JP6510388B2 - Biocompatible gel material, method of manufacturing biocompatible gel material, biocompatible gel electrode, and biological tissue adsorption device - Google Patents

Description

  The present invention relates to a biocompatible gel material, a method for producing a biocompatible gel material, a biocompatible gel electrode, and a biological tissue adsorption device.

  In recent years, with the progress of information communication technologies such as the Internet and big data analysis, processing and analysis techniques for large and complex data aggregations have been improved. In particular, in the medical field, research and development of real-time sensing technology related to human biological information has been actively conducted.

  In order to measure information from the living body with high accuracy by measuring heart rate and electrocardiogram with wearable device attached to the skin surface or directly attaching an implantable sensor such as a pacemaker to an organ It is desirable for the sensor to be in physical contact with the organ or the like to be measured. However, in the case of a sensor device manufactured from a rigid material such as silicon, there is a problem such as an uncomfortable feeling at the time of wearing or movement inhibition when contacting an organ to be measured.

  In order to solve the above problems, research and development has been extensively carried out in which an electronic circuit is integrated in an elastomer film such as an organic transistor or an organic EL, and is directly attached to a living body as a flexible electronic circuit. For example, Non-Patent Documents 1 and 2 disclose a method of measuring a signal from a tissue by applying a sensor to the surface of a living body with excellent flexibility and without damaging the tissue.

  However, although the conventional sensor is excellent in flexibility, there is a problem that the affinity to the target living tissue in the liquid or in the air is still low. Therefore, for example, after the adhesion of the implantable sensor, the position of the electrode in contact with the surface of the living body shifts, or if the living tissue moves, the sensor slips off and falls off, and the implant is implanted for a long time There is a problem that it is difficult to physically contact a measuring device such as a sensor with a living tissue such as an organ to be measured.

  By the way, in Non-Patent Document 3, for the electrocardiographic measurement, an adhesive gel in which polyrotaxane and polyvinyl alcohol are uniformly mixed and dispersed is applied around the polymer film on which the integrated circuit of the organic transistor is drawn. Successful examples are disclosed. However, in the case of the adhesive gel disclosed in Non-Patent Document 3, since it is decomposed or diffused in the living body, it has been the case that measurement for three hours or more can not be realized yet.

Lizhi Xu, et. Al., Materials and Fractal Designs for 3D Multifunctional Integumentary Membranes with Capabilities in Cardiac Electrotherapy, Advanced Materials, 2015, vol.27, 1731-1737 Kyung-In Jang, et. Al., Soft network composite materials with deterministic and bio-inspired designs, Nature Communications, vol. 6, no. Sungwon Lee, et. Al., Strain-absorbing design for tissue-machine interfaces using a tunable adhesive gel, Nature Communications, vol. 5, no. 5898 B. Laulich, R. Langer, J. M. Karpa, Quick-release medical tape, Proceedings of the National Academy of Sciences, 2012, vol. 109, no. 46, 18803-18808 V. Sahni, J. Harris, T. A. Blackledge, A. Dhinojwala, Cobweb-weaving spiders produce different attachment discs for locomotion and prey capture, Nature Communications, 2012, vol. 3, no. 1106 Tetsuhiko Teshima, Shingo Tsukada, Naoko Kasai, Satoshi Sasaki, Aya Tanaka, Hiroshi Nakajima, Koji Sumitomo, Conductive silk gel thin film for adhesive cell handling, The 62nd Annual Meeting of the Applied Physics Society, 12a-P11-12, March 12, 2015

  In view of the above circumstances, the present invention has biocompatibility which has high mechanical strength and excellent flexibility, can be formed into any shape, and can be in contact with living tissue for a long time It is an object of the present invention to provide a material having the

  In addition, the present invention provides an electrode which has high affinity to the surface of a living body, does not break during expansion and contraction, and can maintain a stable adhesion state without slipping on a living tissue even in a wet environment. An object of the present invention is to provide a biological tissue adsorption device including the same.

One aspect of the present invention is formed by blending a conductive polymer and two or more components capable of forming a crosslinked network structure and having biocompatibility, and the component forms a network composed of the crosslinked network structure What hydrogel der, one of the components having the biocompatible is a silk fibroin, a biocompatible gel material.

