JP5415238B2 - Reconstruction member for ear canal and tympanic membrane - Google Patents

Description

  The present invention relates to a reconstruction member for reconstructing a part of the ear canal and the eardrum.

  In middle ear surgery, not only a part of the ear canal but also the middle ear cavity may be deleted in order to secure a visual field and an operation space. Or a part of the ear canal and the eardrum may be damaged due to a disease injury or the like. For these reasons, if the ear canal or tympanic membrane is missing, it must be rebuilt.

  Here, as members for reconstructing these defect sites, different tissues such as skin, temporal bone including bone external auditory canal, cartilage external auditory canal, subcutaneous soft tissue, and external ear canal composed of mucosa, and eardrum And a member that can be engrafted is required. In order to meet such demands, in-house materials such as cartilage plates and artificial materials such as hydroxyapatite have been studied. However, collection is difficult, there is room for improvement in deformation due to early absorption or affinity with tissue, and further foreign body reaction can occur. This foreign body reaction is a reaction in which when a reconstruction member is embedded in a living body, the living body tries to discharge it as a foreign body outside the tissue. In order to eliminate this foreign body reaction, it is known to use a molded article made of a composition of collagen and bone forming factor as a reconstruction member (see Patent Document 1). According to this patent document, such a molded article becomes a member for reconstructing a good external auditory canal and tympanic membrane having excellent tissue affinity and no appearance of a foreign body reaction.

JP 2007-125252 A

  However, according to the study by the present inventors, the molded product has room for improvement in strength as a molded body. For this reason, handling at the time of surgery is difficult, and there is a possibility of deformation when implanted in a living body. In addition, until now, no method has been found for rebuilding the external auditory canal and the eardrum while simultaneously forming them into an arbitrary shape.

  A reconstruction member according to the present invention is for reconstructing a defect portion of the ear canal or the eardrum, wherein the reconstruction member is a flaky molded body made of ceramics having a plurality of through holes in the thickness direction, and the reconstruction When the member is embedded, it is embedded so that the surface with the opening of the through hole is in contact with the defect portion.

  Another reconstructing member according to the present invention is for reconstructing a defect portion of the ear canal and the eardrum, and the reconstructing member has a plurality of through holes in the thickness direction, and is a flaky shaped body made of ceramics, And when one end of the reconstructing member is bent, and the reconstructing member is embedded, the bent end is directed to the eardrum side, and the surface with the opening of the through hole is provided. It is embedded so as to be in contact with the outer ear canal defect portion.

  Since the reconstructed member according to the present invention is made of ceramics, it has high strength, so that it is easy to handle during surgery and hardly deforms after implantation. Furthermore, since a plurality of through holes are provided, cells or the like enter and adhere to the through holes, and a stable ear canal or eardrum can be reconstructed.

It is a perspective view which shows the reconstruction member by one embodiment of this invention. It is sectional drawing which shows the reconstruction member by other embodiment of this invention. It is a perspective view which shows the reconstruction member by the further another embodiment of this invention. It is a conceptual sectional view showing an example of an embedding state of a reconstruction member by the present invention. It is a conceptual sectional view showing another example of the embedding state of the reconstruction member according to the present invention. It is an electron micrograph of the fracture surface of the reconstruction member by Example 4. FIG. 6 is an electron micrograph of a fracture surface of a reconstructed member according to Example 5. FIG. 7 is an electron micrograph of a fracture surface of a reconstructed member according to Example 6. FIG. 7 is an electron micrograph of a fracture surface of a reconstructed member according to Example 7. FIG. 9 is an electron micrograph of a fracture surface of a reconstructed member according to Example 8. 10 is an electron micrograph of a fracture surface of a reconstructed member according to Example 9.

  The reconstruction member according to the present invention will be described below with reference to the drawings.

  FIG. 1 is a perspective view showing a reconstruction member 1 according to an embodiment of the present invention. The reconstruction member 1 of the present invention includes a flaky shaped body 2 made of ceramics, and a plurality of through holes 3 are formed in the thickness direction of the shaped body 2.

