JP7499099B2 - Biological Model - Google Patents

Description

The technology disclosed in this specification relates to biological models.

To restore blood flow in narrowed or blocked areas of blood vessels (hereafter referred to as "lesions"), percutaneous transluminal angioplasty (hereafter referred to as "PTA") and percutaneous transluminal coronary angioplasty (hereafter referred to as "PTCA") are widely performed. In PTA and PTCA (hereafter referred to as "PTA, etc."), various procedures such as thrombus aspiration and balloon dilation are used depending on the condition of the lesion.

The procedure using the thrombus aspiration method is performed, for example, by the following procedure. That is, a guidewire is inserted into a blood vessel and advanced until it passes through the lesion in the blood vessel. Next, the thrombus aspiration catheter is advanced to the vicinity of the lesion, using the guidewire as a rail. The lesion is then aspirated with the thrombus aspiration catheter and removed from the body. The procedure using the balloon expansion method is performed, for example, by the following procedure. That is, the balloon catheter is advanced to the lesion, using the guidewire, which has been inserted into the blood vessel and advanced until it passes through the lesion, as a rail. Then, the balloon of the balloon catheter is expanded to expand the blood vessel wall at the lesion from the inside. These procedures ensure a blood passage and restore blood flow.

PTA and other procedures require delicate manipulation by the operator, and the condition of the lesion in the blood vessel varies from patient to patient, so it is not easy to master such procedures. For this reason, various vascular lesion models have been proposed for training purposes to improve PTA and other procedures, in which a simulated lesion is provided in a simulated blood vessel that mimics a blood vessel (see, for example, Patent Document 1).

On the other hand, a polymer gel is known that is made of a three-dimensional cross-linked polymer formed by chemical cross-linking or physical cross-linking and a solvent, in which the three-dimensional cross-linked polymer has low cross-linking density parts and high cross-linking density parts, and that changes anisotropically in response to an external stimulus. Patent Document 2 discloses a method for producing a polymer gel, in which a polymer with low cross-linking density parts formed therein is irradiated with active light rays to form high cross-linking density parts in a predetermined shape.

JP 2018-132622 A Japanese Patent Application Laid-Open No. 7-216244

As described above, the state of an actual lesion is diverse, and it is formed in various states (shapes and hardness) depending on, for example, individual differences and formation period. In such an actual lesion, particularly a lesion such as a chronic total occlusion (hereinafter referred to as "CTO"), a hardened part (hereinafter referred to as "hardened part") due to calcification, plaque, fibrosis, etc. may be formed locally without regularity inside a highly viscous atheroma-like part (hereinafter referred to as "atheroma part"). In a lesion having such a hardened part, the hardness inside the lesion varies in various ways in the longitudinal direction of the blood vessel, which is the direction of advancement of a guidewire or catheter (hereinafter referred to as "guidewire, etc."), so it is not easy to penetrate the lesion with a guidewire, etc. and operate the guidewire, etc. inside the lesion. For this reason, it is desired to provide a simulated lesion (lesion model) that is sufficiently similar to an actual lesion, for example, for use in training procedures such as PTA, or for use in evaluating the performance of a guidewire, etc.

However, in the polymer gel described in Patent Document 2, the high crosslink density portion is formed by irradiating with active light rays, so it is difficult to form the high crosslink density portion only inside the polymer gel. In addition, in order to form the high crosslink density portion, it is necessary to prepare an apparatus for irradiating with active light rays, so handling tends to be difficult.

The issue of providing the above-mentioned lesion model is a common issue for vascular lesion models that include simulated blood vessels and simulated lesions, and for biological models in general that include simulated lesions that mimic lesions formed other than in blood vessels.

This specification discloses a technology that can solve the above-mentioned problems.

The technology disclosed in this specification can be realized, for example, in the following forms:

(1) The biological model disclosed in the present specification is a biological model including a gel, the gel having a first portion having a physically cross-linked physical cross-linked portion and a chemically cross-linked chemical cross-linked portion, and a second portion having at least the physical cross-linked portion and having a larger proportion of the physical cross-linked portion than the first portion, the first portion being surrounded by the second portion. In general, a gel composed of chemically cross-linked portions (hereinafter also referred to as a "chemically cross-linked gel") has a higher hardness than a gel composed of a physically cross-linked portion (hereinafter also referred to as a "physically cross-linked gel"). In addition, the hardness of the chemically cross-linked gel increases as the degree of chemical cross-linking increases. According to this biological model, it is possible to provide a biological model that is more similar to a biological body having a relatively high hardness first portion and a second portion surrounding the first portion and having a lower hardness than the first portion, such as a lesion having an atheroma portion and a hardened portion formed therein, in an actual biological body.

