silicone skin layer having a shore hardness of 0.1 having a thickness of 1 mm, 2 mm, and 3 mm, respectively, and a 10% (w/v) gelatin subcutaneous fat layer having a thickness of about 10 mm. . The artificial skin phantom manufactured with the above mixing ratio and thickness has a value similar to that of human skin elasticity. The elasticity is not limited to the mixing ratio and thickness, and may be used by appropriately adjusting the composition ratio according to the purpose.

When the sensor is inserted subcutaneously, the continuous blood glucose meter may affect the geometric position of the sensor and measurement accuracy of blood glucose by skin elasticity.

According to one embodiment of the present invention, an effective artificial skin phantom for each elasticity was fabricated using silicone and gelatin in order to properly attach a continuous blood glucose monitor and set an external force for sensor insertion according to skin elasticity.

All technical terms used herein are used with the same meaning as commonly understood by one of ordinary skill in the related art unless otherwise defined. In addition, although preferred methods or samples are described in this specification, those similar or equivalent thereto are also included in the scope of this specification. In addition, numerical values described herein are considered to include the meaning of "about" even if not explicitly stated. The contents of all publications cited herein by reference are hereby incorporated by reference in their entirety.

The terms used in the present invention have been selected from general terms that are currently widely used as much as possible while considering the functions in the present invention, but these may vary depending on the intention of a person skilled in the art or precedent, the emergence of new technologies, and the like. In addition, in certain cases, there are terms arbitrarily selected by the applicant,

In this case, the meaning will be described in detail in the description of the corresponding invention. Therefore, the term used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, not simply the name of the term.

Throughout the specification of the present invention, when a part "includes" a certain component, it means that it may further include other components without excluding other components unless otherwise stated. The terms "about", "substantially", etc., of degrees used throughout the specification of the present invention are used at or close to that value when manufacturing and material tolerances inherent in the stated meaning are given, and the present invention Accurate or absolute figures are used to prevent unfair use by unscrupulous infringers of the disclosed disclosures mentioned for the sake of understanding.

Throughout the specification of the present invention, the term "combination thereof" included in the expression of the Markush form means one or more mixtures or combinations selected from the group consisting of the components described in the expression of the Markush form, It means including one or more selected from the group consisting of components.

The steps constituting the method of the present invention may be performed in any suitable order unless an order is explicitly stated or stated to the contrary. It is not necessarily limited to the order of description of the steps.

Hereinafter, a preferred embodiment is presented to aid understanding of the present invention. However, the following examples are provided to more easily understand the present invention, and the content of the present invention is not limited by the following examples.

Experimental example 1. Body mass index index; BMI ) Measurement of human skin elasticity according to

In order to select a model corresponding to various body characteristics of the continuous blood glucose meter application target, a model group for each compartment was selected based on the body mass index (BMI), and the result value was obtained. DermaLab single parameter skin analysis (Cortex Technology, Hadsund, Denmark) was used as the measurement equipment, and when measuring elasticity, the probe applied sound pressure was a normal condition of 400 mbar. 1 shows the degree of elasticity of main body attachment sites of a continuous blood glucose meter according to the patient's body mass index.

Table of Model Classification and Measurement Range for Continuous Blood Glucose Meter Application Subjects Based on BMI BMI value range model group measurement part Measuring conditions <18.5 underweight
(under-weight) stomach
(Abdomen) lower arm
(under arm) Normal
(400 mbar) 18.5 to 22.9 normal
(normal-weight) 23~24.9 overweight 25 to 30 obesity 30< highly obese
(altitude-obesity)

As a result, as shown in FIG. 1, as a result of evaluation of each BMI standard classification model group in the abdomen and lower arm region, which are the main measurement areas of the continuous blood glucose meter, under-weight (BMI: <18.5), normal-weight, In the BMI: 18.5-22.9), over-weight (BMI: 23-24.9), obesity (BMI: 25-30), and altitude-obesity (BMI: 30<) models, the abdominal area was About 3.2±0.03, 3.1±0.44, 3.1±0.01, 3.3±0.36, and 2.9±0.02 MPa were evaluated.