  In the present invention, the molded body 2 made of ceramics may have any outer shape as long as it is a thin piece, but preferably has a shape that conforms to the form of the ear canal or the like to be reconstructed. That is, the reconstruction member according to the present invention is generally a rectangular parallelepiped shape or a plate shape, but a curved shape matched to the inner curved surface of the ear canal is also preferable. Moreover, the shape of a disk shape etc. may be sufficient. The size of the reconstruction member is appropriately determined according to the type of animal to be applied. For example, when used for the reconstruction of the human ear canal and eardrum, the thickness of the reconstruction member is preferably equal to or less than the thickness of the ear canal from children to adults, for example, 0.5 to 5 mm, particularly 1 to 3 mm is preferable. It is. The width and length are determined according to the site to be treated, but the width is generally 2.0 to 15.0 mm, preferably 3.0 to 10.0 mm, and the length is generally 2.0 to It is 25.0 mm, preferably 3.0 to 20.0 mm.

  The reconstructing member 1 according to the present invention is provided with a plurality of through holes 3 in the thickness direction. By providing this through-hole 3, osteoblasts and blood vessels enter the through-hole 3 when implanted in the defect site of the ear canal, and the bone formation and the engraftment to the surrounding tissue are improved. A strong and stable reconstruction will be done. The cross-sectional shape of the through-hole 3 is arbitrary, and can be an arbitrary shape such as a circle, an ellipse, a triangle, and a quadrangle. However, since cells, blood vessels, etc. enter the through-hole and uniformly adhere to the inner wall of the through-hole, it is possible to grow the layer almost concentrically in bone formation etc., so the cross-sectional shape of the through-hole is circular It is particularly preferred.

  The hole diameter of the through-hole 3 is preferably within a range where cells, blood vessels, bones and the like can be sufficiently generated and grown, and can be appropriately set according to the use conditions. Specifically, the hole diameter of the through hole is preferably 10 to 1000 μm, and more preferably in the range of 200 to 600 μm, which is a diameter suitable for cell entry. In addition, it is essential that the number of through holes is plural, but in general, the larger the number of holes, the greater the bonding effect, which is preferable. Moreover, the cross-sectional shape or hole diameter of the through holes may be uniform, or different ones may be mixed. Furthermore, the arrangement of the through holes may be regular or random.

  Although the number of through holes provided in the reconstruction member varies depending on the size of the reconstruction member, it is preferable that the number of through holes per unit area is large. At this time, there may be a through-hole deviating from the specified hole diameter range, but it is preferable that the majority of the through-hole is included in the specified hole diameter range. If the number of through-holes per unit area is large, the total number of blood vessels and cells entering the hole tends to increase, and bone formation tends to be improved. The diameter of the through-holes is within the specified range. This is because the bone formation in each through-hole is improved. Even if only one through-hole with a large hole diameter that has the same opening area is provided, bone formation in each through-hole is worsened and the total surface area inside the through-hole is reduced, so that it is formed on the surface. Bone mass is also reduced, and good bone formation often cannot be obtained. For the above reasons, it is preferable that a large number of through holes having a hole diameter included in the specified hole diameter range are formed.

  Various ceramics such as metal oxides, silicides, nitrides, fluorides and borides can be used as the ceramics as the main material of the reconstruction member according to the present invention. Any of these may be used, but ceramics used for bone filling materials, cell culture carriers and the like are preferable. For example, aluminum oxide, zirconium oxide, calcium phosphate, and the like can be mentioned. Of these, calcium phosphate ceramics are particularly preferable because they have characteristics close to living tissue. More specifically, examples include primary calcium phosphate, calcium metaphosphate, dicalcium phosphate, calcium pyrophosphate, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, Ca-deficient hydroxyapatite, and the like. Of these, tricalcium phosphate is preferred. These tricalcium phosphates include α-tricalcium phosphate (hereinafter sometimes referred to as α-TCP) and β-tricalcium phosphate (hereinafter sometimes referred to as β-TCP), but prevent inflammation reaction. From this point of view, the content of β-TCP is preferably high, and the content of β-TCP is most preferably 100%. By using β-TCP as ceramics, the biocompatibility is particularly excellent, and there is an effect that the body itself is skeletonized and the appearance of a foreign body reaction hardly occurs. As a result, the engraftment with different tissues such as skin, temporal bone including bone external auditory canal, cartilage external auditory canal, subcutaneous soft tissue, or mucous membrane is improved.