The biocompatible gel material, before Kishirube conductive polymer is preferably a (3,4-ethylenedioxythiophene) / poly (4-styrenesulfonic acid).
Moreover, it is preferable that the said conductive polymer is included in the network structure of the said hydrogel.
Moreover, it is preferable to further include polyethylene glycol dimethacrylate as the component having biocompatibility.
Furthermore, it is preferable that the hydrogel is a double network gel composed of the silk fibroin and the polyethylene glycol dimethacrylate.

Another aspect of the present invention is a method for producing the biocompatible gel material according to one aspect described above , wherein the raw material of two or more components capable of forming a crosslinked network and having biocompatibility and a conductive polymer And b. Forming a network in which the component is a crosslinked network structure by gelling the mixed solution in a state where the conductive polymer is dispersed in the mixed solution. And a method of making a biocompatible gel material.

Another aspect of the present invention is a suction cup structure comprising: an annular contact portion in contact with a living tissue to be adsorbed; and a bottomed cylindrical suction portion having the hollow portion as an opening and the contact portion as an opening. Wherein the electrode is formed by blending two or more components capable of forming a crosslinked network structure and having biocompatibility with a conductive polymer, and the component comprises the crosslinked network structure A biocompatible gel electrode composed of a biocompatible gel material , wherein one of the components having biocompatibility is silk fibroin .

Another aspect of the present invention is a device for adsorbing to a living tissue in vivo and in a wet environment, comprising: at least one electrode unit having a sucker structure; and at least one electrode unit connected to the electrode unit. A wiring portion, wherein at least the electrode portion is formed by blending two or more components capable of forming a crosslinked network structure and having biocompatibility and a conductive polymer, and the components are formed of a crosslinked network structure And a hydrogel having a network formed thereon, wherein one of the components having biocompatibility is silk fibroin, which is composed of a biocompatible gel material.

  The biocompatible gel material of the present invention has high mechanical strength and excellent flexibility, can be formed into any shape, and can be in contact with living tissue for a long time It is possible to provide a material having a property.

  In addition, according to the method for producing a biocompatible gel of the present invention, a biocompatible gel material of any shape can be easily produced.

  In addition, the biocompatible gel electrode of the present invention has high affinity to the surface of the living body, does not break during stretching, and maintains a stable adhesion state even in a wet environment without sliding on living tissue. be able to.

  In addition, the biological tissue adsorption device of the present invention allows two or more electrode parts to be in physical contact with the biological tissue to be measured for a long time, even in a living environment and in a wet environment, Multi-point measurement of

BRIEF DESCRIPTION OF THE DRAWINGS It is a conceptual diagram which shows the form example using the biocompatible gel material which has electroconductivity which is one Embodiment to which this invention is applied. It is a figure for demonstrating the Example of this invention. It is a figure for demonstrating the Example of this invention.

  The inventor of the present application took notice of the form, characteristics, and design of animals and the like, and focused on “biomimetic” technology that enhances the function of products in the fields of engineering and material science. For example, the model of an animal is developed, such as the development of a bandage that does not easily cause inflammation that mimics the structure of the gecko's hand (see Non-Patent Document 4), and a synthetic adhesive that mimics the mucus of B. typhinum (see Non-Patent Document 5). It has succeeded in improving the function of the material dramatically. Therefore, the inventor of the present application focused attention on nematodes, helminths and cestodes belonging to parasites as animals that stably attach to tissues. When they infect a host animal, they utilize their sucker and hook structure even on the surface of any uneven tissue in the body, even in a moist environment exposed to fluids such as body fluids and digestive fluids. And adsorb. Its adsorptive power has strength that does not yield to heart pulsation, peristaltic movement of the intestinal tract, or shear stress received from the flow of digestive matter, so many of the contents contributing to the tissue stabilization adsorption mechanism in the attachment device to the tissue Have. The inventors of the present invention have found that they utilize a stable adsorption mechanism to infected tissues, and completed the present invention.

  Hereinafter, a biocompatible gel material which is an embodiment to which the present invention is applied will be described in detail with reference to the drawings together with a method of manufacturing the same, a biocompatible gel electrode using the same, and a configuration of a biological tissue adsorption device. In the drawings used in the following description, in order to make the features easy to understand, the features that are the features may be enlarged for the sake of convenience, and the dimensional ratio of each component may be limited to the same as the actual Absent.

<Biocompatible gel material>
First, the configuration of a biocompatible gel material according to an embodiment of the present invention will be described.
The biocompatible gel material of the present embodiment is formed of a hydrogel in which a crosslinked network structure can be formed and two or more components having biocompatibility are blended, and the above components form a network formed of the crosslinked network structure. Material.

