JP2013106830A - Model animal, method for producing the model animal, and method for evaluating in-vivo indwelling device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a model animal that facilitates control of the size of swelling and the coil filling rate, minimizes the effects due to the vascular spasm and bleeding caused by indwelling procedure to the inside of the body of a non-human animal, and allows acquisition of filmed images using magnetic resonance in a short period of a few days after the indwelling, a method for producing the model animal, and also, a method for evaluating an in-vivo indwelling device that uses the model animal.SOLUTION: The model animal is used for evaluation of an in-vivo indwelling device. The model animal includes: a metallic in-vivo indwelling device 5; and a hollow body 1 made of industrial chemicals and filled with the in-vivo indwelling device. The model animal is configured such that the hollow body is disposed in a blood vessel 6 of a non-human animal or around the blood vessel. The method for producing the model animal includes: a step for preparing the metallic in-vivo indwelling device; a step for preparing the hollow body made of industrial chemicals and filled with the in-vivo indwelling device; and a step for disposing the hollow body in the blood vessel of the non-human animal or around the blood vessel.

Description

  The present invention relates to a model animal, a method for producing a model animal, and a method for evaluating an indwelling device, and more specifically, for example, a model animal used for evaluating an embolization coil used for embolization treatment of an aneurysm, and the model animal The present invention relates to a production method and a method for evaluating an indwelling device using a model animal.

  Currently, as a less invasive treatment method for aneurysms and the like, vascular embolization is known in which an indwelling device for embolization is placed in an aneurysm. In this vascular embolization, the indwelling device for embolization placed in the aneurysm becomes a physical obstacle to the blood flow, and a thrombus is formed around the indwelling device for embolization. The risk of aneurysm rupture can be reduced. Here, there is an embolization coil made of a metal material as an indwelling device for embolization that is placed at a predetermined site in a blood vessel such as an aneurysm.

  Such an embolization coil is introduced into a predetermined site via an appropriate catheter by an extruding means (inductor) removably connected to an end of the embolization coil, and is detached at the predetermined site. The function is demonstrated by being indwelled. Such an embolization coil is required to have various characteristics such as high flexibility and appropriate resistance to pulling.

  Then, after such vascular embolization is performed, it is necessary to perform a periodic examination in order to confirm whether there is an increase in aneurysm or deviation of the coil to the parent blood vessel. An increase in the aneurysm leads to rupture, and deviation of the coil to the parent vessel leads to ischemia and cerebral infarction. Angiography, CT, MRI, etc. are used for the postoperative examination, but MRI or MRA is the best from the viewpoint of observing blood flow.

  Here, an embolization coil or other indwelling device may generate an artifact when acquiring an MRI image or an MRA image depending on the material, and an image in the vicinity thereof is distorted so that an accurate blood vessel cannot be observed. It is known that the occurrence of artifacts increases as the magnetic susceptibility of a material such as an embolization coil increases away from the magnetic susceptibility of water. The coil for embolization does not generate artifacts during imaging using magnetic resonance whenever a suitable characteristic is required according to the operation situation such as the position and size of the aneurysm that introduces it Alternatively, it is required to use a material that can be reduced to an extent that does not affect imaging. In the field of research and development of these indwelling devices, it is important to finally evaluate the characteristics by animal experiments using non-human animals.

  When evaluating an embolization coil in an animal experiment, it is difficult to create an aneurysm of the same size as a human in the animal's brain. Has been. Before the embolization coil is placed in the rabbit body, it is first necessary to create a simulated aneurysm that resembles a human aneurysm in the rabbit artery. This manufacturing method includes an aneurysm model (Non-Patent Document 1) by a vein pouch method and an aneurysm model (Non-Patent Document 2) by elastase. In the former method, one end of a vein excised from another site is sutured to create a pouch, an incision is made in the artery, the other end of the pouch is sutured to the incision, and the simulation projects about 5 mm from the artery. An aneurysm is produced. In the latter method, an aneurysm is produced by weakening an arterial wall by applying elastase to an artery that is blinded by ligation.