  In the reconstructed member according to the present invention, the ceramic molded body contains minute voids, and the larger the amount of voids, the higher the in vivo solubility and the higher the biocompatibility. For this reason, the porosity indicating the amount of voids is preferably 2% or more, more preferably 10% or more, and further preferably 20% or more. In addition, the lower the porosity, the denser and the higher the mechanical strength. For this reason, the porosity is preferably 40% or less, and more preferably 25% or less.

Here, the porosity of the ceramic molded body can be specifically measured by the Archimedes method. In the present invention, the dry mass W1, the underwater mass W2, and the saturated water mass W3 of the ceramic molded body can be measured and determined by the following formula.
Porosity (%) = (W3-W1) / (W3-W2) × 100

  When it is intended to enter osteoblasts or blood vessels into the through-holes in the ceramic molded body, a better structure can be obtained by arranging an appropriate filler inside at least one, preferably all of the through-holes. A reconstruction effect is expected. Examples of such fillers include polymer compounds and blood having an antibacterial effect. A preferred polymer compound here is a polymer hydrogel composed of a hydrophilic polymer, and such a polymer compound has a feature of promoting the growth of osteoblasts and blood vessels. Preferable polymer compounds include, specifically, cellulose derivatives such as polyvinyl alcohol and sodium carboxymethyl cellulose, proteins such as collagen and gelatin and derivatives thereof, polysaccharides such as alginic acid, starch, dextran, and pullulan, and derivatives thereof, heparin, hyaluronic acid , Glycosaminoglucans such as chondroitin sulfate and heparan sulfate, polysaccharides such as chitin and chitosan, mucopolysaccharides and the like, and these can be used alone or in combination. Blood is preferred in that it protects against inflammation. It is also possible to add a therapeutic agent such as inflammation to the filler.

  FIG. 2 is a cross-sectional view of a reconstruction member that is another embodiment of the present invention. In the reconstructing member in FIG. 2, the inside of the through hole is filled with the filler 5, and two surfaces having openings of the through holes are further coated with the coating 4. By providing the coating 4 on the surface in contact with the living tissue in this way, it is possible to easily engraft with different tissues such as the external auditory canal including the skin, the bone external auditory canal and the cartilage external auditory canal, the subcutaneous soft tissue, the mucous membrane, or the tympanic membrane. . Examples of such a suitable film material include the same materials as those described above.

  In addition, when arrange | positioning a membrane | film | coat, it is more preferable that the filler 5 is arrange | positioned also in the through-hole 3. FIG. At this time, the material of the filler may be the same as or different from that of the coating 4. Moreover, a film | membrane can also be laminated | stacked on two or more layers using a different material.

  In the case of using the above-mentioned film and / or filler, it is preferable to further add an osteogenic factor to the material. This is because the bone morphogenetic factor can be expected to have a more favorable effect on the growth of cells and bones. Specific examples of osteogenic factors that can be used include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-3b, OP-2, OP-3, DPP, Vg-1, Vgr-1, 60A protein, GDF-1, GDF-2, GDF-3, GDF -5, GDF-6, GDF-7, GDF-8, GDF-9, GDF-10, GDF-11, FGF, M-CSF, IL-10, IL-12, IL-17, IL-21, etc. Used. Of these, BMP is preferable, and BMP-2 is particularly preferable. The greater the amount of bone formation factor, the greater the effect of promoting osteogenesis. Therefore, it is generally 0.0001% by mass or more, preferably 0.001% by mass, based on the total mass of the material used for the coating and / or filler. As described above, it is particularly preferably 0.01% by mass or more. Further, since the smaller the amount of bone morphogenetic factor, the more advantageous in terms of the cost for promoting osteogenesis, it is generally 1% by mass or less, preferably 0.5% by mass or less, particularly preferably 0.2% by mass or less. Is done.