  The component having biocompatibility (that is, the material of the gel constituting the gel structure) is particularly limited as long as it has cell adhesiveness and biocompatibility, high transparency, and hydrophilicity. Instead, both synthetic molecules and biomolecules can be used.

  Examples of the synthetic molecule described above include hydrophilic acrylic molecules such as polyethylene glycol and acrylamide. Among these, polyethylene glycol dimethacrylate (hereinafter sometimes referred to as "PEGDMA") is a stretchable polymer, and it has stretchability, visco-elasticity, and fastness as well as affinity to cells and living tissues. It is preferable because it can be improved.

  Further, examples of biomolecules include polysaccharides such as sodium alginate, protein materials such as gelatin and silk, and extracellular matrices such as collagen. Among these, materials containing a large amount of protein are preferable. Therefore, as the biocompatible gel material of the present embodiment, it is preferable to use silk fibroin gel as one of the components having biocompatibility. By using a silk fibroin gel containing a large amount of protein, on the surface of the gel material, the biocompatibility is high, and the cell toxicity can be reduced to such an extent that promotion of cell adhesion can be observed.

  The synthetic molecules and biomolecules described above may be macromolecules or small molecules. Here, the molecular weight (Mw) of the polymer is not particularly limited as long as the polymer can form a gel structure, and for example, a polymer having a molecular weight of about 50,000 to 1,000,000 Da can be used.

  In the biocompatible gel material of the present embodiment, the gel structure is preferably a network composed of a crosslinked network structure. Here, the network consisting of a crosslinked network structure may be a double network in which each of two components capable of forming a crosslinked network structure forms a network, or a network in which three or more components form a network. It may be a network. It is more preferable to construct a gel material by three or more components because plural components can be imparted by the components to be added. For example, when the component of polyacrylic acid is added to construct a conductive biocompatible gel material, the conductivity of the gel material can be further enhanced.

  Further, in the biocompatible gel material of the present embodiment, the network composed of the crosslinked network structure forms a network by randomly bonding two or more components at random, and a plurality of crosslinked network structures exist. It may be. Thus, it is preferable because functions such as high strength and high stretchability can be newly added by covalently bonding a plurality of types of components (polymers) at random.

  In addition, it is preferable that water is contained in gel structure from a viewpoint of improving affinity with respect to biological tissue, such as a skin surface and a cell, of the biocompatible gel material of this embodiment. That is, it is preferable that it is a hydrogel containing water. The content of water contained in the gel material is not particularly limited, but from the viewpoint of maintaining the structural strength, for example, the water content relative to the total mass of the biocompatible gel material is preferably 5 to 95% by mass, 10 to 10%. 80 mass% is more preferable, and 20-70 mass% is further more preferable. The water content can be adjusted by adjusting the type and content (gel concentration) of molecules constituting the gel structure.

  In addition, the biocompatible gel material of the present embodiment may contain a conductive polymer for the purpose of imparting high conductivity. Thereby, a gel material having both biocompatibility and conductivity can be provided.

  The conductive polymer is not particularly limited, and conventionally known conductive polymers having biocompatibility can be used. Specifically, for example, one or a mixture of two or more selected from the group consisting of polypyrrole polymers, polythiophene polymers, and polyaniline polymers can be mentioned. Among these, use of (3,4-ethylenedioxythiophene) / poly (4-styrenesulfonic acid) (hereinafter sometimes referred to as "PEDOT: PSS") of a conductive polymer which is hydrophilic is particularly preferable. Is preferred.

  Furthermore, the biocompatible gel material of the present embodiment may contain, as another component, a factor such as an extracellular matrix or a growth factor. In this way, it is possible to obtain a gel material having an increased affinity to cells and tissues.

  Here, as an example of a specific configuration of the biocompatible gel material of the present embodiment, two components of silk fibroin and PEGDMA which are components having biocompatibility (that is, a material of the gel) and a conductive polymer are used. The PEDOT: PSS-containing PEGDMA / silk gel formulated with PEDOT: PSS will be described.

  In the PEDOT: PSS-containing PEGDMA / silk gel of the above example, silk fibroin and PEGDMA both form a chemical gel by taking a cross-linked structure, and performing gelation treatment as a mixture chemically stable so long as the cross-linked structure is not broken. Form a double network gel with sex.