(2) In the above biological model, the first portion may be configured to have a hardness gradient in which the hardness decreases from the center of the first portion toward the second portion. This biological model can provide a biological model that more closely resembles an actual biological body having a first portion with a higher hardness toward the center, such as a lesion having a hardened portion that gradually grows and hardens within an atheroma portion.

The technology disclosed in this specification can be realized in various forms, such as a biological model, a training kit including a biological model, a simulator including a biological model, a manufacturing method thereof, etc.

FIG. 1 is an explanatory diagram illustrating a schematic external configuration of a lesion model according to an embodiment; FIG. 2 is an explanatory diagram illustrating a schematic XZ cross-sectional configuration of the lesion model shown in FIG. 1 . FIG. 1 is an explanatory diagram showing an outline of how the lesion model is used.

A. Embodiments:
A-1. Construction of the lesion model:
Fig. 1 is an explanatory diagram showing a schematic external configuration of a lesion model in an embodiment, in which mutually orthogonal X, Y and Z axes for specifying a direction are shown. Fig. 2 is an explanatory diagram showing an XZ cross-sectional configuration of the lesion model shown in Fig. 1. For convenience, in this specification, the positive direction of the Z axis is referred to as the upward direction, and the negative direction of the Z axis is referred to as the downward direction, but the lesion model 1 may actually be installed or used in a direction different from these directions. The same applies to Fig. 3 to be referred to later.

Lesion model 1 is a device that mimics an actual lesion. Lesion model 1 can be used alone, in combination with other simulated blood vessels, or as part of a training kit or simulator, for example, in training to improve procedures such as PTA, or for evaluating the performance of medical devices such as guidewires used in PTA. An example of how to use lesion model 1 will be described in detail later.

1 and 2, the lesion model 1 is a solid, approximately cylindrical body extending in the X-axis direction, and has an outer surface S1, an end surface S2, and an end surface S3. In each figure, the outer surface S1, the end surface S2, and the end surface S3 are smooth, but may have irregularities. In this embodiment, the lesion model 1 has four inner parts 10 and an outer part 20 located outside the inner parts 10. More specifically, in the lesion model 1 of this embodiment, all the inner parts 10 are surrounded by the outer parts 20. In other words, the inner parts 10 are not exposed to the outer surface S1 or the end surfaces S2 and S3 of the lesion model 1. In this specification, for example, "the inner part 10 is surrounded by the outer part 20" means that the entire outer surface of the inner part 10 is covered by the outer part 20. That is, in the lesion model 1 of this embodiment, the outer surface S1, the end surface S2, and the end surface S3 are composed of the outer part 20. In this embodiment, an actual lesion is assumed to have an atheromatous portion and a hardened portion that is formed locally without regularity inside the atheromatous portion. The lesion model 1 is an example of a biological model in the scope of the claims. The inner portion 10 is an example of a first portion in the scope of the claims, and the outer portion 20 is an example of a second portion in the scope of the claims.

The inner parts 10 have various shapes and sizes and simulate the hardened parts in an actual lesion. On the other hand, the outer parts 20 simulate the atheroma parts in an actual lesion. The lesion model 1 of this embodiment has three spherical inner parts 10 and one rod-shaped inner part 10.

The lesion model 1 is formed of a gel. More specifically, the lesion model 1 is formed of a swollen gel in which the gel forming material is swollen with a swelling liquid. Therefore, the lesion model 1 has good flexibility and flexibility, similar to an actual lesion. More specifically, the lesion model 1 includes a physically cross-linked portion PP in which the forming material is gelled by physical cross-linking, and a chemically cross-linked portion CP in which the forming material is gelled by chemical cross-linking. In this specification, "gel" means that the lesion model 1 is in a gel state at room temperature or at the temperature at which the lesion model 1 is used (e.g., 20°C to 50°C). The swelling liquid is not particularly limited, but examples thereof include water and organic solvents.