AJNR Am J Neuroradiol 19: 1309-1314, August 1998. AJR 174: 349-354, February 2000.

  However, the aneurysm model by the venous pouch method is highly invasive to the blood vessels, and since the coil is inserted after it has been stable for about two weeks after production, the size of the aneurysm changes due to self-repair during that time, and its control is In addition to being difficult, it takes a long period of time from preparation to testing, and there is a problem that the risk of the embolized coil deviating to the parent vessel is high. On the other hand, the aneurysm model by elastase has the advantage that an aneurysm close to nature can be produced, but the size varies as described above, and it takes time to produce, and there is a risk that the embolized coil will deviate to the parent vessel. There is a problem that it is expensive.

  Therefore, in view of the above-mentioned situation, the present invention intends to solve the problem that the size of the aneurysm and the filling rate of the coil can be easily controlled, and vasospasm and bleeding associated with the indwelling procedure in the body of a non-human animal. The model animal that can suppress the influence of sigma to the minimum and can acquire a captured image using magnetic resonance in a short number of days after placement is provided, and a method for producing the model animal is also provided. It is in the point which provides the evaluation method of the indwelling device using this.

  A first invention made to solve the above-mentioned problems is a model animal used for evaluation of an indwelling device, wherein the indwelling device made of metal, and a hollow body made of a chemical filled with the indwelling device, A model animal in which the hollow body is arranged around a blood vessel of a non-human animal or around the blood vessel (claim 1).

  Here, it is preferable that the hollow body is sewn to the blood vessel that is not incised (Claim 2).

  Moreover, it is preferable that the thickness of the said hollow body is 200 micrometers or more and 700 micrometers or less (Claim 3).

  Furthermore, it is preferable that the hollow body is made of a material having biocompatibility and a material that does not appear in a photographed image using magnetic resonance. Here, the hollow body is more preferably formed of silicon rubber.

  The hollow body is preferably filled with a gel-like material equivalent to the magnetic susceptibility of water (claim 6). Here, the gel-like product is more preferably agar (Claim 7).

  The indwelling device is a coil used for embolization treatment (claim 8).

  The second invention is a method for producing a model animal used for evaluation of an indwelling device, comprising a step of preparing the indwelling device made of metal, and a hollow body made of a chemical filled with the indwelling device. A method for producing a model animal, comprising a step of preparing and a step of placing the hollow body around or in a blood vessel of a non-human animal (claim 9).

  Moreover, 3rd invention is an evaluation method of an indwelling device, Comprising: By imaging | photography using a magnetic resonance with respect to the model animal of any one of Claims 1-8, the said indwelling device is carried out. A method for evaluating an indwelling device including the step of acquiring the hollow body filling the device and an image around the hollow body (claim 10).

  Here, in the indwelling device evaluation method, the imaging using the magnetic resonance is preferably MRI or MRA.

  It is more preferable that the method further includes a step of acquiring at least one of the images and evaluating the indwelling device based on whether or not an artifact image is generated in the acquired image.

  Since the model animal of the present invention and the method for producing the model animal as described above use a hollow body made of a chemical, the size can be accurately controlled, and a metal indwelling device is attached to the hollow body outside the body. Since filling, the filling operation is simple, the filling rate can be accurately controlled, and the hollow body filled with the indwelling device is merely placed around the blood vessel or around the blood vessel of the non-human animal, so that it is less invasive and non-invasive. The stress of a human animal can be reduced, and a captured image using magnetic resonance can be acquired in a short number of days after placement. Also, there is no risk that the indwelling device will fall out of the hollow body. Since a substantially uniform hollow body is attached to a plurality of model animals, individual differences among the model animals can be suppressed as compared with the conventional vein pouch method, which leads to improvement in evaluation accuracy.