  It does not specifically limit as a compounding ratio of the component which has biocompatibility, According to the characteristic to add to a biocompatible gel material, it can select suitably. Specifically, when using a 10 mg / mL silk fibroin gel in a two-component system of silk fibroin and PEGDMA, for example, the silk fibroin gel: PEGDMA (volume ratio) is in the range of 1: 2 to 1:10. Thereby, both uniformity and flexibility properties can be imparted to the biocompatible gel material.

  In addition, the double network gel consisting of silk fibroin and PEGDMA contains PEDOT: PSS particles that are hydrophilic and contains a conductive polymer in the network structure of the gel, so it is highly conductive. Addition is also achieved.

  The particle diameter of the PEDOT: PSS particles is not particularly limited, and the average primary particle diameter is preferably in the range of 20 to 400 nm. The particle size distribution can be measured by a commercially available device capable of tracking the scattered light intensity.

  The blending amount (addition amount) of the conductive polymer is not particularly limited, and can be appropriately selected according to the conductivity to be added to the biocompatible gel material. Specifically, for example, when PEDOT: PSS is in the range of 10 to 50 parts by mass with respect to 100 parts by mass of a double network gel consisting of silk fibroin and PEGDMA, stable conductivity is biocompatibility. It can be applied to gel materials.

  By the way, by mixing silk fibroin gel and PEDOT: PSS in the existing research (see the above-mentioned non-patent document 6), the network structure of the silk fibroin gel induces the electron hopping phenomenon between PEDOT: PSS particles. It is known to lower the resistance value. Similar results are obtained by mixing PEDOT: PSS with the double network gel consisting of silk fibroin and PEGDMA in the PEDOT: PSS-containing PEGDMA / silk gel of the above example.

  As described above, according to the PEDOT: PSS-containing PEGDMA / silk gel of the above example, it is possible to improve not only conductivity but also affinity to cells and living tissues, elasticity, viscoelasticity, and robustness. In addition, PEDOT: PSS-containing PEGDMA / silk gel has biocompatibility high enough to culture and grow cells on its surface.

<Method of producing biocompatible gel material>
Next, a method for producing a biocompatible gel material, which is an embodiment to which the present invention is applied, will be described.
The method for producing a biocompatible gel material according to the present embodiment is a step (first step) of obtaining a mixed solution in which raw materials of two or more components capable of forming a crosslinked network structure and having biocompatibility are blended; And gelling the mixed solution to form a network consisting of a crosslinked network (second step). Hereinafter, a method for producing PEDOT: PSS-containing PEGDMA / silk gel will be described as an example of a specific method for producing the present embodiment.

  First, in the first step, a mixed solution in which raw materials of two or more components having biocompatibility are blended is obtained. Specifically, a monomer of ethylene glycol dimethacrylate and PEDOT: PSS are added to a silk fibroin aqueous solution obtained by dissolving silk in water, and a mixed solution containing 40 to 80% by mass of a gel component (aqueous solution )).

  In addition, the preparation method of a mixed solution is an example, and is not limited to this. For example, after preparing each raw material solution (aqueous solution) of each component, you may mix these and prepare a mixed solution.

  Next, in the second step, the mixed solution prepared in the first step is gelled. Specifically, in the state where the conductive polymer PEDOT: PSS is dispersed in the mixed solution, a network of each component is formed. The method of gelation treatment is not particularly limited, and can be appropriately selected depending on the type of gel component and the like. As a specific gelation treatment, any one of solution treatment such as light curing by light irradiation, heat curing by heat treatment, exposure to an ethanol solution, etc. may be performed, or a treatment combining two or more may be used. .

  Here, a double network gel composed of silk fibroin and PEGDMA can be shaped using photo-curing, and therefore, a gel material having not only a bulk material but also an arbitrary shape or partial pattern is manufactured. be able to.

  Specifically, in the method for producing a biocompatible gel material according to this embodiment, alignment is easy and design based on arbitrary CAD data can be performed. Therefore, the method is applied to formation of a partial conductive circuit pattern in a complex structure. It is possible.

  In addition, in the case of molding using light curing property, gelation starts by irradiating light at an arbitrary timing, so the purpose is to fill the mixed solution in a mold or a silicon tube that is shaped using a 3D printer. It can be easily molded into the shape of

  In addition, a mold designs the target three-dimensional structure with a 3D printer or an optical shaping apparatus. In addition, although an ABS resin can be used as a three-dimensional object by a 3D printer, a resin-based structure manufactured by an optical forming apparatus according to the application or a transparent color such as transferred polydimethylsiloxane (PDMS) Elastomers can also be made.

