Synthetic thrombus model for learning surgical removal of a blood clot during a treatment simulation

Description

[0001] The invention relates to a synthetic thrombus model for learning the surgical removal of a blood clot as part of a treatment simulation. For this purpose, a relevant human vascular tree is represented in a training model using a blood circulation replacement system, enabling the training of stroke scenarios using a blood clot phantom, i.e., a synthetic thrombus model made of a substitute material.

[0002] Ischemic stroke is one of the leading causes of disability and death worldwide. The most common cause of acute stroke is a blockage of a cerebral artery, which leads to oxygen deprivation of a brain region and thus to cerebral infarction. The first-line treatment for such acute vascular occlusions is reopening via a catheter-based procedure known as thrombectomy. Artificial drugs with anticoagulant effects, such as those described in DE 28 32 536 C2, which are intended to prevent the formation of thrombi and use agarose as a carrier material, are of no use in these medical emergencies.

[0003] Thrombectomy is a minimally invasive treatment used for strokes. It involves mechanically removing the blood clot (thrombus) obstructing the brain using a stent retriever. This procedure is performed under extreme time pressure with the goal of reopening the affected vessel as quickly as possible. Patient-specific variables such as vessel curves and narrowing present a challenge for the treating physician. Therefore, continuous training and proficiency in thrombectomy techniques are essential for the physician.

[0004] A common training model for thrombectomy is the porcine animal model. Training is conducted on live pigs that have been prepared and anesthetized for this purpose. The pig's own blood is removed, clotted, and then reinjected to induce strokes. The pig is typically euthanized after several training procedures.

[0005] Animal testing for training and continuing education purposes in stroke treatment must be reduced or completely eliminated, which requires the availability of a blood-free replacement material for thrombi. For example, the use of a synthetic thrombus made of polyurethane is well known. However, such synthetic simulation models suffer from the disadvantage that they cannot replicate the diversity of human thrombi.

[0006] Depending on how they form, thrombi exhibit different compositions of their essential components: red blood cells, fibrin, and calcium. A thrombus is a solid mass that forms through the body's own coagulation cascade due to an injury to a blood vessel or a significant reduction in blood flow. Varying proportions of red blood cells, fibrin, and calcium lead to different physical properties of these thrombi, resulting in different behaviors in terms of hardness, fragmentation, and elasticity. So-called red thrombi contain more red blood cells and are therefore visually different from white thrombi, which contain more fibrin and calcium. Between these thrombus types lies a high diversity of mixed thrombus types and their main components.The range of human thrombi is therefore high, resulting in different properties, which translate into different behavior during treatment. The mechanical properties of thrombi are similar to viscoelastic polymers. Typical dimensions of thrombi are 6 to 15 mm in length and 1 to 3 mm in diameter.

[0007] Another known thrombus substitute is one made from non-biological components, namely water, guar gum, glycerin, talcum powder, and borax. Borax is classified as a hazardous substance because it is toxic to reproduction. Furthermore, it is unknown whether different types of thrombus can be produced. Therefore, the diversity of different types of thrombus is not taken into account.

[0008] The object of the invention is therefore to create a thrombus model free of animal components for a training environment for endovascular stroke treatments under standardized conditions, wherein training of thrombectomy under real conditions is enabled in a training model, in particular a neurointerventional training model, preferably with different levels of difficulty.

[0009] A synthetic thrombus model according to the features of the preamble of claim 1 is known from FR 3 086 089 A1. According to this, an artificial thrombus is prepared from a formulation of agar and gum. The purpose of this formulation is to simulate various types of thrombi.

[0010] This problem is solved by the features of claim 1.

[0011] This creates a synthetic thrombus model whose properties can be varied, allowing the training model to replicate the behavior of a wide variety of real thrombi in humans. Furthermore, these models are free of animal components.

[0012] Various thrombus models can be provided for training, allowing for the simulation of different training scenarios. The various human thrombi that occur in reality, particularly with regard to their realistic shape, can be simulated with at least a certain degree of diversity. Using material properties, structural properties, and combinations, properties such as hardness, elasticity, fragmentation properties, and, if applicable, adhesion to a vascular model can be influenced, thus achieving a wide range of different thrombus models for training purposes. In particular, the combination with additively manufactured structures, and thus the adjustment of thrombus properties via the structure, results in advantageous designs that allow the simulation of real shapes and dimensions.

[0013] According to the invention, the main material used is a Shore A hardness in the range of 0 to 10, in particular agarose or silicone rubber (silicones in the cross-linked state) for imaging thrombi, particularly in a neurointerventional training model, for example. The Shore A hardness of the materials mentioned lies between the strength of gelatin (Shore A 0) and gummy bears (Shore A 10).