  Since the hollow body is simply sewn into the non-incised blood vessel of the non-human animal, a short indwelling procedure is sufficient, and the effects of vasospasm and bleeding associated with the indwelling procedure can be minimized. Further, since the hollow body is sewn on the blood vessel, the possibility of the hollow body peeling off from the blood vessel is reduced.

  Moreover, when the thickness of the hollow body is 200 μm or more and 700 μm or less, there is little risk of breakage when filling the indwelling device, and it can be placed in close proximity to the parent artery, and an actual aneurysm can be obtained. Can be simulated.

  Furthermore, the hollow body is a material having biocompatibility, and is formed of a material that is not reflected in a captured image using magnetic resonance, so that there is little invasion to the model animal, and an artifact caused by the indwelling device itself. It is possible to evaluate the presence or absence of occurrence. Here, it is particularly effective that the hollow body is formed of silicon rubber from the viewpoint of biocompatibility, flexibility, and strength.

  In addition, by filling the hollow body with a gel-like substance equivalent to the magnetic susceptibility of water, the hollow body and the position of the indwelling device become stable, and a state closer to a real aneurysm is achieved. Can be made. Here, if the gel-like material is agar, there is little invasion to the living body, and a state close to the inside of the aneurysm after embolization treatment can be reproduced. The indwelling device is most effective when it is a coil used for embolization treatment.

  Further, the method for evaluating an indwelling device using the model animal of the present invention uses a magnetic resonance for a model animal in which a hollow body made of a chemical compound filled with the indwelling device is placed around or in a blood vessel of a non-human animal. The image of the hollow body filling the indwelling device and an image of the periphery of the hollow body are obtained, so that the presence or absence of artifacts caused by the indwelling device can be easily checked and evaluated. it can. When the imaging using magnetic resonance is MRI or MRA, an artery can be directly imaged, and since it is used for actual embolization treatment, it is highly reliable.

  Furthermore, the method for evaluating an indwelling device includes a step of acquiring at least one of the images and evaluating the indwelling device based on whether or not an artifact image is generated in the acquired image. can do.

The hollow body used for this invention is shown, (a) is the perspective view seen from the balloon part side, (b) is the perspective view seen from the attachment piece side, (c) is sectional drawing. It is a fragmentary perspective view of the state which sewed the hollow body which filled the coil inside to the artery side of a rabbit. It is a perspective view which shows the core material for dipping the hollow body of this invention. The manufacturing process of the hollow body of this invention is shown, (a) is a side view of a state in which a thin film of silicon rubber having a predetermined thickness is dipped around the core material, and (b) is silicon corresponding to a cylindrical portion of the core material. (C) is a side view showing a state where the hollow body is peeled off from the core material, (d) is a side view showing a state where the section is cut off, The side view of the state which adhered the sheet | seat so that an opening part may be closed to the part which cut off the section | slice, (f) is a side view which shows the completed product of the hollow body which cut off the excess part of the sheet | seat. It is a perspective view of the state where the hollow body was attached to the side of the silicon tube. It is a simplified diagram showing a blood vessel simulation phantom device for imaging by MRI while flowing simulated blood inside a silicon tube having a hollow body attached to its side surface. It is a MRI image (Spin Echo) of a state in which a simulated aneurysm is attached to the blood vessel simulated phantom device. It is a MRI image (TOF: time-of-flight) in a state where a simulated aneurysm is attached to the blood vessel phantom device. Using a model animal in which an Au-28Pt alloy coil inserted into a silicon hollow body (Example) and a Pt-8W alloy coil inserted (Comparative Example) are sutured into the outer membrane of a rabbit abdominal aorta It is the acquired TOF-MRA image. Using a model animal in which an Au-28Pt alloy coil inserted into a silicon hollow body (Example) and a Pt-8W alloy coil inserted (Comparative Example) are sutured into the outer membrane of a rabbit abdominal aorta It is the angiography result acquired by the digital subtraction method.

  1st invention provides the model animal used for evaluation of an indwelling device. The model animal includes the indwelling device made of metal and a chemical-made hollow body filled with the indwelling device, and the hollow body is disposed around a blood vessel or a blood vessel of the non-human animal. It is a feature.