<Bio-tissue adsorption device>
Next, an example of the configuration of a biological tissue adsorption device using the above-mentioned biocompatible gel material will be described.
A biological tissue adsorption device according to an embodiment of the present invention includes one or more electrode units having a suction structure and one or more wiring units connected to the electrode units, and at least the electrode units are crosslinked. It is composed of a biocompatible gel material formed by blending two or more components capable of forming a network structure and having biocompatibility and a conductive polymer.

FIG. 1A is a perspective view showing an example of the configuration of the biological tissue suction device of the present embodiment.
As shown in FIG. 1A, the biological tissue adsorption device 10 includes a plurality of electrode units 1 having a suction structure and a plurality of wiring units 2 connected to the electrode units (biocompatible gel electrodes described later) 1. And a conductive gel substrate 3 on which the wiring portions 2 are formed.

  The electrode portion 1 is provided so as to protrude on the wiring portion 2 formed without crossing on the gel substrate 3. In addition, the electrode portions 1 are dispersedly disposed on the plane of the gel substrate 3. Therefore, each electrode unit 1 functions as an independent electrode.

  The wiring portion 2 is covered with an insulator (not shown) except for the portion where the electrode portion 1 is provided. Examples of the insulator include polyparaxylene (parylene) using thermal chemical vapor deposition.

  The biological tissue adsorption device 10 of the present embodiment can easily form a partial conductive circuit by arranging a gel containing a conductive polymer and a gel not containing a conductive polymer in combination. .

  Specifically, for example, applying “PEDOT: PSS-containing PEGDMA / silk gel” having conductivity to the electrode part 1 and the wiring part 2 and applying “PEGDMA / silk gel” having no conductivity to the gel substrate 3 Thus, the stretchability of the electrode unit 1, the wiring unit 2 and the gel substrate 3 is high, and only the portions of the electrode unit 1 and the wiring unit 2 have conductivity. It can function as a sensor capable of following dynamic tissue regardless of fluid.

  As described above, the biological tissue adsorption device 10 of the present embodiment is a film-like (or sheet-like) sensor capable of following dynamic tissue regardless of whether in the air or in liquid, and it is not only skin but also heart. It can be used by sticking to tissues in the body that exercise. Therefore, it is possible to apply it to an implantable electronic system, and measure biological information without stress as a multipoint measurement sensor that can follow dynamic motion of the living body simply by directly attaching it to the living body. Is possible.

<Biocompatible gel electrode>
Next, an example of the configuration of the biocompatible gel electrode applicable to the electrode unit of the above-described biological tissue adsorption device will be described.
The biocompatible gel electrode according to one embodiment to which the present invention is applied has a bottomed cylindrical shape having a hollow structure inside with an annular contact portion in contact with a living tissue to be adsorbed and the contact portion as an opening. An electrode having a suction structure comprising: a suction portion; and a biocompatible gel material obtained by blending two or more components having biocompatibility and a conductive polymer. Hereinafter, the shape of the biocompatible gel electrode of the present embodiment will be described.

FIG. 1 (b) is a perspective view showing an example of the configuration of the biocompatible gel electrode of the present embodiment.
As shown in FIG. 1 (b), the biocompatible gel electrode 1 of this embodiment has a ring-shaped (annular) contact portion 4 in direct contact with a living tissue to be adsorbed, and the contact portion 4 as an opening. And, it has a suction cup structure consisting of a bottomed cylindrical suction part 5 having a hollow structure 6 inside.

  The suction cup structure of the biocompatible gel electrode 1 has a hollow structure 6 inside the cylindrical suction part 5, and when the contact part 4 comes in contact with the target tissue, the suction part 5 is distorted in the longitudinal direction ( That is, the hollow structure 5 is distorted in the longitudinal direction to enhance the function as a suction cup. More specifically, when the ring-shaped contact portion 4 is adsorbed to the target tissue and stress is applied in the vertical direction to the ring, the entire suction cup is distorted and the volume of the lumen portion of the suction portion 5 is reduced. Since an internal pressure is applied to the inside of the suction cup due to this volume change, it is possible to stably adsorb whether the substance inside the hollow structure 6 is a gas or a liquid.

FIG. 1 (c) is a cross-sectional view showing another example of the configuration of the biocompatible gel electrode of the present embodiment.
As shown in FIG. 1 (c), the suction cup structure of the biocompatible gel electrode 1 increases the volume change of the internal structure 6 when distortion occurs in the suction cup, so that the upper space 6A and the lower space 6B communicate with each other. It is good also as composition which has internal structure 6 divided into two.