  FIG. 3 shows a reconstruction member according to yet another embodiment of the present invention. This reconstruction member has an L-shaped structure with one end bent. That is, one end in the longitudinal direction of a rectangular parallelepiped or plate-like thin piece is bent at an angle of about 90 °. It is preferable that such a shape is determined corresponding to the shape of the part where the reconstruction member is embedded. In particular, a reconstruction member having a structure as shown in FIG. 3 is suitable for being implanted at the joint site between the eardrum and the ear canal and treating both at the same time. The bent portion 2A is mainly used for protecting or reconstructing the eardrum by joining to the eardrum connected to the external auditory canal bone tissue, and has a favorable effect particularly in a portion where the connection between the eardrum and the surrounding tissue is weak. . Such a bent structure can be obtained as a combination of flat surfaces or can be obtained by integral molding. In the reconstructing member having such a structure, the bending angle and mounting direction of the bent portion 2A are determined by the size of the defect and the angle between the bone tissue to be reconstructed and the eardrum. When operating on the ear canal relatively close to normal, it is often joined to the eardrum near the bent portion of the bent portion 2A, and when there is a large amount of defect, it is worn in the opposite direction and bent. It seems that it often joins with the eardrum near the tip of 2A. Here, since the angle between the bone tissue and the eardrum varies depending on the position in the ear canal, it is necessary to set it appropriately according to the position and the amount of defect. Therefore, the bent angle is not a right angle but may be an acute angle or an obtuse angle. In order to improve the bonding between the reconstruction member and the eardrum, it is preferable to provide the above-described coating.

  Moreover, it can also be set as a T-shaped structure or a rectangular structure as needed. These structures can be appropriately employed according to the part to be treated. Furthermore, these reconstructing members are not only embedded in the required shape such as L-shape in advance, but for example, by arranging and embedding plate-shaped reconstruction members in L-shape, The same effect as that of the reconstructed member having the structure can be obtained.

  The embedded state of the reconstruction member according to the present invention is as shown in FIG. 4 or 5, for example. Here, although the example using the reconstruction member which has L-shaped structure is shown, when it has other structures, it can embed according to this.

  In the example shown in FIG. 4, the reconstruction member is embedded so that the longitudinal portion of the reconstruction member is in contact with the defect portion of the ear canal. Here, it is the surface of the long part which has the opening part of the through-hole of a reconstruction member that touches the defect | deletion part of an ear canal. In this example, the bent portion of the reconstruction member is embedded so as to be disposed on the eardrum side. On the other hand, in the example of FIG. 5, the bent portion is embedded so as to be on the opposite side of FIG. 4. These arrangements are appropriately adjusted according to the defect state of the ear canal or the eardrum. In addition, as needed, a through hole may be provided only on the required side of the ear canal or the eardrum, that is, only the longitudinal portion or the bent portion.

  4 and 5 show the position where the reconstruction member is embedded in the structure of the ear canal in a normal state. However, the shape of the ear canal or eardrum that is actually damaged varies, and the ear canal may be occluded or distorted. Therefore, when using a reconstruction member in such a case, it is common that the embedding position is appropriately adjusted according to the state.

Although the reconstruction member by this invention can be manufactured by arbitrary methods, it can manufacture by the following methods as a preferable method.
Preparing a composition containing ceramics;
Using the composition, a flaky ceramic material is produced by molding,
A plurality of through holes extending in the thickness direction are formed in the flaky ceramic material,
The ceramic material is dried or fired at a temperature of 600 ° C. or higher.

  This method will be described more specifically as follows. First, a composition in which a binder such as a resin and a solvent such as water are added to a main material such as ceramics as necessary is prepared. Next, using the composition, a flaky ceramic material is produced by a molding process such as extrusion molding, injection molding, or press molding, and an appropriate number of through holes are formed by a drill or the like in the thickness direction of the ceramic material. . As necessary, before or after the formation of the through hole, the thin piece is bent or bent in accordance with the shape of the ear canal or the like. The obtained ceramic material is dried or fired at a temperature of 800 ° C. or higher, so that it becomes a ceramic molded body to obtain a reconstructed member. Thereafter, a film containing a polymer compound may be formed in the through holes and / or on the surface of the ceramic molded body as necessary.

