WO2024067711A1 - 一种生物仿真材料及其制备方法和用途 - Google Patents

一种生物仿真材料及其制备方法和用途 Download PDF

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WO2024067711A1
WO2024067711A1 PCT/CN2023/122088 CN2023122088W WO2024067711A1 WO 2024067711 A1 WO2024067711 A1 WO 2024067711A1 CN 2023122088 W CN2023122088 W CN 2023122088W WO 2024067711 A1 WO2024067711 A1 WO 2024067711A1
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biomimetic material
biomimetic
total weight
water
plasticizer
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PCT/CN2023/122088
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English (en)
French (fr)
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李欣泽
赵荣楠
李兴旺
张国信
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中新巨成医学科技有限公司
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Publication of WO2024067711A1 publication Critical patent/WO2024067711A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L29/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers
    • C08L29/02—Homopolymers or copolymers of unsaturated alcohols
    • C08L29/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
    • G—PHYSICS
    • G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
    • G09B—EDUCATIONAL OR DEMONSTRATION APPLIANCES; APPLIANCES FOR TEACHING, OR COMMUNICATING WITH, THE BLIND, DEAF OR MUTE; MODELS; PLANETARIA; GLOBES; MAPS; DIAGRAMS
    • G09B23/00—Models for scientific, medical, or mathematical purposes, e.g. full-sized devices for demonstration purposes
    • G09B23/28—Models for scientific, medical, or mathematical purposes, e.g. full-sized devices for demonstration purposes for medicine
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/38—Boron-containing compounds
    • C08K2003/387—Borates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K2201/00—Specific properties of additives
    • C08K2201/014—Additives containing two or more different additives of the same subgroup in C08K

Definitions

  • the present disclosure relates to the field of bio-simulation materials. Specifically, embodiments of the present disclosure relate to a bio-simulation material and a preparation method and use thereof.
  • Simulated tissues or organs that are highly similar in composition to human tissues and organs have many uses, such as film and television props, toys, medical teaching, etc.
  • the first type is relatively traditional, with a special laparoscopic training box with built-in plastic models or animal organs.
  • plastic models cannot complete real resection training, and the source of animal organs is limited and restricted by relevant laws and regulations.
  • the second type is computer simulation operation based on virtual reality technology, which can only provide highly similar scenes, cannot provide real touch, and cannot be objectively evaluated, which can easily cultivate students' bad habits of rough operation.
  • the third type is augmented reality technology that has been extended and developed on the basis of the second type.
  • the present disclosure provides a biomimetic material comprising: polyvinyl alcohol, a water retaining agent, a plasticizer, a coagulant and water.
  • 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 cross-linked polyvinylpyrrolidone, preferably one or more of pullulan, carboxymethyl cellulose, and hydroxypropyl cellulose.
  • the weight percentage of the water retaining agent is 0.5%-5%, for example, 0.9%-4.5%, based on the total weight of the biomimetic material.
  • the water retaining agent is 0.5%-3% carboxymethyl cellulose, 0.2%-1% hydroxypropyl cellulose and 0.2%-0.5% amylopectin, based on the total weight of the biomimetic material.
  • the plasticizer is selected from one or more of pyrrolidone, ethylene glycol, propylene glycol, butylene glycol, pentanediol, hexylene glycol, cyclohexanedimethanol, 2,2,4-trimethylpentane-1,3-diol, diethylene glycol, polyethylene glycol (200-600), glycerol, pentaerythritol, sorbitol, mannitol, lactitol, monosaccharide, sucrose, maltose, and lactose, preferably one or more of pyrrolidone, ethylene glycol, and glycerol.
  • the weight percentage of the plasticizer is 23-45%, based on the total weight of the biomimetic material.
  • the plasticizer is 10-25% ethylene glycol, 15-25% glycerol and 2-5% pyrrolidone, or the plasticizer is 10-25% ethylene glycol and 15-35% glycerol, based on the total weight of the biomimetic material.
  • the coagulant is selected from one or more of sodium tetraborate, potassium tetraborate, boric acid, calcium chloride and magnesium chloride.
  • the polyvinyl alcohol is a polyvinyl alcohol with a degree of polymerization of 1000-2000 and a degree of alcoholysis of more than 98%, such as polyvinyl alcohol 1799.
  • the weight percentage of polyvinyl alcohol is 3%-12%, such as 6%-9%, based on the total weight of the biomimetic material.