  The adhesion to the living tissue by the sucker structure is caused by the change in internal pressure due to the volume change of the gas or liquid filling the inside of the sucker. For this reason, when an external force in the direction perpendicular to the direction from the upper space 6A to the lower space 6B is applied, first, the gel adhering to the object around the upper space 6A is distorted in the same direction, and the distortion further occurs in the lower space 6B. It also transfers to the internal structure, leading to volume change. Therefore, since the total volume and the amount of change thereof are increased as compared with the suction cup having a configuration having only the upper space 6A, the adsorption function can be more efficiently improved.

  As described above, the biocompatible gel electrode 1 of the present embodiment is composed of a biocompatible gel material, and since the gel surface has a sucker structure, it is stably fixed to living tissue at the time of adhesion. be able to. Therefore, the biological tissue adsorption device 10 described above can be applied as a biological electrode (that is, the electrode unit 1) that measures a bioelectric signal.

  As explained above, according to the biocompatible gel material of this embodiment, two or more components capable of forming a crosslinked network structure and having biocompatibility are blended, and these components are crosslinked Since the network structure is a network structure, it has high mechanical strength and excellent flexibility, can be molded into any shape, and can be in contact with living tissue for a long time .

  In addition, when silk fibroin and polyethylene glycol dimethacrylate (PEGDMA) are used as two or more components having biocompatibility, they become both chemical gels by taking a cross-linked structure, as long as the cross-linked structure is not broken. It is possible to form double network gels with non-dissolving chemical stability.

  In addition to using silk fibroin and PEGDMA as highly biocompatible gel materials, the conductive polymer has hydrophilicity (3,4-ethylenedioxythiophene) / poly (4-styrenesulfonic acid) (PEDOT: Conductivity can be added to the biocompatible gel material by dispersing and mixing PSS) in a double network gel.

  Furthermore, according to PEDOT: PSS-containing PEGDMA / silk gel, not only conductivity, but also affinity to cells and living tissues, elasticity, viscoelasticity, and robustness can be improved.

  In addition, according to the method for producing a biocompatible gel of the present embodiment, a step of obtaining a mixed solution containing raw materials of two or more components having biocompatibility capable of forming a crosslinked network structure, and the obtained mixed solution And the step of gelling, a biocompatible gel material of any shape can be easily produced.

  Moreover, since the double network gel which consists of silk fibroin and PEGDMA can be shape | molded using photocurability, the gel which has arbitrary shapes and a partial pattern can be manufactured simply.

  Furthermore, when preparing the mixed solution, the affinity to cells and tissues can be further enhanced by encapsulating factors such as extracellular matrix and growth factor in the mixed solution.

  Moreover, according to the biological tissue adsorption device 10 of the present embodiment, one or more electrode parts (biocompatible gel electrode) 1 having a sucker structure formed of a biocompatible gel material having conductivity, and this electrode part 1 or more wiring parts 2 connected to 1 and physically contact a plurality of electrode parts 1 with a living tissue to be measured for a long time even in a living body and in a wet environment Since it can be made to do, multipoint measurement of a long time becomes possible.

  In addition, according to the biocompatible gel electrode 1 of the present embodiment, a suction disk structure including an annular contact portion 4 in contact with a living tissue and a bottomed cylindrical suction portion 5 having a hollow structure 6 inside is provided. Since the suction cup structure is formed of a conductive biocompatible gel material, it has high affinity to the surface of the living body, does not break when stretched, and is in a wet environment. It is possible to maintain a stable adhesion without slipping even on a living tissue. That is, it can be stably adsorbed to a living tissue in vivo and in a moist environment.

  The embodiment of the present invention has been described in detail with reference to the drawings. However, the specific configuration is not limited to this embodiment, and includes design and the like within the scope of the present invention.

  For example, in the embodiment described above, the configuration using the sheet-like biological tissue adsorption device 10 has been described as an example, but a configuration that can easily analyze the bioelectric signal by combining with a conventional biological signal measuring device It may be

  Specifically, as shown in FIG. 1D, a setup in which the wiring material 12 is coupled between the biocompatible gel electrode 11 in close contact with the living tissue 7 and the biosignal measuring device 8 is employed. May be Under the present circumstances, although you may manufacture with the conductive hydrogel which comprises a sucker structure as the wiring material 12, you may use the metal fine wire marketed.