[0014] Agarose is characterized by high fragmentation upon contact with a treatment instrument, whereas silicone rubber forms very compact thrombi. The properties of silicone rubber- or agarose-based thrombus models can be optimized during the manufacturing process to create a variety of realistic thrombi by combining materials and varying them by adding 5 to 40% by weight of an adhesive and / or a reinforcing material to form a composite structure. For this purpose, the silicone rubber or agarose base is first weighed as the starting material, and then, based on this, a certain weight percent of adhesive and / or other components is added. The adhesive can increase elasticity.The reinforcing material, for example additively manufactured support structures and / or microglass beads, can be used to stabilize highly fragmenting agarose thrombi and / or to increase the fragmentation of silicone rubber-based thrombus models.

[0015] The mold in which the thrombus model is manufactured can also influence these properties. For example, the properties of models manufactured in a mold differ from those cured in a syringe and delivered by the syringe cone. These properties can also be specifically influenced by storage, for example, by reducing the adhesive properties of silicone thrombi by storing them in vegetable oil.

[0016] The preferred adhesive is chloromethylisothiazolinone (CMIT) and / or a mixture with methylisothiazolinone (MIT).

[0017] The structure of the medical training model with synthetic thrombus models can be modular and can consist of standardized components (used in every training scenario), variant components (training scenario-defining components) and patient-specific components (adapted according to an original patient-specific anatomy).

[0018] The advantageous use of real instruments can also be combined with the simulation of physiological properties such as temperature, blood flow, and pulsation. The high geometric freedom of additive or generative manufacturing processes enables the production of vascular models that are exact three-dimensional replicas of the patient's individual vascular interior. To train a mechanical thrombectomy, a microcatheter can be inserted into the vascular system of a training model, and a basket-like mesh—a so-called stent retriever—can be advanced via a guidewire to a vessel occluded with a synthetic thrombus model. The stent retriever is positioned, captures the thrombus model, and then retracted. This mechanical removal restores blood flow.

[0019] The synthetic thrombus model according to the invention thus offers the following advantages: The development of an in vitro simulation model of thrombectomy treatments is possible, avoiding animal testing. A training environment for endovascular stroke treatments under standardized conditions with varying levels of difficulty under real-world conditions is created. The diversity of occurring thrombi can be simulated. Adjustable properties can be reproduced through material properties, additives, or structure. Structures can be obtained through additive manufacturing. A binding agent is generated by adding the adhesive chloromethylisothiazolinone and / or methylisothiazolinone (CMIT + MIT). The addition of microglass beads enables increased fragmentation. Different manufacturing processes and storage options are applicable. The product is non-toxic.

[0020] Further embodiments and advantages of the invention can be found in the following description and the dependent claims.

[0021] The invention is explained in more detail below with reference to the embodiments shown in the attached figures. Fig. 1 shows a schematic representation of a medical training model for simulating various stroke scenarios using thrombectomy, with a thrombus model placed in a cerebral vessel. Fig. 2 shows an overview of the various parameters for adjusting the properties of the thrombus models according to the invention, such as hardness, fragmentation, elasticity and stickiness, as well as their direction. Fig. 3 shows various forms of reinforcing materials as additives.

[0022] The invention relates to a synthetic thrombus model for learning the surgical removal of a blood clot from a blood vessel using mechanical thrombectomy in a simulation of various stroke scenarios in a training model. The thrombus model replicates a lifelike shape with a realistic feel of a human blood clot by providing an elongated base body based on an elastically deformable main material with a Shore A hardness in the range of 0 to 10, in particular 0 to 4. The property profile of the base body, at least with regard to hardness and fragmentation, can be varied by providing a material combination of the main material / starting material with at least one addition of an adhesive with a concentration of 5 to 40 wt.% and / or with a reinforcing material.

[0023] The elastically deformable main material is formed from a cured agarose gel base or silicone rubber base. The agarose gel base is preferably made from a 2% to 15% agarose gel. The adhesive contains a chloromethylisothiazolinone and / or a mixture with methylisothiazolinone.

[0024] The reinforcement material is designed as a support structure, whereby the support structure / reinforcement structure can be designed as a spiral structure, a wave structure, or a spike-like structure. Additive manufacturing allows for further differentiation and combination. A number of support structure elements can be incorporated into the base body, spaced apart and individually oriented such that their longitudinal direction follows the longitudinal direction of the thrombus model.

[0025] The support structure can comprise microglass beads. The support structure preferably accounts for an added proportion of 10 to 40 wt.%.

[0026] The elongated base body can exhibit reduced surface energy through temporary storage in vegetable cooking oil, which reduces surface adhesion. The base body can be formed using a casting or injection molding process.

[0027] The invention further provides for the use of the synthetic thrombus model in a training model as part of a catheter-based treatment simulation of stroke scenarios.