  • the biomimetic material further comprises one or more additives selected from the group consisting of a preservative, a colorant, a thickener, and a super absorbent polymer (SAP).
  • a preservative selected from the group consisting of a preservative, a colorant, a thickener, and a super absorbent polymer (SAP).
  • SAP super absorbent polymer
  • the thickener is 0.1% potassium oleate, based on the total weight of the biomimetic material.
  • the liquid content of the biomimetic material is greater than 50%, such as 60-93%, based on the total weight of the biomimetic material.
  • the present disclosure provides a method for preparing a biomimetic material, comprising: dispersing the components of the biomimetic material except water in water; adjusting the toughness with water and/or glycerol; and injecting into a mold for low-temperature freezing and cross-linking.
  • low temperature freeze cross-linking is performed at a temperature of -18°C to -40°C, such as -20°C to -40°C.
  • low temperature freeze cross-linking is continued for 6-18 hours, such as 8-12 hours.
  • the present disclosure provides the use of the above-mentioned biosimulation material for preparing a simulated medical teaching model.
  • the simulated medical teaching model is, for example, an intestine, liver, blood vessel, skin, peritoneum, pancreas, spleen or kidney.
  • FIG1 is a bionic liver provided by an embodiment of the present invention.
  • FIG2 is a bionic kidney provided by an embodiment of the present invention.
  • FIG3 is the elastic modulus of a bionic liver provided by an embodiment of the present invention.
  • FIG. 4 shows the elastic modulus of the bionic kidney provided in one embodiment of the present invention.
  • the inventors After screening a large number of formulas, the inventors found that the formula disclosed herein can produce simulated tissues or organs that are highly similar to the composition of human tissues and organs. The inventors tested the physical and chemical parameters of simulated tissues or organs and animal tissues or organs and found that the elastic modulus, liquid content and conductivity of the two are very close, with a deviation of less than 20%.
  • the present disclosure provides a biomimetic material comprising: polyvinyl alcohol, a water retaining agent, a plasticizer, a coagulant and water.
  • the water retaining agent in this application refers to a highly absorbent substance, which mainly enables the prepared biosimulation material to maintain a high liquid content for a long time.
  • the water retaining agent can be selected from one or more of pullulan, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), sodium polyacrylate, and cross-linked polyvinylpyrrolidone, preferably one or more of pullulan, carboxymethyl cellulose, and hydroxypropyl cellulose.
  • the weight percentage of the water retaining agent is 0.5%-5%, for example, 0.9%-4.5%, based on the total weight of the biomimetic material.
  • the water retaining agent is 0.5%-3% carboxymethyl cellulose, 0.2%-1% hydroxypropyl cellulose and 0.2%-0.5% pullulan, based on the total weight of the biomimetic material.
  • plasticizer refers to a class of substances that can be filled into the three-dimensional structure of biosimulation materials and enhance the stability of the three-dimensional structure through hydrogen bonds.
  • the plasticizer is selected from one or more of pyrrolidone, ethylene glycol, propylene glycol, butanediol, pentanediol, hexanediol, cyclohexanedimethanol, 2,2,4-trimethylpentane-1,3-diol, diethylene glycol, polyethylene glycol (200-600), glycerol, pentaerythritol, sorbitol, mannitol, lactitol, monosaccharide, sucrose, maltose, and lactose, preferably one or more of pyrrolidone, ethylene glycol, and glycerol.
  • the weight percentage of the plasticizer is 23-45%, based on the total weight of the biomimetic material.
  • the plasticizer is 10-25% ethylene glycol and 15-35% propylene glycol, based on the total weight of the biomimetic material.
  • the plasticizer is 10-25% ethylene glycol, 15-25% propylene glycol, alcohol and 2-5% pyrrolidone, based on the total weight of the biomimetic material.
  • a coagulant refers to a substance added to solidify the shape of a biomimetic material, reduce or eliminate its fluidity, prevent the tissue structure from deforming, and increase the solid content.
  • the coagulant is selected from one or more of boric acid, sodium tetraborate, potassium tetraborate, calcium chloride, and magnesium chloride.
  • the weight percentage of the coagulant is 0.1%-1.5%, based on the total weight of the biomimetic material.
  • the coagulant is 0.1%-0.2% sodium tetraborate, 0.05%-1% boric acid and 0.01%-0.1% calcium chloride, based on the total weight of the biomimetic material.