The above-mentioned "physically cross-linked site" refers to a site that is cross-linked by non-covalent bonds such as hydrogen bonds and ionic bonds, and refers to a site where cross-linking points are reversibly generated and eliminated by external forces such as temperature changes. On the other hand, the "chemically cross-linked site" refers to a site that is cross-linked by covalent bonds, and refers to a site where cross-linking points do not disappear due to external forces such as temperature changes.

The material for forming the gel of the lesion model 1 is not particularly limited as long as it is a material capable of forming physical and chemical crosslinks. Examples of such materials include polyvinyl alcohol, agarose, starch, chitosan, collagen, gelatin, polyacrylamide, sodium polyacrylate, carboxyvinyl polymer, polyvinylpyrrolidone, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

As described above, the lesion model 1 has an inner part 10 and an outer part 20 that covers the inner part 10. The lesion model 1 also includes a physical cross-linked site PP and a chemical cross-linked site CP. More specifically, the inner part 10 is composed of a physical cross-linked site PP and a chemical cross-linked site CP. On the other hand, the outer part 20 is composed of a physical cross-linked site PP. That is, the proportion of physical cross-linked sites PP in the outer part 20 is greater than the proportion of physical cross-linked sites PP in the inner part 10. In other words, the proportion of chemical cross-linked sites CP in the inner part 10 is greater than the proportion of chemical cross-linked sites CP in the outer part 20.

The hardness of the gel constituting the lesion model 1 increases as the proportion of chemically cross-linked sites increases. Therefore, in the lesion model 1 of this embodiment, the outer part 20 and the inner part 10 can respectively simulate the atheroma part and the hardened part that is locally formed by calcification or the like and has a higher hardness and elasticity than the atheroma part in an actual lesion.

Here, in the above gel, the "magnitude relationship of the proportion of physical cross-linked sites" and the "magnitude relationship of the proportion of chemical cross-linked sites" can be expressed by a conventionally known method, such as the hardness of the gel, the light transmittance of the gel, and the intensity of the spectrum of the substituents formed by chemical cross-linking in the gel. This is because the gel tends to have higher hardness, lower light transmittance (cloudy white), and higher intensity of the above spectrum as chemical cross-links are formed. Specifically, "the proportion of physical cross-linked sites in a certain part (part X) is greater than the proportion of physical cross-linked sites in another part (part Y)" is expressed by the fact that the hardness of part X is lower than the hardness of part Y, the light transmittance of part X is higher than the light transmittance of part Y, and the intensity of the above spectrum in part X is smaller than the intensity of the spectrum in part Y.

The method of identifying the inner part 10 and the outer part 20 using the above method is as follows. First, a plate-shaped evaluation sample having an XZ cross section shown in FIG. 2 and a predetermined thickness is prepared from the lesion model 1. The evaluation sample is measured for hardness, light transmittance, etc. of each measurement part at a predetermined pitch along a direction parallel to the X-axis direction and a direction parallel to the Z-axis direction. The inner part 10 and the outer part 20 in the evaluation sample can be identified, for example, by the following method. In the case of hardness, the measurement part with the lowest hardness is set as the reference part, and the hardness value of the reference part is set to 100%. At this time, the inner part 10 can be identified as being composed of a measurement part whose hardness value is 200% or more of the hardness value of the reference part. In the case of light transmittance, the measurement part with the highest light transmittance is set as the reference part, and the light transmittance value of the reference part is set to 100%. At this time, the inner part 10 can be identified as being composed of a measurement part whose light transmittance value is 60% or less of the light transmittance value of the reference part. The measurement methods for hardness, light transmittance, etc. are described in detail below.

The hardness of the gel can be measured by a conventional method, for example, by measuring the load or shear stress during compression. Specifically, the method is as follows. The gel is sandwiched between plates equipped with a detector and compressed to measure the load during compression, or the gel is sandwiched between plates equipped with a detector and rotated to measure the shear stress.

The light transmittance of the above gel can be measured by a conventional method, for example, by observing the gel under white light and observing the contrast of the transmitted image with a detector. Specifically, the method is as follows. When the gel is irradiated with white light, the transmitted image is binarized and a numerical value is recorded, and the light transmittance is measured based on the numerical value.