[0028] How Fig. 1 As shown, such a training model comprises at least one relevant vascular tree 1 with a circulatory replacement system 2, which has at least one training region 3 and can be connected to an anatomically simulated circulatory replacement system 2 with a delivery system 4. To train a mechanical thrombectomy with stent retrievers for capturing and removing a synthetic thrombus model 5, such a stent can also be placed in front of a stenosis 6. The circulatory replacement system 2 can be designed to simulate a human circulatory system with regard to the temperature and pressure of the fluid.

[0029] A preferably modular basic structure of the training model enables the combination of modules, namely standardized or variant modules with interchangeable customized modules. A key focus is on the integration of patient-specific and customized geometries. Patient-specific aneurysm models or other training areas 3, 6 can be manufactured additively, i.e., using layered construction or 3D printing, based on patient medical image data in a standardized customization process. A portfolio of a wide variety of aneurysm geometries or stenoses 6 can be provided as a training basis.

[0030] Fig. 2 describes the formation of agarose thrombi. The agarose is produced, for example, in 2, 5, and 10 wt.% concentrations. The agarose can be heated to over 95°C in a solvent and colored with food coloring in a ratio of 0.1 g to 25 g. The mixture can be cooled for 2 hours. It can be produced in two different ways. Curing can occur either in a silicone tube with an inner diameter of 3 mm, for example, or in the form of a block from which the thrombi are punched out. Before the agarose gels, at temperatures of 34-38°C, for example, additional additives can be added. This is used to add stabilizing components to the agarose. Agarose glue is added as a stabilizing component. This consists, for example, of a 3:1 mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT).This additive helps reduce agarose fragmentation without reducing elasticity. For this purpose, 1, 2, and 5% agarose mixtures can be prepared, to which 5, 20, or 40 wt.% CMIT + MIT are added. Agarose thrombi with a 2% concentration and 5-20 wt.% CMIT + MIT are particularly preferred.

[0031] For example, to stabilize highly fragmenting agarose thrombi, three different structures can be used as reinforcement material. The structures are produced using additive manufacturing. The structures can be placed in a mold and encapsulated with liquid agarose. Fig. 3 shows the three different structures mentioned as examples. According to this, a first structure 10 is, for example, a spiral structure. This spiral structure preferably has two symmetrical spirals that are offset by 180° and are connected to one another by four additional rings with cross connections. The diameter of the cutting surface can be in the range of 0.5 mm. The cross connection is intended to stabilize the model without significantly affecting the elasticity. The spirals and circles are intended to prevent compression of the agarose in the transverse direction, although compression in the longitudinal direction is possible. A cavity in the model is intended to enable the thrombus to be punctured with a treatment instrument.

[0032] In addition to the spiral structure, a wave structure 11 can be provided. The structure is constructed from several, in particular three, waves and a continuous rod. The waves form a sine curve of, for example, 1.5 pi. This results in three chambers 12 that are filled with agarose. The structure is advantageous in that the model is stable against compression in the longitudinal and transverse directions, yet allows for slight bending and perforation.

[0033] A third concept for the combination of agarose and support structure is based on a spike-like structure 13, which comprises an elongated rod with spikes with a diameter in the range of 0.5 mm. For additional stability, the connection points can be reinforced with spheres 14. The spike-like structure can reduce fragmentation of the agarose by absorbing loads in the transverse direction. The structure can be designed to allow for slight bending and perforation of the model.

[0034] Agarose thrombi with a material combination of agarose and support structure as described above depict hard, calcium-rich thrombi.

[0035] Fig. 2also shows silicone thrombi based on silicone rubber as synthetic thrombus models. Silicone models with a base proportion in the range of 10 to 50 wt.% of pure silicone with a Shore hardness (ShA) of 0 are dimensionally stable. A base proportion of 30 to 40 wt.% is particularly advantageous, as this results in high elasticity with moderate stickiness (adhesion). With the addition of adhesive in the range of 20 to 60 wt.%, the models exhibit greater deformation, increased fragmentation under compression, and a decrease in stickiness. This applies in particular to the adhesive CMIT as well as to mixtures of CMIT with MIT. The addition of 30 to 50 wt.% CMIT or CMIT+MIT is particularly advantageous. The advantage in this respect is the increase in elasticity.To prevent excessive adhesion of the models to the artificial vessel models and thus an unrealistic rolling along the vessel wall, the stickiness of the models can be reduced by storing the produced thrombus models in sunflower oil. Furthermore, it is possible to add microglass beads at a concentration of 10 to 40 wt.%. The addition of microglass beads also reduces stickiness. The addition of 10 to 20 wt.% microglass beads is particularly preferred. Under mechanical stress, the models with microglass beads show increased fragmentation and deformation. The silicone thrombi produced in this way replicate the behavior of soft and compact thrombi, which primarily only fragment under significant mechanical stress.