  Further, in the above-described embodiment, the configuration of the biocompatible gel material having conductivity has been described as an example of the material of the electrode to be adsorbed to the living tissue, but it may be applied as a carrier for cell culture.

  Specifically, in order to further promote cell adhesion and achieve higher affinity and long-term cell adhesion maintenance, extracellular matrix solutions such as fibronectin, collagen and laminin are appropriately added to the multi-network gel. It may be configured to

  Fig. 1 (e) shows that when the culture solution is filled in a culture dish, the gel after solution substitution is suspended therein, and cells are seeded on the surface of the gel, the adherent cells cultured on the gel surface It is a figure which shows the mode after 1 week culture | cultivation of (CHO cell). As shown in FIG. 1 (e), on the gel surface 9, the adherent cells 14 repeat spreading and proliferating similarly to the surface of the culture dish 13, and it can be confirmed that they are useful as a growth substrate. .

  Hereinafter, the effects of the present invention will be described in detail using the following examples. The present invention is not limited by the following examples.

Example 1
Polyethylene glycol dimethacrylate and silk were used as raw materials of the gel. 100 μL of a silk fibroin solution with a concentration of 10 mg / mL and 50 μL of a mixed monomer of ethylene glycol dimethacrylate (EGDMA, Tokyo Chemical Industry Co., Ltd.), obtained by dissolving silk thread (Fujix, Tya-Silk thread, White No. 9) Prepare a solution, and after mixing 400 μL of 4-hydroxybutyl acrylate (4HBA, Tokyo Chemical Industry Co., Ltd.) and 400 μL of a conductive polymer PEDOT: PSS solution (manufactured by Helius, “Clebios P”), The mixture was poured into a mold having a shape and cured to prepare a biocompatible gel electrode having a sucker structure.

In addition, photopolymerization was used as a hardening method of gel. Specifically, LAP (lithium phenyl-2,4,6-trimethylbenzoylphosphinate) is added as a polymerization initiator, and using a 300 W xenon light source (Asahi Spectroscopic Co., Ltd., MAX-302) as a light source, about 30 mW / cm ² Irradiated at an irradiance of 3 minutes.

  The mold formed what designed the target three-dimensional structure by 3D printer. Under the present circumstances, ABS resin was used for the modeling thing by 3D printer.

Example 2
The gel electrode having a sucker structure manufactured in Example 1 was directly attached to the surface of the skin or rat heart, and physiological electrical signals such as physical quantities such as strain and electrocardiograms could be measured. As in the case of a stethoscope, it was verified that the tissue could be stably adsorbed by simply pressing it on the surface of the heart. Since the portion of the sucker-like structure in contact with the heart surface contains a conductive polymer, it was possible to specifically measure the electrical signal from the contact portion.

  Specifically, as shown in FIG. 2 (a), when adsorption is attempted on the rat heart surface 15 moistened by fluid removed in the air, a sucker structure is stably adsorbed on the tissue surface.

  Furthermore, the state of the suctioned organ which contacted the organ after extraction which was made to infiltrate in a pure water is shown in FIG.2 (b). The removed organ is composed of the heart 15, the thymus 17, the airway, and a pair of lungs 18, and is fixed in pure water by holding the thymus part with tweezers while keeping the sucker 16 attached to the heart surface. It was vibrated and the stability of the fixed state and position was verified.

  As a result, the device produced in Example 1 is made of a highly hydrophilic gel, so that it can be attached not only to the pericardial surface via a suction disk structure, but also in a vibration test in water without detachment. Was found to maintain good contacts. In addition, by applying an external force and pulling in a direction perpendicular to the adhesive surface, the sucker structure could be easily detached from the surface of the heart. In addition, since the adhesion of this gel was physically adhered via the suction disk structure, the target tissue was not damaged during the process of adhesion and detachment.

  Moreover, PEDOT: PSS is stable in the electrolyte solution when heat-cured, but is still unstable in pure water and has the property of easily eluting, but in this gel, the network structure of the gel Since it contains PEDOT: PSS particles in it, it does not elute when immersed in pure water, and successfully maintained its shape and conductivity stably.

  The elution of PEDOT: PSS particles into pure water was measured by measuring the intensity of the color of the particles with the passage of time, and the change in the intensity of the luminance. This proves to be effective for tissues with relatively low surface roughness surrounded by dura such as pericardium 15 and kidney capsule.

Example 3
Fig. 3 (a) and Fig. 3 (b) show a suction cup adsorbed on the membrane surface of the heart isolated from a rat. High adhesion was confirmed between the heart 19 removed outside the body and the electrode 1 having a sucker structure.