The intensity of the spectrum exhibited by the substituents formed by chemical crosslinking in the above gel can be evaluated by a conventionally known method. For example, the spectrum (chemical shift or peak) specific to the substituents formed when the above gel is chemically crosslinked using a chemical crosslinking agent can be identified using nuclear magnetic resonance spectroscopy (NMR spectroscopy), infrared spectroscopy (IR spectroscopy), XPS (X-ray photoelectron spectroscopy), TOF-MS (time-of-flight mass spectrometer), etc., and the intensity of the identified spectrum can be calculated.

In the lesion model 1 of this embodiment, the inner part 10 has a hardness gradient in which the hardness decreases from the center of the inner part 10 toward the outer part 20. Specifically, as shown in the dotted frame in FIG. 2, in one inner part 10, the hardness gradient decreases from the center point PO toward points P1, P2, and P3 near the boundary with the outer part 20. In other words, in the lesion model 1 of this embodiment, the inner part 10 and the outer part 20 are formed integrally. Therefore, inside the lesion model 1, the inner part 10 is unlikely to separate from the outer part 20. Therefore, in the lesion model 1 of this embodiment, unlike a lesion model in which the inner part 10 and the outer part 20 are formed separately, it is possible to simulate a hardened part that gradually grows and hardens in the atheroma part, like an actual lesion. Since such a lesion model 1 has properties similar to those of an actual lesion, it can be particularly suitably used for procedural training applications such as PTA and performance evaluation applications such as guidewires. The hardness gradient inside the inner portion 10 can be confirmed using the method described above.

Next, a method for manufacturing the lesion model 1 in the embodiment will be described. First, a solid, approximately cylindrical first precursor formed of a physical cross-linked gel PG is prepared. The physical cross-linked gel PG is a gel composed of a physically cross-linked portion PP, and can be prepared by swelling a swelling liquid in a physical cross-linked gel prepared by a known method such as a cast-dry method or a freeze-thaw method. The cast-dry method is a method in which a gel-forming material is added to a swelling liquid and heat-treated to prepare a solution of a predetermined concentration, and the solution is dried to obtain a physical cross-linked gel. The freeze-thaw method is a method in which a physical cross-linked gel is obtained by repeating a freezing process and a thawing process a predetermined number of times for the same solution as above. When preparing the physical cross-linked gel PG, the hardness and elasticity of the lesion model 1 can be increased by increasing the concentration of the gel-forming material constituting the physical cross-linked gel to increase the degree of physical cross-linking. The first precursor can be prepared by molding the physical cross-linked gel PG obtained by the above method into a columnar shape.

Next, the second precursor is prepared by incorporating a crosslinking agent into the first precursor. The method for preparing the second precursor is not particularly limited, but for example, a method of immersing the first precursor in an aqueous solution of the crosslinking agent at a predetermined pressure and temperature for a predetermined time can be mentioned. The crosslinking agent is not particularly limited, but for example, dialdehydes such as glutaraldehyde, glyoxal, formalin, and terephthalaldehyde can be mentioned. Here, a dialdehyde is an aldehyde having two aldehyde groups (formyl groups). By the above method, a second precursor, which is a physically crosslinked gel PG in which the crosslinking agent is swollen, can be prepared.

Next, an acid catalyst solution is injected into the target site of the second precursor to prepare a third precursor. Here, the target site is a site located inside the second precursor, and corresponds to a site in the lesion model 1 where the formation of the inner part 10 is desired. In this embodiment, the acid catalyst solution is injected into the four target sites to form four inner parts 10 inside the lesion model 1. The acid catalyst used in the acid catalyst solution is not particularly limited, and examples thereof include citric acid and hydrochloric acid. By the above method, a catalytic exchange reaction between the acid catalyst and the crosslinking agent proceeds in the target site, and a chemical crosslinking site CP is formed in at least a part of the target site. The shape, size, and chemical crosslinking density of the chemical crosslinking site CP can be changed by adjusting the amount and concentration of the crosslinking agent and acid catalyst added, the range to be added, the pH of the acid catalyst solution, the reaction pressure, the reaction temperature, the reaction time, and the like.