[0036] A particularly advantageous material combination for a soft and compact thrombus model is 30 to 35 wt.% pure silicone ShA 0 as the silicone base and main material for a silicone rubber base body, the addition of 30 to 40 wt.% adhesive, particularly CMIT or CMIT + MIT, and preferably temporary storage in vegetable oil. To create a thrombus model that is prone to fragmentation, the addition of 10 to 20 wt.% glass microbeads is also advantageous.

[0037] To produce a soft silicone with a Shore A hardness (ShA) of 0 to 10, an additive cold-curing silicone elastomer is preferably mixed with a base and catalyst, for example, in a ratio of 1:1, and the liquid silicone mixture is cured for several hours. The amount of catalyst can be adjusted accordingly to also influence the softness of the model. The mixing and curing process offers the opportunity to influence the properties of the silicone by changing the mixing ratio of base and catalyst or by adding additional components. For example, the elasticity and stickiness of the silicone can be changed by varying the mixing ratio of base and catalyst.

[0038] To increase the fragmentation property, micro glass beads with a diameter of preferably 0.25 to 0.5 mm can be added to the silicone models.

[0039] The silicone models can be manufactured in a mold. The resulting thrombus models preferably have a diameter of 2.5 to 3.5 mm and a length of 8 to 15 mm, for example. Alternatively, the liquid silicone mixture can be placed in a syringe for curing and then extruded from the syringe after the silicone has cured, with the dimensions specified above being selected.

Claims

1. Synthetic thrombus model (5) for learning the surgical removal of a blood clot from a blood vessel using mechanical thrombectomy in a simulation of various stroke scenarios in a training model, which simulates a lifelike shape with a realistic feel of a human blood clot thereby that an elongated base body based on an elastically deformable main material with a Shore A hardness in the range of 0 to 10 together with an additive for the simulation of different types of thrombi is provided, characterized in that, the property profile of the base body is variable at least with respect to hardness and fragmentation by providing a material combination of the main material and of at least an added amount of a stabilizing component, being an adhesive between 5 and 40 wt.-%, and / or a reinforcing material, made of additively manufactured structures having an incorporated orientation, to form a composite structure.

2. Synthetic thrombus model (5) according to claim 1, characterized in that the elastically deformable main material is formed by a gelled agarose base or a silicone rubber base.

3. Synthetic thrombus model (5) according to claim 2, characterized in that the gelled agarose base is prepared with a 2% to 5% concentration.

4. Synthetic thrombus model (5) according to any one of claims 1 to 3, characterized in that the adhesive is a chloromethylisothiazolinone (CMIT) and / or a mixture with methylisothiazolinone (MIT).

5. Synthetic thrombus model (5) according to claim 4, characterized in that an agarose thrombus is formed with 2 to 3% concentration and 5-20 wt% adhesive of CMIT + MIT.

6. Synthetic thrombus model (5) according to claim 4, characterized in that a silicone rubber thrombus is formed with a silicone base portion of silicone ShA 0 of 30 to 35 wt% and with 30-40 wt% addition of adhesive such as CMIT + MIT.

7. Synthetic thrombus model (5) according to claim 5 or 6, characterized in that the mixing ratio of CMIT to MIT is 3 : 1.

8. Synthetic thrombus model (5) according to any one of claims 1 to 7, characterized in that the reinforcing material is formed as a support structure.

9. Synthetic thrombus model (5) according to claim 8, characterized in that the support structure is formed as a spiral structure (10), wave structure (11) or spike-like structure (13), the respective longitudinal extension of which follows the longitudinal extension of the elongated base body.

10. Synthetic thrombus model (5) according to any one of claims 7 to 9, characterized in that the support structure comprises micro glass beads.

11. Synthetic thrombus model (5) according to any one of claims 7 to 10, characterized in that the support structure provides an addition of 10 to 40% by weight.

12. Synthetic thrombus model (5) according to any one of claims 1 to 11, characterized in that the elongated base body has reduced surface adhesion behaviour due to temporary storage in a vegetable edible oil.

13. Synthetic thrombus model (5) according to any one of claims 1 to 12, characterized in that the shaping has been carried out according to a casting process or an injection process.

14. Use of the synthetic thrombus model (5) according to any one of claims 1 to 13 in a training model by means of a catheter-based clinic testing procedure of stroke scenarios, comprising at least one relevant vascular tree (1) having a blood circulation replacement system (2) with a delivery system (4), comprising at least one training region (3), and being connectable to an anatomically replicated blood circulation replacement system (2).

15. Use of the synthetic thrombus model (5) according to claim 14, characterized in that a mechanical thrombectomy with stent retrievers is provided for trapping and removing or aspirating the synthetic thrombus model.

16. Use of the synthetic thrombus model (5) according to claim 14 or 15, characterized in that the blood circulation replacement system (2) with the delivery system (4) is designed to simulate a human blood circulation system with respect to temperature and pressure of the fluid.