  The metal indwelling device is intended for a coil used for embolization treatment of an aneurysm, but may be a stent.

  The hollow body is a material having biocompatibility, and is formed of a material that does not appear in a photographed image using magnetic resonance. Here, it is most preferable that the hollow body is formed of silicon rubber, but other than silicon, an organic compound that is compatible with the animal body can be used. A material that does not contain metal is used as a material that is not reflected in a photographed image using magnetic resonance. Since the colorant contains metal, a colored material is not used. A material that can be molded thinly is used. The thickness of the hollow body is preferably 200 μm or more and 700 μm or less. If the thickness of the hollow body is less than 200 μm, there is a risk of tearing when filling the indwelling device, and if the thickness of the hollow body exceeds 700 μm, it becomes too thick and leaves the form of an actual aneurysm. Cannot be placed in close proximity to the parent artery.

  Next, the present invention will be described in more detail based on the embodiments shown in the accompanying drawings. FIG. 1 shows a hollow body 1 used in the present invention. The hollow body 1 is formed by adhering a balloon portion 2 having a predetermined thickness and a silicon rubber sheet 3 on the outer surface of the balloon portion 2 so as to close an opening 4 generated in the manufacturing process. The indwelling device 5 (emboli forming coil) was filled in the balloon portion 2 from the opening 4 before the sheet 3 was bonded, and formed on the sheet 3 after the sheet 3 was bonded. The inside of the balloon part 2 is filled through the fine hole.

  Then, as shown in FIG. 2, the hollow body 1 filled with the indwelling device 5 is sewn to the arterial blood vessel 6 in the abdomen of the rabbit that has not been incised. Specifically, the balloon 2 is sewn to the blood vessel 6 with a surgical thread 7 in a state where the sheet 3 of the hollow body 1 is placed along the outer periphery of the blood vessel 6. Since the blood vessel 6 is not incised, a short indwelling procedure is sufficient, and the effects of vasospasm and bleeding associated with the indwelling procedure can be minimized. In addition to rabbits, any non-human animal having an artery with a thickness approximately the same as that of a human brain artery can be used.

  The method for producing the model animal used for the evaluation of the indwelling device of the second invention is as described above. The step of preparing the indwelling device 5 made of metal, and the chemical filling with the indwelling device 5 are performed. A step of preparing a hollow body 1 made of a product, and a step of arranging the hollow body 1 around a blood vessel 6 or a blood vessel 6 of a non-human animal. Here, in order to arrange the hollow body 1 around the blood vessel 6 or the blood vessel 6, it is preferable to sew the hollow body 1 with the surgical thread 7 as described above, but it is also possible to bond the hollow body 1 with a surgical adhesive. It is also possible to mechanically hold the hollow body 1 on the outer peripheral surface of the blood vessel 6 with a fastener that does not strongly restrain the blood vessel 6.

  Moreover, the inside of the balloon part 2 of the hollow body 1 may be filled with a gel-like substance equivalent to the magnetic susceptibility of water. Specifically, it is preferable to use agar as the gel. Here, the magnetic susceptibility of blood is about the same as that of water, but varies depending on individual differences. Since the present invention evaluates the presence or absence of artifacts in the indwelling device 5, blood that causes fluctuations in magnetic susceptibility is not required inside the balloon portion 2 of the hollow body 1. Therefore, a gel-like substance instead of blood, for example, agar, is filled in the balloon portion 2 of the hollow body 1 together with the indwelling device 5. However, it has been confirmed that MRI images can be taken without any problem without filling the balloon portion 2 with a gel-like material.

  Next, a method for manufacturing the hollow body 1 will be briefly described. The hollow body 1 is manufactured by dipping using the core material 8. The core material 8 used here is one in which the sphere 10 is fixed to the outer periphery of the cylindrical body 9 by point contact. The sphere 10 is changed according to the required diameter of the balloon part 2.