  • the amount of water added during the preparation of biosimulation materials is determined based on the water content in the tissues or organs of the human body or animals such as pigs, dogs, and rabbits.
  • the polyvinyl alcohol is a polyvinyl alcohol with a degree of polymerization of 1000-2000 and a degree of alcoholysis of more than 98%, for example, polyvinyl alcohol 1799, that is, a degree of polymerization of 1700 and a degree of alcoholysis of 99%.
  • the weight percentage of polyvinyl alcohol is 3%-12%, such as 6%-9%, based on the total weight of the biomimetic material.
  • the biomimetic material further comprises one or more additives selected from the group consisting of a preservative, a colorant, a thickener, and a super absorbent polymer (SAP).
  • a preservative selected from the group consisting of a preservative, a colorant, a thickener, and a super absorbent polymer (SAP).
  • SAP super absorbent polymer
  • the preservative may be selected from, for example, paraben, sodium acetate, hexylene glycol, chlorpheniramine, sorbitol and the like.
  • the colorant may be selected from, for example, carmine, amaranth, sunset yellow, erythrosine, lemon yellow, new red, indigo, brilliant blue, and the like.
  • the thickener may be selected from, for example, potassium oleate, sodium alginate, sodium caseinate, gum arabic, pectin, agar, gelatin, alginate, carrageenan, dextrin, and the like.
  • Preservatives, colorants, and thickeners may be commercially available additives for the food industry.
  • the thickener is 0.1% potassium oleate, based on the total weight of the biomimetic material.
  • the superabsorbent polymer may be selected, for example, from sodium polyacrylate, polyacrylate, polyacrylamide.
  • the biomimetic material of the present disclosure may also contain other additives as long as they do not affect the physical and chemical properties of the biomimetic material, such as water retention, toughness and conductivity.
  • the biomimetic material disclosed in the present invention can retain a large amount of water for a long time, which is very close to the liquid content of tissues or organs of the human body or animals.
  • the liquid content in the biomimetic material is greater than 50%, such as 60-93%, based on the total weight of the biomimetic material.
  • the electrolyte level of the biomimetic material disclosed in the present invention is 50-150mmol/L, which is similar to that of a normal human body or Animal tissues and organs have consistent electrolyte levels and therefore have similar electrical conductivity to human tissues.
  • the human tissues and organs made with the biomimetic materials disclosed herein meet one or more of the following requirements:
  • the deviation of liquid content from normal human or animal tissues and organs is less than 20%, 15%, 10% or 5%;
  • the elastic modulus deviates from the elastic modulus of normal human or animal tissues and organs by less than 20%, 15%, 10% or 5%;
  • the conductivity deviation from the conductivity of normal human or animal tissues and organs is less than 20%, 15%, 10% or 5%.
  • human tissues and organs made of biomimetic materials meet the following requirements:
  • the fluid content deviates from the fluid content of normal human or animal tissues and organs by less than 20%, 15%, 10% or 5%;
  • the elastic modulus deviates from the elastic modulus of normal human or animal tissues and organs by less than 20%, 15%, 10% or 5%.
  • human tissues and organs made of biomimetic materials meet the following requirements:
  • the fluid content deviates from the fluid content of normal human or animal tissues and organs by less than 20%, 15%, 10% or 5%;
  • the elastic modulus deviates from the elastic modulus of normal human or animal tissues and organs by less than 20%, 15%, 10% or 5%;
  • the conductivity deviation from the conductivity of normal human or animal tissues and organs is less than 20%, 15%, 10% or 5%.
  • the biosimulation materials disclosed in the present invention use natural and artificially synthesized biomaterials as the main raw materials, which are highly similar to the composition of human tissues and organs (polymer carbohydrates with similar structures), and thus exhibit similar apparent characteristics such as vision, touch, and toughness and elasticity; they can be used for practical training and teaching of laparoscopic surgeries such as electrosurgery, radiofrequency scalpels, and ultrasonic scalpels.
  • Another aspect of the present disclosure provides a method for preparing a biomimetic material, comprising: dispersing the components of the biomimetic material except water in water; adjusting the toughness with water, ethylene glycol and/or glycerol; and injecting into a mold for low-temperature freezing and cross-linking.