  Here, the firing temperature when obtaining the ceramic molded body is closely related to the porosity and ceramic composition described above. Usually, the sintering of ceramics is said to start from about 600 ° C., but the firing temperature, the porosity and the ceramic composition have a certain relationship. When manufacturing the ear canal reconstruction member of the invention, the firing temperature for obtaining a ceramic molded body is preferably 800-2000 ° C. If the lower limit is not reached, powdery deposits are generated on the surface and the handling tends to be poor. If the upper limit is exceeded, it may stick to the apparatus, which is not preferable. In addition, when tricalcium phosphate is used as the ceramic, it is preferable to select a firing temperature at which β-TCP is generated in a large amount and α-TCP is not generated at all or is small even if generated. A preferable temperature range in view of the production amount of β-TCP is 800 to 1500 ° C, and more preferably 1150 to 1400 ° C.

  The present invention will be described below with reference to various examples. Hereinafter, “part” means “part by mass” unless otherwise specified.

Example 1
100 parts of water is added to 80 parts of β-tricalcium phosphate as a main material and 20 parts of polyvinyl alcohol as a binder, and after extrusion, it is extruded to have a length of 4.0 mm, a width of 3.0 mm, and a thickness of 1 A ceramic material of 0.0 mm was produced. Twenty-five holes having a diameter of 300 μm were drilled in this ceramic material in the thickness direction. This material was fired at 1190 ° C. in an oxygen atmosphere to obtain a ceramic molded body made of β-tricalcium phosphate. This ceramic molded body had a porosity of 23%.

  Next, a gel aqueous solution of collagen in which rhBMP-2, which is a bone formation factor, is blended as a polymer compound is prepared, this gel solution is filled into the pores of the ceramic body, and further, the same gel solution is used to form a ceramic. A film was formed on the surface of the body to obtain a reconstructed member.

  When this reconstructed member was embedded in a bone defect portion of the ear canal of a rat and observed at 4 weeks, sufficient bone formation was achieved, and both skin, subcutaneous soft tissue, and mucous membrane were engrafted. Also, no foreign body reaction or member discharge was observed.

  As described above, the reconstructed member of Example 1 was confirmed to be extremely good, such as excellent biocompatibility, sufficient strength to maintain the form, and easy handling. It was.

Example 2
A ceramic material in which a through hole was provided by the same method as in Example 1 and one end in the length direction was bent by 0.5 mm was manufactured. This ceramic material was fired in the same process as in Example 1, filled with a gel solution, and formed with a film to obtain a reconstructed member. This reconstruction member was embedded in the bone defect portion at the eardrum junction of the ear canal of a rat so as to be in contact with both the eardrum and the ear canal, and observed at 4 weeks. The bent part was engrafted on the eardrum, and the eardrum was not displaced.

Example 3
In contrast to Example 1, the reconstruction temperature was changed to 1300 ° C. when the ceramic molded body was manufactured to manufacture a reconstructed member. When this reconstructed member was evaluated in the same manner as in Example 1, bone formation was observed in most of the through holes, and a sufficient effect was observed. However, when compared with Example 1, a slight level of inflammatory cell infiltration was observed at a level that was not a problem.

Examples 4-9
Compared to Example 1, the firing temperature at the time of producing the ceramic molded body was 1100 ° C. (Example 4), 1140 ° C. (Example 5), 1250 ° C. (Example 7), or 1500 ° C. (Example 9). A reconstructed member was produced in the same manner as in Example 1 except that the above was changed.
Moreover, as an example without a filler and a film, the firing temperature in producing a ceramic molded body was not changed with respect to Examples 1 and 3 {1190 ° C. (Example 6), 1300 ° C. (Example 8). } A reconstructed member was produced in the same manner as in Example 1 except that the filler and film were not used.
These reconstructed members were evaluated in the same manner as in Example 1.

  The evaluation results obtained were as shown in Table 1. Table 1 also shows the results of Examples 1 to 3. The column “Evaluation” in the table indicates an evaluation comprehensively determined from bone formation and engraftment. Moreover, when the fracture surface of the reconstruction member of Examples 4-9 was observed with the electron microscope, it was as showing in FIGS. Further, when the reconstructed members of Examples 1 to 3 were also observed with an electron microscope, it was confirmed that Examples 1 and 2 had the same structure as Example 6 and Example 3 had the same structure as Example 8. .

