CN115536965A

CN115536965A - Biological simulation material and preparation method and application thereof

Info

Publication number: CN115536965A
Application number: CN202211185373.1A
Authority: CN
Inventors: 李欣泽; 赵荣楠; 李兴旺; 张国信
Original assignee: Zhongxin Jucheng Medical Technology Co ltd
Current assignee: Jucheng Mingyi Beijing Medical Simulation Technology Research Institute Co ltd; Yingkou Jucheng Teaching Science & Technology Development Co ltd; Zhongxin Jucheng Medical Technology Co ltd
Priority date: 2022-09-27
Filing date: 2022-09-27
Publication date: 2022-12-30
Also published as: WO2024067711A1

Abstract

The present disclosure provides a bio-simulation material, comprising: polyvinyl alcohol, a water-retaining agent, a plasticizer, a coagulant and water. The disclosure also provides a preparation method of the biological simulation material and application of the biological simulation material in preparing a simulated medical teaching model.

Description

Biological simulation material and preparation method and application thereof

Technical Field

The present disclosure relates to the field of biomimetic materials. Specifically, the embodiment of the disclosure relates to a biological simulation material, a preparation method and an application thereof.

Background

The simulated tissue or organ with high similarity to the composition of human tissue and organ has multiple uses, such as film and television props, toys, medical teaching, etc.

At present, the clinical practice training teaching products of minimally invasive surgery represented by endoscopic surgery such as an electrotome, a radio frequency knife, an ultrasonic knife and the like mainly have three types. The first type is more traditional, a plastic model or animal viscera is arranged in a special endoscope training box, however, the plastic model cannot complete real excision training, and the animal viscera has limited sources and is limited by related laws and regulations. The second type is computer simulation operation in a virtual reality technology, which can only provide highly similar scenes, cannot provide real touch feeling, cannot perform objective evaluation, and is easy to develop bad habits of rough operation of students. The third type is augmented reality technology which is developed on the basis of the second type, and has great progress compared with the second type, but the simulation degree of model materials is insufficient, the difference between simulation operation and real operation is too large, relatively few cases can be completed, and a complete course teaching system cannot be established.

Therefore, there is still a need to develop a bio-simulation material for preparing a simulated tissue or organ having a high similarity with the composition of human tissues and organs.

Disclosure of Invention

One aspect of the present disclosure provides a bio-simulation material, including: polyvinyl alcohol, a water-retaining agent, a plasticizer, a coagulant and water.

For example, the water retaining agent is selected from one or more of pullulan, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), sodium polyacrylate, and crospovidone, preferably one or more of pullulan, carboxymethyl cellulose, and hydroxypropyl cellulose.

In one embodiment, the weight percent of water retaining agent is 0.5% to 5%, for example, 0.9% to 4.5%, based on the total weight of the biomimetic material. In a specific embodiment, the water retaining agent is 0.5% to 3% carboxymethyl cellulose, 0.2% to 1% hydroxypropyl cellulose, and 0.2% to 0.5% pullulan, based on the total weight of the biomimetic material.

For example, the plasticizer is selected from one or more of pyrrolidone, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, cyclohexanedimethanol, 2, 4-trimethylpentane-1, 3-diol, diethylene glycol, polyethylene glycol (200-600), glycerol, pentaerythritol, sorbitol, mannitol, lactitol, monosaccharides, sucrose, maltose, lactose, preferably one or more of pyrrolidone, ethylene glycol, and glycerol.

In one embodiment, the plasticizer is present in an amount of 23 to 45 weight percent, based on the total weight of the biomimetic material. For example, the plasticizer is 10 to 25% of ethylene glycol, 15 to 25% of glycerin and 2 to 5% of pyrrolidone, or the plasticizer is 10 to 25% of ethylene glycol and 15 to 35% of glycerin, based on the total weight of the biomimetic material.

For example, the coagulant is selected from one or more of sodium tetraborate, potassium tetraborate, boric acid, calcium chloride and magnesium chloride.

In one embodiment, the coagulant is present in an amount of 0.1% to 1.5% by weight, based on the total weight of the biomimetic material. For example, the coagulant is 0.1% to 0.2% sodium tetraborate, 0.05% to 1% boric acid, and 0.01% to 0.1% calcium chloride, based on the total weight of the biomimetic material.