  • Low temperature freezing cross-linking takes different cross-linking temperatures and times according to different toughness requirements. The lower the temperature, the greater the toughness of the biomimetic material.
  • low temperature freeze cross-linking is performed at a temperature of -18°C to -40°C, such as -20°C to -40°C.
  • Low temperature freezing cross-linking generally takes 6-8 hours as one cross-linking cycle. In one embodiment, low temperature freezing cross-linking lasts for 6-18 hours, such as 8-12 hours.
  • the present disclosure provides the use of the above-mentioned biosimulation material for preparing a simulated medical teaching model.
  • the simulated medical teaching model is, for example, an intestine, liver, blood vessel, skin, peritoneum, pancreas, spleen or kidney.
  • livers, blood vessels, skin, peritoneum, pancreas, spleen or kidneys were prepared according to the above method.
  • the prepared bionic liver and bionic kidney are shown in Figures 1 and 2.
  • the samples were cut into sizes of 4 cm in length, 1 cm in width, and 0.3 cm in thickness, and a DMA instrument was used for variable temperature testing.
  • the elastic moduli of the bionic liver and bionic kidney are shown in Figures 3 and 4.
  • a small piece was taken from the complete sample and placed in a specific mold (50 mm in height and 10 mm in diameter).
  • a press was used to apply a pressure of 1 MPa.
  • the resistance value under the pressure was measured using a Tonghui conductivity tester (TH2683B) (test frequency was 3 GHz).
  • the volume resistivity of the sample was then calculated based on the mold size. The reciprocal of the resistivity is the conductivity.
  • the organs of white pigs of about 3 months old were removed and the above-mentioned water content, elastic modulus and electrical conductivity were tested as the qualification criteria.