Then, the third precursor is washed with a washing solution to prepare the lesion model 1. The washing method is not particularly limited, but may be, for example, a method of immersing the third precursor in a washing solution under a predetermined pressure and at a predetermined temperature for a predetermined time. Through the above steps, a lesion model 1 can be prepared having an inner part 10 made up of the target site, the inner part 10 being made up of the chemically cross-linked parts CP and the physically cross-linked parts PP, and an outer part 20 surrounding the inner part 10, the outer part 20 being made up of the physically cross-linked parts PP.

A-2. How to use Lesion Model 1:
Next, a method of using the lesion model 1 in this embodiment will be described. Fig. 3 is an explanatory diagram that shows a schematic usage form of the lesion model 1 in this embodiment. As shown in Fig. 3, the lesion model 1 of this embodiment can be used as a vascular lesion model 100 in combination with a simulated blood vessel 110.

The simulated blood vessel 110 is a tubular (e.g., circular) member having a hollow portion (inner hole) 110L that imitates an actual blood vessel. Note that in FIG. 3, a portion (both ends) of the simulated blood vessel 110 is not shown.

The simulated blood vessel 110 is formed, for example, from a gel of a polymer material. Therefore, the simulated blood vessel 110 has good flexibility, similar to that of an actual blood vessel. More specifically, the simulated blood vessel 110 is formed from a physically cross-linked gel, a chemically cross-linked gel, or a gel containing both of the above-mentioned polymer materials. The polymer material is not particularly limited, and examples thereof include polymer materials having a hydroxyl group (-OH), a carboxylic acid group (-COOH), an amine group (NH ₂ ), and a sulfone group (-SO ₃ H). More specifically, examples of the material include polysaccharides such as polyvinyl alcohol, hyaluronic acid, alginic acid, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, nitrocellulose, cellulose acetate, agar, carrageenan, agarose, and agaropectin, polyethers such as polyethylene glycol and polypropylene glycol and structural analogs thereof, acrylic acid esters such as polyhydroxyethyl acrylate and polyhydroxyethyl methacrylate (HEMA) and structural analogs thereof, amides such as polyacrylamide, poly N-isopropylacrylamide, and polyacrylamide-2-methylpropanesulfonic acid, polyacrylic acid or polymethacrylic acid and alkali metal salts thereof, proteins, gelatin, polylactic acid, natural rubber, and copolymers thereof. The material for forming the simulated blood vessel 110 used in the lesion model 1 of this embodiment can be, for example, the same material as that for the lesion model 1.

The lesion model 1 is located in a portion of the hollow portion 110L of the simulated blood vessel 110. That is, the lesion model 1 is located in a portion of the vascular lesion model 100 in the longitudinal direction of the vascular lesion model 100. In this embodiment, the lesion model 1 is positioned so as to completely block the hollow portion 110L at a predetermined position along the longitudinal direction of the simulated blood vessel 110.

The vascular lesion model 100 of this embodiment can be manufactured, for example, by inserting the lesion model 1 into the hollow portion 110L of the simulated blood vessel 110.

In such a vascular lesion model 100, the lesion model 1 has a shape similar to a lesion such as a CTO formed in an actual blood vessel (a shape in which hardened parts are formed locally without regularity inside the atheroma part). In other words, the hardness inside the lesion model 1 varies in various ways along the longitudinal direction of the simulated blood vessel 110. For this reason, it can be suitably used for procedural training such as PTA for lesions having such a shape, or for performance evaluation of guidewires and the like.

A-3. Advantages of this embodiment:
As described above, the lesion model 1 of this embodiment includes a gel having an inner portion 10 and an outer portion 20. The inner portion 10 is composed of a physically cross-linked site PP and a chemically cross-linked site CP. On the other hand, the outer portion 20 is composed of a physically cross-linked site PP. That is, the proportion of the physically cross-linked site PP in the outer portion 20 is greater than the proportion of the physically cross-linked site PP in the inner portion 10. In addition, each of the inner portions 10 is surrounded by the outer portions 20. According to the lesion model 1 of this embodiment, it is possible to provide a lesion model that more closely resembles a lesion having an inner portion 10 with a relatively high hardness and an outer portion 20 surrounding the inner portion 10 and with a lower hardness than the inner portion 10, such as a lesion having an atheroma portion and a hardened portion formed therein, among actual lesions.