In one embodiment, the polyvinyl alcohol is a polyvinyl alcohol having a degree of polymerization of 1000 to 2000 and a degree of alcoholysis of 98% or more, such as polyvinyl alcohol 1799.

In one embodiment, the polyvinyl alcohol is present in an amount of 3% to 12%, for example 6% to 9%, by weight based on the total weight of the biomimetic material.

In one embodiment, the biomimetic material further comprises one or more additives selected from the group consisting of: preservatives, colorants, thickeners, and superabsorbent polymers (SAP).

For example, the thickener is 0.1% potassium vegetable oleate, based on the total weight of the biomimetic material.

In one embodiment, the content of the biological simulation material is 50% or more, for example, 60 to 93%, based on the total weight of the biological simulation material.

Yet another aspect of the present disclosure provides a method of preparing a bio-simulation material, comprising: dispersing the components except water in the biological simulation material in water; adjusting the toughness with water and/or glycerol; injecting into a mold for low-temperature freezing and crosslinking.

In one embodiment, the low temperature freeze crosslinking is carried out at a temperature of-18 ℃ to-40 ℃, e.g., -20 ℃ to-40 ℃.

In one embodiment, low temperature freeze crosslinking is continued for 6 to 18 hours, such as 8 to 12 hours.

The present disclosure further provides a use of the above biological simulation material for preparing a simulated medical teaching model. The simulated medical teaching model is, for example, intestinal tract, liver, blood vessel, skin, peritoneum, pancreas, spleen or kidney.

Drawings

To illustrate the technical solutions of the embodiments of the present invention more clearly, the drawings of the embodiments will be briefly introduced, and it is obvious that the drawings in the following description only relate to some embodiments of the present invention, and are not to limit the present invention.

FIG. 1 is a diagram of a biomimetic liver according to an embodiment of the present invention;

FIG. 2 illustrates a bionic kidney according to an embodiment of the present invention;

FIG. 3 is a diagram illustrating the elastic modulus of a bionic liver according to an embodiment of the present invention;

fig. 4 is an elastic modulus of a bionic kidney according to an embodiment of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.

The present invention may be embodied in other specific forms without departing from its essential attributes. It is to be understood that, without conflict, any and all embodiments of the present invention may be combined with features of any other embodiment or embodiments to arrive at further embodiments. The invention includes additional embodiments resulting from such combinations.

The various documents and publications referred to in this disclosure are incorporated herein by reference. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood in the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.

Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of properties such as dosages set forth in the specification and claims are to be understood as being modified in all instances by the term "about". It should also be understood that any numerical range recited herein is intended to include all sub-ranges within that range and any combination of the individual endpoints of that range or sub-ranges.

The amounts or levels in the formulations of the present disclosure are understood to be on a weight basis.

The use of "including," "comprising," or "containing" and similar words in this disclosure is intended to mean that the elements listed before the word cover the elements listed after the word and their equivalents, without excluding unrecited elements. The terms "comprising" or "including" as used herein can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of or" consisting of 823030A ".

The inventors have discovered, after screening a large number of formulations, that a simulated tissue or organ having a high degree of similarity to the composition of human tissue and organs can be made according to the formulations of the present disclosure. The inventor tests the physicochemical parameters of the simulated tissue or organ and the animal tissue or organ and finds that the elastic modulus, the liquid content and the conductivity of the two are very close and the deviation is less than 20%.

The water retention agent is a high water absorption substance which mainly enables the prepared biological simulation material to keep high liquid content for a long time. For example, the water retaining agent may be selected from one or more of pullulan, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), sodium polyacrylate, crospovidone, preferably one or more of pullulan, carboxymethyl cellulose and hydroxypropyl cellulose.

In one embodiment, the weight percent of water retaining agent is 0.5% to 5%, for example, 0.9% to 4.5%, based on the total weight of the biomimetic material.

In a specific embodiment, the water retaining agent is 0.5% to 3% carboxymethyl cellulose, 0.2% to 1% hydroxypropyl cellulose, and 0.2% to 0.5% pullulan, based on the total weight of the biomimetic material.

Plasticizers refer in this application to a class of substances that are capable of filling into the three-dimensional structure of a biomimetic material and enhancing the stability of the three-dimensional structure through hydrogen bonding. For example, the plasticizer is selected from one or more of pyrrolidone, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, cyclohexanedimethanol, 2, 4-trimethylpentane-1, 3-diol, diethylene glycol, polyethylene glycol (200-600), glycerol, pentaerythritol, sorbitol, mannitol, lactitol, monosaccharides, sucrose, maltose, lactose, preferably one or more of pyrrolidone, ethylene glycol, and glycerol.