In the lower arm area, elasticity was 3.5±0.06, 3.8±0.68, 3.8±0.08, 4.5±0.33, and 4.3±0.06 MPa, respectively. The average elasticity of was evaluated as 4.02±0.39 MPa.

Experimental Example 2. Measurement of human skin elasticity according to body position

In order to measure the change in elasticity according to the body position of the subject to which the continuous blood glucose monitor is applied, the elasticity according to the position of each main attachment site of the continuous blood glucose monitor was measured. Figure 2 shows the degree of elasticity of the main body attachment part of the continuous blood glucose meter according to the patient's body position.

Motion classification table of the region of interest of a patient using a continuous blood glucose meter measurement part model group Position classification of the measurement site stomach
(Abdomen) normal
(normal-weight) Normal Position Extension Right side bending (Rt. lateral bending) Left side bending (Lt. lateral bending) Flexion lower arm
(under arm) Normal: arms extended (Normal Position) Arm Flexion Internal rotation of the upper arm (Supination) Upper arm lateral rotation (pronation)

As a result, as shown in FIG. 2, the elasticity in the abdominal area, which is the main measurement area of the continuous blood glucose meter, is normal position, extension, right bending (Rt. lateral bending), left bending (Lt. In the body conditions such as lateral bending) and flexion, each elasticity was evaluated as 3.2±0.03, 3.0±0.06, 3.1±0.01, 3.2±0.03, and 3.0±0.01 MPa, respectively.

The degree of elasticity in the lower arm area was 3.8±0.05, 4.05±0.1, 3.8±0.02, And by showing the elasticity of 3.5±0.08 MPa, the average elasticity of the abdominal area was evaluated as 3.13±0.12 MPa, and the average elasticity of the upper arm area was evaluated as 3.83±0.2 MPa.

Example 1. Gelatin Fabrication of the gelatin subcutaneous layer

The gelatin subcutaneous layer consists of a 7% gelatin solution obtained by mixing 1.4 g of gelatin compound with 19 ml of tertiary distilled water, and a 10% gelatin solution obtained by mixing 2 g of gelatin compound with 18 ml of tertiary distilled water. solution, and 3 g of 17 ml of tertiary distilled water was prepared as a 15% gelatin solution. Each mixed gelatin solution was dispensed into a conical tube and then melted in a constant temperature water bath at 66 °C for 24 hours. The molten gelatin solution was dispensed into a circular Petri dish with a diameter of 60 mm and a height of 15 mm, and then cured at room temperature for 24 hours.

Example 2. Fabrication of silicone skin layer

A silicone stock solution having a Shore hardness of 0.1 and a curing agent were dispensed into a conical tube at a volume ratio of about 1:1, and then diluted at room temperature for about 10 minutes.

As shown in FIG. 3, 2 ml, 4 ml, and 6 ml of the diluted silicone solution were placed in a circular Petri dish having a diameter of 60 mm and a height of 15 mm equipped with each of the gelatin subcutaneous layers. Busy. The petri dish in which each silicone solution was dispensed was mounted on the vacuum chuck of the spin coater, and then 30 RPM for 3 seconds under the conditions of Ramp 1, 300 RPM for 12 seconds, and 30 RPM By rotating for 3 seconds, silicon layers having a thickness of 1 mm, 2 mm, and 3 mm, respectively, were fabricated.

Example 3. Evaluation of elasticity of artificial skin phantom

A silicone skin layer with a thickness of 1 mm, 2 mm, and 3 mm, respectively, and a 7%, 10%, and 15% gelatin subcutaneous layer with a thickness of about 10 mm were placed in a Petri dish with the silicone layer on top. After mounting, the elasticity measurement was performed.

As a result, as shown in FIG. 4 , it was confirmed that the mixing ratio and elasticity of each structure of the artificial skin phantom were shown.