  First, when the core material 8 is dipped in a tank containing a silicon rubber sol solution, and then pulled up and dried and cured, a silicon rubber film 11 having a uniform thickness is formed on the surface of the core material 8 (FIG. 4 ( a)). This operation is repeated until the thickness of the silicon rubber film 11 reaches the required thickness. Next, cuts 12 are made in the silicon rubber film 11 corresponding to the cylindrical body 9 of the core material 8 leaving the section 3A (see FIG. 4B). Then, the silicon rubber film 11 is peeled off from the sphere 10 of the core material 8 to obtain a precursor having the balloon portion 2 and the slice 3A (see FIG. 4C). Here, since the opening 4 is inevitably formed by the presence of the contact portion between the cylindrical body 9 and the sphere 10 of the core material 8, when the silicon rubber film 11 is peeled from the core material 8, the slice 3 </ b> A. The opening 4 is forcibly expanded by passing the spherical body 10 through the sphere 10. Then, the section 3A is cut off from the balloon portion 2 (see FIG. 4D). Next, a silicon rubber sheet 3B is adhered so as to close the opening 4 (see FIG. 4E), and finally the excess sheet 3B is cut off to close the opening 4 with the substantially circular sheet 3. The completed hollow body 1 is completed (see FIG. 4F). In addition, by fixing a plurality of spheres 10 to the cylindrical body 9, a plurality of hollow bodies 1 having the same thickness can be simultaneously manufactured.

  And the evaluation method of the indwelling device of 3rd invention is the said hollow body 1 with which the said indwelling device 5 is filled, and its hollow body 1 by imaging | photography using the magnetic resonance with respect to the above-mentioned model animal. It includes a step of acquiring a peripheral image. Here, in the indwelling device evaluation method, the imaging using the magnetic resonance is MRI or MRA. Then, at least one image is acquired, and the indwelling device is evaluated based on whether or not an artifact image is generated in the acquired image. Image processing software that can automatically perform data mapping and artifact extraction from the obtained image data was created to extract and quantify the artifacts.

  5 and 6 show a blood vessel simulation phantom device 21 capable of simulating an aneurysm environment in a living body by generating a water flow similar to a blood flow. With this apparatus, the F2119 test (MR image artifact test) can be performed in the US FDA medical device MRI compliance test method. FIG. 5 shows a state in which the hollow body 1 is attached to the outer peripheral surface of the silicon tube 20. In this case, when the hollow body 1 having the section 3A is used, it is easy to adhere to the outer peripheral surface of the silicon tube 20. Of course, it is possible to attach the hollow body 1 in which the opening 4 is closed by the sheet 3. is there. FIG. 6 shows a blood vessel simulation phantom device 21 in which a silicon tube 20 with the hollow body 1 attached is disposed inside a water tank 22, and both ends of the silicon tube 20 are a supply tube 23 and a recovery tube 24 made of a silicon tube. And the water is supplied to the supply tube 23 through a pump 27 that resembles the heartbeat, and the water that has passed through the silicon tube 20 is recovered. The tube 24 constitutes a circulation system for recovery to the buffer tank 26. A commercially available artificial heart can also be used as the pump 27.

  The blood flow velocity of a human artery is 40 cm to 50 cm / s. The blood vessel phantom device 21 can generate a flow using a manual pump 27. When the blood flow phantom device 21 was actually used and the flow velocity was measured, the speed was about 40 cm / s. Therefore, it is considered that this device can simulate an actual blood vessel (artery). Next, imaging was performed by MRI while actually generating a flow. FIG. 7 shows an image picked up by Spin Echo, and FIG. 8 shows an image picked up by TOF (time-of-flight) that shows only an artery used for blood vessel imaging in clinical practice.

  TOF is a technique capable of selectively imaging a flowing solution with high brightness. In the image picked up using the blood vessel simulation phantom device 21, only the solution with a flow in the tube is imaged with high brightness, and the flow of the blood vessel can be simulated by using this device. Thereby, before evaluating using a model animal, preliminary evaluation can be performed using this blood vessel simulation phantom device 21, and screening of the indwelling device 5 can be performed.