In one embodiment, the plasticizer is present in an amount of 23 to 45 weight percent, based on the total weight of the biomimetic material. For example, the plasticizer is 10-25% ethylene glycol and 15-35% glycerin, based on the total weight of the biomimetic material. For example, the plasticizer is 10 to 25% ethylene glycol, 15 to 25% propylene glycol, and 2 to 5% pyrrolidone, based on the total weight of the biomimetic material.

The coagulant is added to the biological simulation material in order to solidify the form of the biological simulation material, reduce or eliminate the fluidity of the biological simulation material, prevent the deformation of the tissue structure, and increase the solid content of the biological simulation material. For example, the coagulant is selected from one or more of boric acid, sodium tetraborate, potassium tetraborate, calcium chloride, and magnesium chloride.

The water amount added in the preparation process of the biological simulation material is determined according to the water content in tissues or organs of human bodies or animals such as pigs, dogs, rabbits and the like.

In one embodiment, the polyvinyl alcohol is a polyvinyl alcohol having a degree of polymerization of 1000 to 2000 and a degree of alcoholysis of 98% or more, such as polyvinyl alcohol 1799, i.e., a degree of polymerization of 1700 and a degree of alcoholysis of 99%.

In one embodiment, the biomimetic material further comprises one or more additives selected from the group consisting of: preservatives, colorants, thickeners, and superabsorbent polymers (SAPs).

Preservatives can be selected, for example, from parabens, sodium acetate, hexanediol, chlorophenyl glycoside ether, sorbitol and the like.

The coloring agent may be selected from carmine, amaranth, sunset yellow, erythrosine, tartrazine, neored, indigo, brilliant blue, etc., for example.

The thickener can be selected from potassium plant oleate, sodium alginate, sodium caseinate, acacia, pectin, agar, gelatin, alginate jelly, carrageenan, dextrin, etc.

Preservatives, colorants, thickeners may be commercially available food industry additives.

In one embodiment, the thickening agent is 0.1% potassium vegetable oleate, based on the total weight of the biomimetic material.

The superabsorbent polymers may be chosen, for example, from sodium polyacrylates, polyacrylamides.

The biomimetic material of the present disclosure may further comprise other additives as long as they do not affect physicochemical properties of the biomimetic material, such as water retention, toughness, and electrical conductivity.

The disclosed bio-simulation material can hold a large amount of water for a long period of time, and is very close to the liquid content of the tissue or organ of a human body or an animal.

In one embodiment, the content of the liquid in the biomimetic material is more than 50%, such as 60-93%, based on the total weight of the biomimetic material.

The electrolyte level of the biological simulation material is 50-150mmol/L, and is consistent with that of normal human or animal tissues and organs, so that the biological simulation material has similar conductivity with human tissues.

Human tissues and organs made of the disclosed biological simulation material meet one or more of the following requirements:

1. the deviation of the liquid content from the liquid content of the tissues and organs of normal human or animals is less than 20%, 15%, 10% or 5%;

2. the deviation of the elastic modulus from the elastic modulus of the tissues and organs of a normal human body or animal is lower than 20%, 15%, 10% or 5%;

3. the conductance deviates from the conductance of normal human or animal tissue and organs by less than 20%, 15%, 10% or 5%.

In one embodiment, the human tissue and organ made of the biological simulation material satisfies the following conditions:

1. the deviation of the liquid content from the liquid content of the tissues and organs of normal human or animals is less than 20%, 15%, 10% or 5%; and

2. the elastic modulus deviates less than 20%, 15%, 10% or 5% from the elastic modulus of normal human or animal tissue and organs.

2. the deviation of the elastic modulus from the elastic modulus of the tissues and organs of a normal human body or animal is lower than 20%, 15%, 10% or 5%; and

3. the electrical conductivity deviates less than 20%, 15%, 10% or 5% from that of normal human or animal tissue and organs.

From the aspect of tissue components, the biological simulation material disclosed by the invention adopts natural and artificial synthetic biological materials as main raw materials, has high similarity (macromolecular carbohydrate with similar structure) with the composition of human tissues and organs, and thus shows similar apparent characteristics such as vision, touch and toughness and elasticity; the training teaching device can be used for training teaching of endoscopic surgeries such as electric knives, radio-frequency knives, ultrasonic knives and the like.