  Any of the examples could function as a reconstruction member. As the firing temperature is increased, the porosity is lowered and the amount of α-TCP produced in the ceramic composition is increased, but when the porosity is low and the composition ratio of α-TCP is increased, It was found that the degree of inflammation in the embedded portion changed, and Examples 1 to 3 and 6 to 8 showed good results with little inflammation, and Examples 1 and 2 were the best. In Examples 1 to 3 and 6 to 8, bone formation was observed, and in Examples 1 and 2, vigorous bone formation was confirmed. On the other hand, although it can function as a reconstruction member, in Example 9, the finding of the example in which the embedded material melts was observed.

Example 10
A reconstructed member of Example 10 was produced in the same manner as in Example 1 except that seven through holes fewer than those in Example 1 were provided radially. The diameter of each through hole was set to 300 μm, the same as in Example 1. When this reconstructed member was evaluated in the same manner as in Example 1, bone formation was observed, and it was confirmed that the reconstructed member functions sufficiently as a reconstructed member. However, there was little bone formation in the inner surface of the through-hole of a reconstruction member compared with Example 1. FIG. This is presumed to be because the number of through holes is small, the total number of blood vessels and cells entering the hole is small, and the total surface area inside the hole is small.

Comparative Example 1
The reconstruction member of Comparative Example 1 was manufactured in the same manner as in Example 1 except that the single hole structure in which one through hole having a hole diameter of 1000 μm was provided instead of the plurality of through holes. When this reconstructed member was evaluated in the same manner as in Example 1, compared with Example 1, the evaluation of bone formation tended to be poor. This is because the hole diameter of the through hole is out of a specific range, so that the bone formation inside the through hole is poor, and the total surface area inside is also small because the number of through holes is small, so that the bone formed on the surface This is thought to be due to a decrease in the total amount.

Comparative Example 2
The reconstructed member of Comparative Example 2 was manufactured and evaluated using collagen. Such a reconstructed member has advantages such as high biocompatibility, easy replacement with bone tissue, fast resorption, and beneficial effects on bone formation because it is a protein similar to the main component of bone (collagen). It is said to have. However, the reconstructed member of Comparative Example 2 has a conventionally known problem. Specifically, since the strength is low, the function of the treatment site can hardly be expected until bone formation is completed, and since it is a protein, degeneration and the like must be considered, and formation is difficult.

  The reconstruction member according to the present invention can promote the formation of blood vessels and cell proliferation, and can realize excellent engraftment with different tissues such as skin, tympanic membrane, ear canal, subcutaneous soft tissue, and mucous membrane. Applicable to the request.

DESCRIPTION OF SYMBOLS 1 Reconstruction member 2 Ceramic molded body 3 Through-hole 4 Film 5 Filler 2A Bending part of ceramic molded body 41 Tympanic membrane 42 Ear canal

Claims (7)

A reconstructing member for reconstructing a defect part of the ear canal, wherein the reconstructing member has a plurality of through-holes in the thickness direction, and is formed by molding and firing a composition containing ceramics. It is a flaky shaped body of 2% or more and 40% or less , and when the reconstruction member is embedded, the surface with the opening of the through hole is embedded so as to be in contact with the defect portion Reconstruction material to be. A reconstruction member for reconstructing a defect part of the ear canal and the eardrum, wherein the reconstruction member has a plurality of through holes in the thickness direction, and is formed by molding and firing a composition containing ceramics When the rate is 2% or more and 40% or less of a flaky molded body and one end of the reconstructing member is bent and the reconstructing member is embedded, the bent end The reconstruction member is characterized by being embedded so that the surface with the opening portion of the through hole is in contact with the ear canal and the deficient portion of the eardrum .   The reconstruction member according to claim 1 or 2, wherein the main component of the ceramic is calcium phosphate.   The reconstruction member according to any one of claims 1 to 3, wherein a filler is disposed in the through hole of the molded body.   The reconstruction member according to claim 4, wherein the filler comprises an osteogenic factor.   The reconstruction member according to any one of claims 1 to 5, wherein a film is formed on at least one of the surfaces having the through-hole openings of the molded body.   The reconstruction member according to claim 6, wherein a bone morphogenetic factor is blended in the film.