  • the present disclosure illustrates the process method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned process steps, that is, it does not mean that the present invention must rely on the above-mentioned process steps to be implemented.

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Abstract

本公开提供一种生物仿真材料，其包含：聚乙烯醇、保水剂、增塑剂、凝固剂和水。本公开还提供了上述生物仿真材料的制备方法和用于制备仿真医疗教学模型的用途。

Description

一种生物仿真材料及其制备方法和用途
本申请要求于2022年9月27日递交的中国专利申请202211185373.1的优先权，在此全文引用上述中国专利申请公开的内容以作为本申请的一部分。
技术领域
本公开涉及生物仿真材料领域。具体而言，本公开的实施例涉及一种生物仿真材料及其制备方法和用途。
背景技术
与人体组织与器官的组成有高度相似相近性的仿真组织或器官有多种用途，例如可用于影视道具、玩具、医学教学等。
目前以腔镜手术如电刀、射频刀、超声刀等为代表的微创手术临床实训教学产品主要有三类。第一类是比较传统的，专门的腔镜训练箱内置塑胶模型或动物脏器，然而塑胶模型无法完成真实切除训练，动物脏器来源有限且受相关法律法规限制。第二类是其于虚拟现实技术的电脑模拟操作，只能提供高度相似场景，无法提供真实触感，更无法进行客观评价，容易养成学生粗暴操作的坏习惯。第三类是在第二类基础上延伸发展起来的增强现实技术，较第二类有较大进步，但终因模型材质仿真度不够，模拟操作与真实手术差距太大，且可完成病例相对较少，无法建立完整的课程教学体系。
因此，仍然需要开发一种生物仿真材料，用于制备与人体组织与器官的组成有高度相似相近性的仿真组织或器官。
发明内容
本公开一方面提供一种生物仿真材料，其包含：聚乙烯醇、保水剂、增塑剂、凝固剂和水。
例如，所述保水剂选自支链淀粉、羧甲基纤维素、羟丙基纤维素、羧甲基淀粉钠、羟乙基纤维素(HEC)、羟基丙基甲基纤维素(HPMC)、聚丙烯酸钠、交联聚维酮中的一种或多种，优选为支链淀粉、羧甲基纤维素和羟丙基纤维素中的一种或多种。
在一种实施方案中，保水剂的重量百分含量为0.5％-5％，例如，0.9％-4.5％，基于生物仿真材料的总重量。在一种具体的实施方案中，保水剂为0.5％-3％羧甲基纤维素、0.2％-1％羟丙基纤维素及0.2％-0.5％的支链淀粉，基于生物仿真材料的总重量。
例如，增塑剂选自吡咯烷酮、乙二醇、丙二醇、丁二醇、戊二醇、己二醇、环己烷二甲醇、2,2,4-三甲基戊烷-1,3-二醇、二甘醇、聚乙二醇(200-600)、丙三醇、季戊四醇、山梨醇、甘露醇、乳糖醇、单糖、蔗糖、麦芽糖、乳糖中的一种或多种，优选为吡咯烷酮、乙二醇和丙三醇中的一种或多种。
在一种实施方案中，增塑剂的重量百分含量为23-45％，基于生物仿真材料的总重量。例如，增塑剂为10-25％的乙二醇、15-25％的丙三醇和2-5％吡咯烷酮，或者增塑剂为10-25％的乙二醇和15-35％的丙三醇，基于生物仿真材料的总重量。
例如，凝固剂选自四硼酸钠、四硼酸钾、硼酸、氯化钙和氯化镁中的一种或多种。
在一种实施方案中，凝固剂的重量百分含量为0.1％-1.5％，基于生物仿真材料的总重量。例如，凝固剂为0.1％-0.2％四硼酸钠、0.05％-1％的硼酸和0.01％-0.1％的氯化钙，基于生物仿真材料的总重量。
在一种实施方案中，所述聚乙烯醇是为聚合度1000-2000、醇解度98％以上的聚乙烯醇，例如聚乙烯醇1799。
在一种实施方案中，聚乙烯醇的重量百分含量为3％-12％，例如6％-9％，基于生物仿真材料的总重量。
在一种实施方案中，所述生物仿真材料还包含选自以下的一种多种添加剂：防腐剂、着色剂、增稠剂和超吸收性聚合物(SAP)。
例如，增稠剂为0.1％的植物油酸钾，基于生物仿真材料的总重量。
在一种实施方案中，生物仿真材料的含液量为50％以上，例如60-93％，基于生物仿真材料的总重量。
本公开又一方面提供一种制备生物仿真材料的方法，其包括：使上述生物仿真材料中的除水之外的各组分分散在水中；用水和/或丙三醇调节韧性；注入模具中低温冷冻交联。
在一种实施方案中，低温冷冻交联在-18℃至-40℃，例如-20℃至-40℃的温度下进行。
在一种实施方案中，低温冷冻交联持续6-18小时，例如8-12小时。