Yet another aspect of the present disclosure provides a method of preparing a bio-simulation material, comprising: dispersing the components except water in the biological simulation material in water; adjusting the toughness by using water, glycol and/or glycerol; injecting into a mold for low-temperature freezing crosslinking.

And (3) selecting different crosslinking temperatures and crosslinking times for low-temperature freezing crosslinking according to different toughness requirements. The lower the temperature is, the higher the toughness of the prepared biological simulation material is.

The higher the glycerol content is, the higher the toughness of the prepared biological simulation material is.

In one embodiment, low temperature freeze crosslinking is carried out at a temperature of-18 ℃ to-40 ℃, e.g., -20 ℃ to-40 ℃.

Low temperature freeze crosslinking typically takes 6-8 hours for a crosslinking cycle. In one embodiment, low temperature freeze crosslinking lasts 6 to 18 hours, such as 8 to 12 hours.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Preparation of simulated visceral organs

The material formula of the simulated visceral organs is as follows:

according to the formula in the table, the dosage of water, glycol and/or glycerol is adjusted according to the toughness requirements of different organs, the materials are stirred and mixed for 4 hours at the temperature of 80-95 ℃, the mixture is injected into a mould and then is crosslinked at the temperature of-20 ℃ at the low temperature, and the crosslinking period is 8 hours, and then the mixture is unfrozen, demoulded and packaged.

The above method can be used for preparing intestinal tract, liver, blood vessel, skin, peritoneum, pancreas, spleen or kidney. The bionic liver and the bionic kidney prepared in the method are shown in figures 1 and 2.

Liquid content testing method

In this test item, the sample was vacuum dried in a vacuum drying oven (DZF-6000) at 100 ℃ for 12 hours. The liquid content of the sample is obtained by weighing the mass difference before and after drying the sample. In the testing process, the excessive force is avoided in the sample weighing process, the liquid loss is avoided, and the untested sample is stored in a refrigerator, so that the liquid loss is avoided.

Elastic modulus test method

And cutting the sample into the sizes of 4cm in length, 1cm in width and 0.3cm in thickness, and performing temperature change test by adopting a DMA instrument. The elastic modulus of the bionic liver and the bionic kidney are shown in fig. 3 and fig. 4.

Conductivity testing method

Taking a small block from the complete sample, putting the small block into a specific die (with the height of 50mm and the diameter of 10 mm), applying pressure of 1MPa by using a press machine, measuring the resistance value (the test frequency is 3 GHz) under the pressure by using a homoeotropic conductivity tester (TH 2683B), and then calculating the volume resistivity of the sample according to the size of the die, wherein the reciprocal of the resistivity is the conductivity.

Comparison of animal experiments

The viscera of the white pig of about 3 months are picked, and the water content, the elastic modulus and the conductivity are tested as qualified criteria.

Table 1: test result of liquid content of simulated visceral organ

Sample name	Eligibility criterion	Results	Conclusion
				Intestinal tract	80.6-85.4％	78.6％	Deviation-2.5%
Liver disease	68-75％	81.1％	Deviation 8.1%
				Blood vessel	48-57％	63.9％	Deviation of 12.1%
Skin(s)	64-75％	63.6％	Deviation-0.3%
				Kidney (A)	79-85％	91.4％	Deviation 7.5%

Table 2: test results of elastic modulus of simulated visceral organs

Sample name	Eligibility criterion	Results	Conclusion
				Intestinal tract	4.0-11.5kPa	12.8kPa	Deviation 11.3%
Liver disease	3.2-16.2kPa	12.0kPa	Without deviation
				Blood vessel	17.1-56.3kPa	14.4kPa	Deviation-15.7%
Skin(s)	22-240kPa	33.3kPa	Without deviation
				Kidney (A)	3.37-16.2kPa	3.3kPa	Deviation-2.1%

Table 3: conductivity test result of simulated organ

Sample name	Eligibility criterion	Results	Conclusion
				Intestinal tract	0.01-0.25S/m	0.011S/m	Without deviation
Liver disease	0.02-0.10S/m	0.087S/m	Without deviation
				Blood vessel	0.02-0.18S/m	0.026S/m	Without deviation
Skin(s)	0.02-0.19S/m	0.078S/m	Without deviation
				Kidney (A)	0.03-0.29S/m	0.089S/m	Without deviation

From the above table, it can be found that the deviation of the elastic modulus, the liquid content and the conductivity of the simulated organ from the corresponding indexes of the real organ is not more than 20%.