In the lesion model 1 of this embodiment, the inner portion 10 has a hardness gradient in which the hardness decreases from the center of the inner portion 10 toward the outer portion 20. According to the lesion model 1 of this embodiment, it is possible to provide a lesion model 1 that more closely resembles an actual lesion having an inner portion 10 with a higher hardness toward the center, such as a lesion having a hardened portion that gradually grows and hardens within an atheroma portion.

B. Variations:
The technology disclosed in this specification is not limited to the above-described embodiments, and can be modified in various forms without departing from the spirit of the invention. For example, the following modifications are also possible.

The number and shape of the inner parts 10 of the lesion model 1 of the above embodiment are not limited to the above and can be adjusted as appropriate. In addition, in the lesion model 1 of the present embodiment, all of the hardened parts in the actual lesion are simulated by the inner parts 10, but this is not limited to this. For example, the lesion model 1 may have, in addition to the inner parts 10, hardened parts exposed on the outer surface S1 and end faces S2 and S3 of the lesion model 1 (i.e., hardened parts not surrounded by the outer parts 20) as the above-mentioned hardened parts.

In the lesion model 1 of the above embodiment, depending on the state of the actual lesion, a configuration may be adopted in which the outer surface S1 and the end faces S2, S3 are made of chemically cross-linked sites. By forming the outer surface S1 and the end faces S2, S3 from chemically cross-linked sites (increasing their hardness), it is possible to simulate a lesion in which the outer surface and end faces have hardened due to exposure to the pressure of the blood flow for a long period of time, for example.

The inner part 10 in the above embodiment has a hardness gradient in which the hardness decreases from the center of the inner part 10 toward the outer part 20, but is not limited to this. For example, a configuration in which the hardness inside the inner part 10 is uniform, or a configuration in which the hardness gradient increases from the center of the inner part 10 toward the outer part 20 may be adopted.

The inner portion 10 in the above embodiment is configured to include a physical cross-linked portion PP and a chemical cross-linked portion CP, but is not limited to this and may be configured only with a chemical cross-linked portion CP. The outer portion 20 in the present embodiment is configured with a physical cross-linked portion PP, but is not limited to this. In other words, the outer portion 20 may include a chemical cross-linked portion CP within a range in which the proportion of the physical cross-linked portion PP contained in the outer portion 20 is greater than the proportion of the physical cross-linked portion PP contained in the inner portion 10.

In the above embodiment, the lesion model 1 is formed from a gel, but this is not limited to the above. For example, the lesion model 1 may include elements other than the gel in addition to the gel.

In the above embodiment, the lesion model 1 is not limited to a solid, approximately cylindrical body, but may have other shapes, such as a cylindrical body with a hollow portion.

In the manufacturing method of the lesion model 1 of the above embodiment, a method may be adopted in which the inner part 10 composed of the chemically cross-linked parts CP and the physically cross-linked parts PP and the outer part 20 composed of the physically cross-linked parts PP are separately manufactured, and the inner part 10 is disposed inside the outer part 20.

In the manufacturing method of the lesion model 1 of the above embodiment, the step of forming the physically cross-linked gel PG may include, for example, a step of applying a physical external force (e.g., kneading).

In the vascular lesion model 100 equipped with the lesion model 1 of the above embodiment, the lesion model 1 is arranged so as to occlude the hollow portion 110L of the simulated blood vessel 110, but this is not limited thereto. For example, the vascular lesion model 100 may be arranged so as not to completely occlude the hollow portion 110L of the simulated blood vessel 110. The method of fixing the lesion model 1 to the simulated blood vessel 110 is not particularly limited, and a conventionally known method such as fixing with an adhesive can be used.

1: Lesion model 10: Inner part 20: Outer part 100: Vascular lesion model 110: Simulated blood vessel 110L: Hollow part CP: Chemically cross-linked part PG: Physically cross-linked gel PP: Physically cross-linked parts P1, P2, P3: Point PO: Center point S1: Outer surface S2: End surface S3: End surface

Claims (1)

A biological model comprising a gel,
The gel is
A first portion having a physically cross-linked portion that is physically cross-linked and a chemically cross-linked portion that is chemically cross-linked;
a second portion having at least the physical cross-linked site and a ratio of the physical cross-linked site greater than that of the first portion;
The first portion is surrounded by the second portion ,
The first portion has a hardness gradient in which the hardness decreases from the center of the first portion toward the second portion.
Biological model.

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