本公开再一方面提供上述生物仿真材料用于制备仿真医疗教学模型的用途。仿真医疗教学模型例如为肠道、肝脏、血管、皮肤、腹膜、胰腺、脾脏或者肾脏等。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例的附图作简单地介绍，显而易见地，下面描述中的附图仅仅涉及本发明的一些实施例，而非对本发明的限制。
图1为本发明一实施例提供的仿生肝脏；
图2为本发明一实施例提供的仿生肾脏；
图3为本发明一实施例提供的仿生肝脏的弹性模量；
图4为本发明一实施例提供的仿生肾脏的弹性模量。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例的附图，对本发明实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于所描述的本发明的实施例，本领域普通技术人员在无需创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明可在不偏离本发明基本属性的情况下以其它具体形式来实施。应该理解的是，在不冲突的前提下，本发明的任一和所有实施方案都可与任一其它实施方案或多个其它实施方案中的技术特征进行组合以得到另外的实施方案。本发明包括这样的组合得到的另外的实施方案。
本公开提及的各类文献和出版物在此引入作为参考。除非另外定义，本公开使用的技术术语或者科学术语应当为本发明所属领域内具有一般技能的人士所理解的通常意义。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的通常含义。倘若对于某术语存在多个定义，则以本文定义为准。
除了在工作实施例中或另外指出之外，在说明书和权利要求中陈述的定量性质例如剂量的所有数字应理解为在所有情况中被术语“约”修饰。还应 理解的是，本申请列举的任何数字范围意在包括该范围内的所有的子范围和该范围或子范围的各个端点的任何组合。
本公开的配方中的用量或含量应理解为基于重量。
本公开中使用的“包括”、“含有”或者“包含”等类似的词语意指出现该词前面的要素涵盖出现在该词后面列举的要素及其等同，而不排除未记载的要素。本文所用的术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…组成”、或“由…组成”。
发明人在筛选大量配方之后发现，根据本公开的配方可制得与人体组织与器官的组成有高度相似相近性的仿真组织或器官。发明人测试了仿真组织或器官和动物组织或器官的物理化学参数，发现二者在弹性模量、含液量和电导率非常接近，偏差小于20％。
本公开一方面提供一种生物仿真材料，其包含：聚乙烯醇、保水剂、增塑剂、凝固剂和水。
保水剂在本申请中是指一种高吸水性物质，其主要使得制备的生物仿真材料能够长期保持很高的含液量。例如，保水剂可选自支链淀粉、羧甲基纤维素、羟丙基纤维素、羧甲基淀粉钠、羟乙基纤维素(HEC)、羟基丙基甲基纤维素(HPMC)、聚丙烯酸钠、交联聚维酮中的一种或多种，优选为支链淀粉、羧甲基纤维素和羟丙基纤维素中的一种或多种。
在一种实施方案中，保水剂的重量百分含量为0.5％-5％，例如，0.9％-4.5％，基于生物仿真材料的总重量。
在一种具体的实施方案中，保水剂为0.5％-3％羧甲基纤维素、0.2％-1％羟丙基纤维素及0.2％-0.5％的支链淀粉，基于生物仿真材料的总重量。
增塑剂在本申请中是指能够填充至生物仿真材料的三维结构中并通过氢键增强三维结构的稳定性的一类物质。例如，增塑剂选自吡咯烷酮、乙二醇、丙二醇、丁二醇、戊二醇、己二醇、环己烷二甲醇、2,2,4-三甲基戊烷-1,3-二醇、二甘醇、聚乙二醇(200-600)、丙三醇、季戊四醇、山梨醇、甘露醇、乳糖醇、单糖、蔗糖、麦芽糖、乳糖中的一种或多种，优选为吡咯烷酮、乙二醇和丙三醇中的一种或多种。
在一种实施方案中，增塑剂的重量百分含量为23-45％，基于生物仿真材料的总重量。例如，增塑剂为10-25％的乙二醇和15-35％的丙三醇，基于生物仿真材料的总重量。例如，增塑剂为10-25％的乙二醇、15-25％的丙三 醇和2-5％吡咯烷酮，基于生物仿真材料的总重量。
凝固剂在本申请中是指使生物仿真材料的形态固化、降低或消除其流动性、且使组织结构不变形、增加固形物而加入的物质。例如，凝固剂选自硼酸、四硼酸钠、四硼酸钾、氯化钙、氯化镁中的一种或多种。
在一种实施方案中，凝固剂的重量百分含量为0.1％-1.5％，基于生物仿真材料的总重量。例如，凝固剂为0.1％-0.2％四硼酸钠、0.05％-1％的硼酸和0.01％-0.1％的氯化钙，基于生物仿真材料的总重量。
生物仿真材料根据人体或猪、狗、兔子等动物中的组织或器官中的含水量确定制备过程中加入的水量。