  By joining the electrode 1 having a suction disk structure and the wiring portion 2 connected thereto, the suction disk can be stably adsorbed to the heart, and in any strain in any of the three-dimensional directions. By following the shape of a violent movement such as the heart beat and measuring the disconnection or resistance value with the biological signal measuring device 8, it is difficult to cause a change in resistance value or disconnection when an external force is applied. Was confirmed.

  Since conduction was confirmed also in the deep part of the tissue and at the terminal part of the conductive gel in the dry state, it was confirmed that the application to measurement of electric signals is possible.

  In addition, as shown in Fig. 3 (c), although the gel swells by being embedded in the tissue, there is no change in the adsorptive capacity even after aspiration of blood or tissue fluid in the body, thoracotomy and cutting the diaphragm, It was confirmed by sticking to a beating heart with an open rib 20.

  Moreover, by arraying 21 of the gel electrodes, it becomes possible to simultaneously measure information of multiple points on the surface of the same tissue (heart). While the measurement is continued, this gel electrode is checked at the time of conduction check or when applied with an alternating voltage of 0.1 Hz to 100 kHz, the change in resistance value corresponds to the concentration of PEDOT: PSS and the shape of the gel. The value was constant in the range of 1 to 200 kΩ, no change occurred, and no leakage of PEDOT: PSS particles was observed.

  In addition, when an external force in the vertical direction was applied to the suction disk structure, it was possible to easily remove the device after measurement without applying a load to the heart when a force in the direction opposite to the tissue was applied.

DESCRIPTION OF SYMBOLS 1 ... Electrode part (Biocompatible gel electrode), 2 ... Wiring part, 3 ... Gel board | substrate, 4 ... Contact part, 5 ... Suction part, 6 ... Interior space structure, 6A ... Upper space, 6B ... Lower space, 7 ... Biological tissue, 8: biological signal measuring device, 9: gel surface, 10: biological tissue adsorption device, 11: biocompatible gel electrode, 12: wiring material, 13: culture dish, 14: adhesive cell

Claims (8)

Composed of two or more biocompatible components capable of forming a crosslinked network structure and a conductive polymer ,
What hydrogel der said component to form a network of crosslinked network,
A biocompatible gel material , wherein one of the components having biocompatibility is silk fibroin . Composed of two or more biocompatible components capable of forming a crosslinked network structure and a conductive polymer ,
What hydrogel der said component to form a network of crosslinked network,
One of the components having biocompatibility is silk fibroin,
A biocompatible gel material , wherein the conductive polymer is (3,4-ethylenedioxythiophene) / poly (4-styrenesulfonic acid) . The biocompatible gel material according to claim 1, wherein the conductive polymer is included in a network structure of the hydrogel. The biocompatible gel material according to any one of claims 1 to 3, further comprising polyethylene glycol dimethacrylate as the component having biocompatibility.   The biocompatible gel material according to claim 4, wherein the hydrogel is a double network gel consisting of the silk fibroin and the polyethylene glycol dimethacrylate. A method for producing the biocompatible gel material according to any one of claims 1 to 5, comprising:
Obtaining a mixed solution in which a conductive polymer and a raw material of two or more components capable of forming a crosslinked network structure and having biocompatibility are obtained;
A process of gelling the mixed solution in a state where the conductive polymer is dispersed in the mixed solution to form a network of the crosslinked network structure, and a method of producing a biocompatible gel material . An annular contact portion in contact with the living tissue to be adsorbed;
An electrode having a suction cup structure comprising a bottomed cylindrical suction part having a hollow structure inside and having the contact part as an opening,
The electrode is a hydrogel formed by blending two or more components capable of forming a crosslinked network structure and having biocompatibility and a conductive polymer, and the components forming a network composed of a crosslinked network structure. A biocompatible gel electrode composed of a biocompatible gel material , wherein one of the components having biocompatibility is silk fibroin . A device for adsorbing to living tissue in vivo and in a moist environment, comprising:
And one or more electrode parts having a suction structure, and one or more wiring parts connected to the electrode parts,
Hydrogel in which at least the electrode portion is formed by blending two or more components capable of forming a crosslinked network structure and having biocompatibility and a conductive polymer, and the components forming a network formed of a crosslinked network structure A biological tissue adsorption device composed of a biocompatible gel material , wherein one of the biocompatible components is silk fibroin .