The present disclosure illustrates the process of the present invention by the above examples, but the present invention is not limited to the above process steps, i.e., it is not meant that the present invention must rely on the above process steps to be practiced.

It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention. The protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A biomimetic material comprising:

polyvinyl alcohol, a water-retaining agent, a plasticizer, a coagulant and water.

2. The biomimetic material of claim 1 wherein the water retaining agent is selected from one or more of pullulan, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), sodium polyacrylate, crospovidone, preferably one or more of pullulan, carboxymethyl cellulose, and hydroxypropyl cellulose.

3. The biomimetic material of claim 1 or 2, wherein the weight percentage content of water retaining agent is 0.5-5%, for example, 0.9-4.5%, based on the total weight of the biomimetic material.

4. The biomimetic material of claim 3 wherein the water retaining agent is 0.5% to 3% carboxymethyl cellulose, 0.2% to 1% hydroxypropyl cellulose, and 0.2% to 0.5% pullulan based on total weight of the biomimetic material.

5. The biomimetic material according to any of claims 1-4, wherein the plasticizer is selected from one or more of pyrrolidone, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, cyclohexanedimethanol, 2, 4-trimethylpentane-1, 3-diol, diethylene glycol, polyethylene glycol (200-600), glycerol, pentaerythritol, sorbitol, mannitol, lactitol, monosaccharides, sucrose, maltose, lactose, preferably one or more of pyrrolidone, ethylene glycol, and glycerol.

6. The biomimetic material of any of claims 1-5 wherein the weight percentage content of plasticizer is 23-45%, for example based on the total weight of the biomimetic material.

7. The biomimetic material of claim 6 wherein the plasticizer is 10-25% ethylene glycol, 15-25% propylene glycol, and 2-5% pyrrolidone, or the plasticizer is 10-25% ethylene glycol and 15-35% glycerol, based on total weight of the biomimetic material.

8. The biomimetic material of any one of claims 1-7, wherein the clotting agent is selected from one or more of sodium tetraborate, potassium tetraborate, boric acid, calcium chloride, and magnesium chloride.

9. The biomimetic material of any of claims 1-8, wherein the weight percent content of the coagulating agent is 0.1% to 1.5% based on the total weight of the biomimetic material.

10. The biomimetic material of claim 9 wherein the coagulating agent is 0.1% to 0.2% sodium tetraborate, 0.05% to 1% boric acid, and 0.01% to 0.1% calcium chloride, based on total weight of the biomimetic material.

11. The biomimetic material of any of claims 1-10 wherein the polyvinyl alcohol is a polyvinyl alcohol having a degree of polymerization of 1000-2000, a degree of alcoholysis of greater than 98%, such as polyvinyl alcohol 1799.

12. The biomimetic material of any of claims 1-11 wherein the weight percent polyvinyl alcohol is between 3% and 12%, such as between 6% and 9%, based on the total weight of the biomimetic material.

13. The biomimetic material of any of claims 1-12, further comprising one or more additives selected from the group consisting of: preservatives, colorants, thickeners, and superabsorbent polymers (SAPs).

14. The biomimetic material of claim 13 wherein the thickener is 0.1% potassium vegetable oleate based on the total weight of the biomimetic material.

15. The biomimetic material of any one of claims 1-14 wherein the liquid content is 60-93% based on the total weight of the biomimetic material.

16. A method for preparing a bio-simulation material comprises

Dispersing in water the components of the biomimetic material of any of claims 1-15 other than water;

adjusting the toughness by using water and/or glycerol;

injecting into a mold for low-temperature freezing and crosslinking.

17. The method for preparing a biomimetic material according to claim 16, wherein the cryo-cross-linking is performed at a temperature of-18 ℃ to-40 ℃, such as-20 ℃ to-40 ℃.

18. The method for preparing a biomimetic material according to claim 17, wherein the cryo-cross-linking lasts for 6-18 hours, such as 8-12 hours.

19. Use of the biomimetic material of any of claims 1-18 for preparing a simulated medical teaching model.

20. The use of claim 19, wherein the simulated medical teaching model is intestinal, liver, blood vessels, skin, peritoneum, pancreas, spleen, or kidney.