在一种实施方案中，所述聚乙烯醇是为聚合度1000-2000、醇解度98％以上的聚乙烯醇，例如聚乙烯醇1799，即聚合度为1700、醇解度99％。
在一种实施方案中，聚乙烯醇的重量百分含量为3％-12％，例如6％-9％，基于生物仿真材料的总重量。
在一种实施方案中，所述生物仿真材料还包含选自以下的一种多种添加剂：防腐剂、着色剂、增稠剂和超吸收性聚合物(SAP)。
防腐剂例如可选自尼泊金酯，乙酸钠，已二醇，氯苯苷醚，山梨糖醇等。
着色剂例如可选自胭脂红、苋菜红、日落黄、赤藓红、柠檬黄、新红、靛蓝、亮蓝等。
增稠剂例如可选自植物油酸钾、海藻酸钠、酪蛋白酸钠、阿拉伯胶、果胶、琼脂、明胶、海藻胶、角叉胶、糊精等。
防腐剂、着色剂、增稠剂可以是可商购的食品行业添加剂。
在一种实施方案中，增稠剂为0.1％的植物油酸钾，基于生物仿真材料的总重量。
超吸收性聚合物例如可选自聚丙烯酸钠、聚丙烯酸酯、聚丙烯酰胺。
本公开的生物仿真材料还可包含其它添加剂，只要其不影响生物仿真材料的保水性、韧性和导电性等物理化学性能。
本公开的生物仿真材料可长期保持大量的水，与人体或动物的组织或器官的含液量非常接近。
在一种实施方案中，生物仿真材料中的含液量为50％以上，例如60-93％，基于生物仿真材料的总重量。
本公开的生物仿真材料的电解质水平为50-150mmol/L，与正常人体或 动物组织与器官的电解质水平一致，因此与人体组织有相近的电导性。
用本公开的生物仿真材料制作的人体组织与器官满足一种或多种以下要求：
1.含液量与正常人体或动物的组织与器官的含液量偏差低于20％、15％、10％或5％；
2.弹性模量与正常人体或动物的组织与器官的弹性模量偏差低于20％、15％、10％或5％；
3.电导性与正常人体或动物的组织与器官的电导性偏差低于20％、15％、10％或5％。
在一种实施方案中，生物仿真材料制作的人体组织与器官满足：
1.含液量与正常人体或动物的组织与器官的含液量偏差低于20％、15％、10％或5％；和
2.弹性模量与正常人体或动物的组织与器官的弹性模量偏差低于20％、15％、10％或5％。
在一种实施方案中，生物仿真材料制作的人体组织与器官满足：
1.含液量与正常人体或动物的组织与器官的含液量偏差低于20％、15％、10％或5％；和
2.弹性模量与正常人体或动物的组织与器官的弹性模量偏差低于20％、15％、10％或5％；和
3.电导性与正常人体或动物的组织与器官的电导性偏差低于20％、15％、10％或5％。
从组织成份上看，本公开的生物仿真材料采用天然及人工合成生物材料为主要原料，与人体组织与器官的组成有高度相似相近性(结构相似的高分子碳水化合物)，因而表现出相近的表观特征如视觉、触觉及韧弹性；可用于腔镜手术如电刀、射频刀、超声刀等的实训教学。
本公开又一方面提供一种制备生物仿真材料的方法，其包括：使上述生物仿真材料中的除水之外的各组分分散在水中；用水、乙二醇和/或丙三醇调节韧性；注入模具中低温冷冻交联。
低温冷冻交联依不同韧性需求取不同的交联温度和交联时间。温度越低，制得的生物仿真材料韧性越大。
丙三醇含量越高，制得的生物仿真材料韧性越大。
在一种实施方案中，低温冷冻交联在-18℃至-40℃，例如-20℃至-40℃的温度下进行。
低温冷冻交联一般以6-8小时作一个交联周期。在一种实施方案中，低温冷冻交联持续6-18小时，例如8-12小时。
本公开再一方面提供上述生物仿真材料用于制备仿真医疗教学模型的用途。仿真医疗教学模型例如为肠道、肝脏、血管、皮肤、腹膜、胰腺、脾脏或者肾脏等。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
仿真脏器的制备
仿真脏器的材料配方：
按上表中的配方，依不同脏器的韧性需求调节水、乙二醇和/或丙三醇的用量，在80-95℃下搅拌混合4小时，注入模具后低温-20℃下交联，以8小时为一个交联周期，后解冻脱模包装。
按上述方法制备了肠道、肝脏、血管、皮肤、腹膜、胰腺、脾脏或者肾脏。其中制备的仿生肝脏和仿生肾脏如图1和图2所示。
含液量测试方法
在该测试项目中，在100℃条件下在真空干燥箱(DZF-6000)中真空干燥 样品12小时。通过称量样品干燥前后的质量差得到样品的含液量。测试过程中应注意在样品称量中避免用力过大，避免液体的流失，未测试样品应置于冰箱中保存，避免液体流失。
弹性模量测试方法
将样品裁剪为尺寸长4cm、宽1cm、厚度0.3cm，采用DMA仪器进行变温测试。仿生肝脏和仿生肾脏的弹性模量如图3和图4所示。
电导率测试方法