  A spherical hollow body having an inner diameter of 6 mm and a wall thickness of 0.3 mm was prepared using two-component curable silicon. A straight coil having an outer diameter of 0.25 mm, which was produced by winding a 0.035 mm diameter wire of an Au-28Pt alloy, was inserted into the hollow body from the opening. The number of straight coils used is 1 and the length is 81 cm. The embolization rate calculated from the ratio of the volume of the aneurysm and the volume of the straight coil used (approximate the straight coil as a cylinder having an outer diameter of 0.25 mm) was 35%. An example in which the opening was sealed using a sheet prepared from two-part curable silicon was used. What was produced like the Example except having used Pt-8W alloy was made into the comparative example.

  A rabbit (New Zealand White, male, weight 3.5 kg) was opened under anesthesia to expose the abdominal aorta. Each of the examples and comparative examples was sutured to the outer membrane of the abdominal aorta and then closed, and the indwelling was terminated. Three days after indwelling, a TOF-MRA image was obtained by a maximum value projection method using a superconducting magnet type whole body MR apparatus having a static magnetic field strength of 1.5 Tesla using this model animal. The result is shown in FIG. Further, FIG. 10 shows the result of angiography performed by the digital subtraction method.

  From the angiographic image, it can be seen that there is no stenosis in the abdominal aorta near the example and the comparative example, and a good blood flow is obtained. In the TOF-MRA image, an artifact is generated in the abdominal aorta near the comparative example, whereas no artifact is generated in the vicinity of the example.

DESCRIPTION OF SYMBOLS 1 Hollow body 2 Balloon part 3A Section 3B Wide sheet 3 Sheet 4 Opening part 5 Indwelling device (coil for embolization)
6 Blood vessel 7 Thread 8 Core material 9 Cylindrical body 10 Sphere 11 Silicon rubber film 12 Notch 20 Silicon tube 21 Blood vessel simulation phantom device 22 Water tank 23 Supply tube 24 Collection tube 25 Holder 26 Buffer tank 27 Pump

Claims (12)

A model animal used for evaluation of an indwelling device,
The indwelling device made of metal,
A hollow body made of a chemical filled with the indwelling device;
Including
A model animal in which the hollow body is disposed around or around a blood vessel of a non-human animal.   The model animal according to claim 1, wherein the hollow body is sewn to the blood vessel that is not incised.   The model animal according to claim 1 or 2, wherein the hollow body has a thickness of 200 µm or more and 700 µm or less.   The model animal according to any one of claims 1 to 3, wherein the hollow body is a material having biocompatibility and is formed of a material that is not reflected in a captured image using magnetic resonance.   The model animal according to claim 4, wherein the hollow body is formed of silicon rubber.   The model animal according to any one of claims 1 to 5, wherein the hollow body is also filled with a gel-like substance equivalent to the magnetic susceptibility of water.   The model animal according to claim 6, wherein the gel is agar.   The model animal according to any one of claims 1 to 7, wherein the indwelling device is a coil used for embolization treatment. A method for producing a model animal used for evaluation of an indwelling device,
Preparing a metal indwelling device;
Preparing a chemical-made hollow body filled with the indwelling device;
Placing the hollow body around or around a blood vessel of a non-human animal;
A method for producing a model animal comprising A method for evaluating an indwelling device,
The model animal according to any one of claims 1 to 8, wherein the hollow animal filling the indwelling device and an image of the periphery of the hollow body are acquired by performing imaging using magnetic resonance. Process,
For evaluating indwelling devices including   The method for evaluating an indwelling device according to claim 10, wherein the imaging using the magnetic resonance is MRI or MRA. Acquiring at least one of the images, and evaluating the indwelling device based on whether or not an artifact image is generated in the acquired image;
The evaluation method of the indwelling device of Claim 10 or 11 containing this.