Specifically, as a result of measuring the elasticity of the silicone skin layer combined with the subcutaneous fat layer composed of 7% gelatin, the elasticity of the artificial skin phantom combined with the subcutaneous fat layer composed of 7% gelatin and the silicone skin layer having a thickness of 1 mm and 2 mm was measured. was not measured because the silicon layer was damaged by the negative pressure in the chamber. On the other hand, the elasticity of the artificial skin phantom in which a subcutaneous fat layer composed of 7% gelatin and a silicone skin layer having a thickness of 3 mm were combined was about 6.33±0.29 MPa.

As a result of measuring the elasticity of the silicone skin layer combined with the subcutaneous fat layer composed of 10% gelatin, the elasticity of the artificial skin phantom combined with the subcutaneous fat layer composed of 10% gelatin and the silicone skin layer having a thickness of 1 mm, 2 mm, and 3 mm was 3.62±0.03 MPa, 3.61±0.03 MPa, and 2.94±0.03 MPa, respectively.

As a result of measuring the elasticity of the silicone skin layer combined with the subcutaneous fat layer composed of 15% gelatin, the elasticity of the artificial skin phantom combined with the subcutaneous fat layer composed of 15% gelatin and the silicone skin layer having a thickness of 1 mm, 2 mm, and 3 mm is 8.4±0.18 MPa, 5.09±0.04 MPa, and 4.75±0.03 MPa, respectively.

That is, the artificial skin phantom fabricated by combining a 3 mm thick silicone layer with a shore hardness of 0.1 on top of a 10% gelatin layer with a thickness of 10 mm showed the lowest elasticity.

In addition, the artificial skin phantom fabricated by combining a 10 mm thick 15% gelatin layer with a 1 mm thick silicon layer having a shore hardness of 0.1 showed the highest elasticity.

In addition, on top of the 10% gelatin layer with a thickness of 10mm, the silicone layer with a thickness of 1mm, 2mm, and 3mm, with a shore hardness of 0.1, has the most similar elasticity to the abdomen and lower arm, which are the main mounting sites of the continuous blood glucose meter. confirmed that there is In addition, it was confirmed that artificial skin phantoms having various elasticity ranging from 3 MPa to 8 MPa could be fabricated and implemented.

In summary, phantoms having various degrees of elasticity can be manufactured using the artificial skin phantom including the silicone layer and the gelatin layer of the present invention, and it is expected that the phantom can be applied to various skin-related measuring devices.

The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.

Claims (13)

a skin layer made of silicon; And an artificial skin phantom for evaluating the sensor insertability of a continuous blood glucose meter including a subcutaneous layer containing gelatin,
The gelatin is included in a concentration of 8 to 14% (w / v),
The artificial skin phantom, characterized in that the subcutaneous fat layer has a thickness of 5mm to 30mm.
According to claim 1,
The artificial skin phantom, characterized in that the skin layer simulates the epidermal layer and the dermal layer of the human body.
According to claim 1,
The artificial skin phantom is characterized in that it has an elasticity of 3 MPa to 8 MPa, the artificial skin phantom.
According to claim 1,
The artificial skin phantom, characterized in that the skin layer has a hardness of 0.05 to 5 Shore.
According to claim 1,
The artificial skin phantom, characterized in that the skin layer has a thickness of 0.1mm to 10mm.
delete delete According to claim 1,
The artificial skin phantom, characterized in that the skin layer and the subcutaneous fat layer are included in a bilayer structure.
According to claim 1,
The artificial skin phantom is characterized in that for the development and evaluation of skin implantation, artificial skin phantom.
delete A measuring device comprising an artificial skin phantom for evaluating the sensor insertability of the continuous blood glucose meter of claim 1 and a measuring device structure.
delete Preparing a gelatin layer by dispensing and curing the gelatin solution;
Preparing a silicon layer by coating after dispensing a silicon solution; and
A method of manufacturing the artificial skin phantom of claim 1, comprising mounting a silicone layer on top of the gelatin layer,
The gelatin is included in a concentration of 8 to 14% (w / v),
The method of manufacturing an artificial skin phantom, characterized in that the gelatin layer has a thickness of 5 mm to 30 mm.

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