从完整样品上取下一小块，放入特定的模具(高50mm、直径10mm)中，使用压力机，施加压力为1MPa，使用同惠电导率测试仪(TH2683B)测定该压力下的电阻值(测试频率为3GHz)，然后根据模具尺寸计算该样品的体积电阻率，电阻率的倒数即为电导率。
动物试验对比
摘取3个月左右的白猪的脏器，测试上述含水量、弹性模量和电导率作为合格判据。
表1：仿真脏器的含液量测试结果
表2：仿真脏器的弹性模量的测试结果
表3：仿真脏器的电导率测试结果
从上述表格可以发现仿真脏器的弹性模量、含液量和电导率与真实脏器相应指标偏差不超过20％。
本公开通过上述实施例来说明本发明的工艺方法，但本发明并不局限于上述工艺步骤，即不意味着本发明必须依赖上述工艺步骤才能实施。
所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明所选用原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。本发明的保护范围应以所述权利要求的保护范围为准。

Claims (20)

  1. 一种生物仿真材料，其包含：
    聚乙烯醇、保水剂、增塑剂、凝固剂和水。
  2. 权利要求1的生物仿真材料，其中所述保水剂选自支链淀粉、羧甲基纤维素、羟丙基纤维素、羧甲基淀粉钠、羟乙基纤维素(HEC)、羟基丙基甲基纤维素(HPMC)、聚丙烯酸钠、交联聚维酮中的一种或多种，优选为支链淀粉、羧甲基纤维素和羟丙基纤维素中的一种或多种。
  3. 权利要求1或2的生物仿真材料，其中保水剂的重量百分含量为0.5％-5％，例如，0.9％-4.5％，基于生物仿真材料的总重量。
  4. 权利要求3的生物仿真材料，其中保水剂为0.5％-3％羧甲基纤维素、0.2％-1％羟丙基纤维素及0.2％-0.5％的支链淀粉，基于生物仿真材料的总重量。
  5. 权利要求1-4任一项的生物仿真材料，其中所述增塑剂选自吡咯烷酮、乙二醇、丙二醇、丁二醇、戊二醇、己二醇、环己烷二甲醇、2,2,4-三甲基戊烷-1,3-二醇、二甘醇、聚乙二醇(200-600)、丙三醇、季戊四醇、山梨醇、甘露醇、乳糖醇、单糖、蔗糖、麦芽糖、乳糖中的一种或多种，优选为吡咯烷酮、乙二醇和丙三醇中的一种或多种。
  6. 权利要求1-5中任一项的生物仿真材料，其中增塑剂的重量百分含量为23-45％，例如基于生物仿真材料的总重量。
  7. 权利要求6的生物仿真材料，其中增塑剂为10-25％的乙二醇、15-25％的丙三醇和2-5％吡咯烷酮，或者增塑剂为10-25％的乙二醇和15-35％的丙三醇，基于生物仿真材料的总重量。
  8. 权利要求1-7中任一项的生物仿真材料，其中所述凝固剂选自四硼酸钠、四硼酸钾、硼酸、氯化钙和氯化镁中的一种或多种。
  9. 权利要求1-8中任一项的生物仿真材料，其中凝固剂的重量百分含量为0.1％-1.5％，基于生物仿真材料的总重量。
  10. 权利要求9的生物仿真材料，其中凝固剂为0.1％-0.2％四硼酸钠、0.05％-1％的硼酸和0.01％-0.1％的氯化钙，基于生物仿真材料的总重量。
  11. 权利要求1-10中任一项的生物仿真材料，其中聚乙烯醇是为聚合度1000-2000、醇解度98％以上的聚乙烯醇，例如聚乙烯醇1799。
  12. 权利要求1-11中任一项的生物仿真材料，其中聚乙烯醇的重量百分含量为3％-12％，例如6％-9％，基于生物仿真材料的总重量。
  13. 权利要求1-12中任一项的生物仿真材料，其还包含选自以下的一种多种添加剂：防腐剂、着色剂、增稠剂和超吸收性聚合物(SAP)。
  14. 权利要求13的生物仿真材料，其中增稠剂为0.1％的植物油酸钾，基于生物仿真材料的总重量。
  15. 权利要求1-14中任一项的生物仿真材料，其中含液量为60-93％，基于生物仿真材料的总重量。
  16. 一种制备生物仿真材料的方法，其包括
    使权利要求1-15中任一项的生物仿真材料中除水之外的各组分分散在水中；
    用水和/或丙三醇调节韧性；
    注入模具中低温冷冻交联。
  17. 权利要求16的制备生物仿真材料的方法，其中低温冷冻交联在-18℃至-40℃，例如-20℃至-40℃的温度下进行。
  18. 权利要求17的制备生物仿真材料的方法，其中低温冷冻交联持续6-18小时，例如8-12小时。
  19. 权利要求1-15任一项所述的生物仿真材料用于制备仿真医疗教学模型的用途。
  20. 权利要求19的用途，其中仿真医疗教学模型为肠道、肝脏、血管、皮肤、腹膜、胰腺、脾脏或者肾脏。
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