CN115154663B - 具有双相药物缓释功能的水凝胶型组织工程支架及其光固化3d打印制备方法、光敏树脂 - Google Patents
具有双相药物缓释功能的水凝胶型组织工程支架及其光固化3d打印制备方法、光敏树脂 Download PDFInfo
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Abstract
本发明公开了一种具有双相药物缓释功能的水凝胶型组织工程支架及其光固化3D打印制备方法。打印水凝胶型支架所用光敏树脂的原料组分质重量份数计如下：聚氨酯甲基丙烯酸酯乳液40～80份、水溶性光固化单体10～60份、水溶性药物100～1000 ppm、脂溶性药物100～1000 ppm、光引发剂0.1～5份，经光固化3D打印得到水凝胶支架。本发明提供的水凝胶支架具有良好的生物相容性和体内稳定性，光固化3D打印可以精确控制其三维结构和多孔结构，而且基于乳液水油双相共存的特点，可以同时负载水溶性和脂溶性药物，实现双相药物缓释功能。动物实验表明，制备的水凝胶支架可以促进软骨细胞的生成，抑制骨关节炎的发展。
Description
技术领域
本发明属于组织工程技术领域，具体涉及一种具有双相药物缓释功能的水凝胶型组织工程支架及其光固化3D打印制备方法、光敏树脂。
背景技术
关节软骨是覆盖在关节表面的一种白色透明软骨。其光滑的表面可以明显降低运动过程中关节面间的摩擦力。近年来，关节软骨损伤发病率逐年上升，严重影响人们的日常生活。但是，关节软骨部位一般缺乏血液供应、神经支配及淋巴回流，损伤后自我修复能力很差；如得不到及时治疗，将会发展成骨性关节炎。目前临床上用于治疗关节软骨损伤的方法主要有切除术、骨软骨移植术、自体软骨细胞移植术等，这些方法在一定程度能缓解膝关节疼痛及改善功能，但远期疗效并不理想。上世纪90年代提出的组织工程的概念，即在充分了解组织器官正常及病理状态下结构与功能关系，构建可以修复受损组织或器官的替代物，可以取得良好的治疗效果。水凝胶是一种以水为分散介质的具有三维空间网状结构的聚合物体系。由于其优异的生物相容性、渗透扩散性，水凝胶已经在生物组织工程支架材料中获得了广泛的应用。近年来，3D打印技术的发展为材料的成型加工以及精细结构的高精度制备提供了新的思路。基于光聚合反应的3D打印，如数字投影技术（digital lightprocessing，DLP）、光固化立体成型技术（stereolithography，SLA）在打印精度上具有明显的优势，可以构筑具有精细结构的水凝胶支架。
人体关节软骨损伤后，不仅会导致关节局部疼痛、肿胀，还会导致骨关节炎的发生。此外，手术治疗存在感染的可能。因此，如若能构建人工材料缓释系统，实现多种药物的缓慢释放，如抗生素、消炎止痛药、促软骨再生药物等，不仅能为关节软骨修复提供良好的环境，还能抑制骨关节炎进展，必将使术后功能恢复及患者主观感受得到明显改善，从而改善患者预后。研究表明，KGN（kartogenin，卡列宁）是一种smad4/smad5 通路激活剂，具有极强的促软骨分化能力，能有效地促进间充质干细胞向软骨细胞的分化。而且，KGN可以募集体内自身间充质干细胞在软骨损伤处聚集，促进软骨的修复，不需要植入种子细胞[Science 2012, 336 (6082), 717-721]。而氨基葡萄糖可以显著促进干细胞向软骨细胞分化，增加软骨细胞内软骨特异性标志物（Col2a1、Acan）的表达，抑制骨关节炎进展（Osteoarthritis and cartilage 2006, 14 (3), 250-257）。然而，KGN为脂溶性药物，氨基葡萄糖为水溶性药物，通常在水凝胶支架中只能负载水溶性的氨基葡萄糖，无法实现脂溶性和水溶性药物的同时负载。
发明内容
本发明的目的在于提供一种具有双相药物缓释功能的水凝胶型组织工程支架及其光固化3D打印制备方法。
本发明制备的水凝胶型组织工程支架，由于其采用乳液型树脂固化而成，基于乳液水油双相共存的特点，可以同时负载水溶性和脂溶性的药物，实现双相药物缓释功能。体内动物实验表明制备的水凝胶组织工程支架可以促进软骨细胞的生成，抑制骨关节炎的发展。
本发明所提供的具有双相缓释功能的水凝胶型组织工程支架的光固化3D打印制备方法，包括下述步骤：
1）制备光敏树脂，所述光敏树脂的原料组分按质量份数计含量如下：
水性聚氨酯（甲基）丙烯酸酯乳液 40～80份
水溶性光固化单体 10～60份
水溶性药物 100～1000 ppm
脂溶性药物 100～1000 ppm
光引发剂 0.1～5份
2）将步骤1）所述光敏树脂进行光固化3D打印，得到水凝胶支架。
上述方法步骤1）中，所述聚氨酯（甲基）丙烯酸酯乳液，其先由二异氰酸酯与羟基封端的多元醇及带亲水链段的多元醇反应得到异氰酸酯基封端的预聚物，然后与含羟基的（甲基）丙烯酸酯反应制备得到聚氨酯（甲基）丙烯酸酯树脂，再经过乳化制备得到水性聚氨酯（甲基）丙烯酸酯乳液。
其中，所述二异氰酸酯选自氢化苯基甲烷二异氰酸酯、异佛尔酮二异氰酸酯、六亚甲基二异氰酸酯中的至少一种。
所述羟基封端的多元醇选自聚醚多元醇、聚酯多元醇、聚烯烃多元醇中的至少一种。
根据本发明的实施方案，所述聚醚多元醇选自聚乙二醇、聚丙二醇、聚四氢呋喃二醇中的至少一种。
根据本发明的实施方案，所述聚酯多元醇选自聚己内酯二醇，聚乳酸二醇、聚己二酸乙二醇酯二醇、聚己二酸丁二醇酯二醇中的至少一种。
根据本发明的实施方案，所述聚烯烃多元醇选自聚丁二烯二醇。
根据本发明的实施方案，所述羟基封端的多元醇数均分子量为1000～10000 g/mol。
所述带亲水性链段的多元醇选自聚乙二醇或聚乙二醇-聚丙二醇嵌段共聚物。
所述的含羟基的（甲基）丙烯酸酯选自（甲基）丙烯酸羟乙酯、（甲基）丙烯酸羟丙酯中的至少一种。
所述水性聚氨酯（甲基）丙烯酸酯乳液具体可按照包括如下步骤的方法制备得到：
S1：在催化剂存在下，使二异氰酸酯与羟基封端的多元醇、带亲水性链段的多元醇混合，发生逐步加成聚合反应得到异氰酸酯基封端的聚氨酯类树脂；
S2：将上述制备的异氰酸酯基封端的聚氨酯类树脂与含羟基的（甲基）丙烯酸酯反应，期间加入阻聚剂，得到水性聚氨酯（甲基）丙烯酸酯；
S3：将上述制备的水性聚氨酯（甲基）丙烯酸酯乳化，得到固含量为10～30%（具体如25%）的水性聚氨酯（甲基）丙烯酸酯乳液，乳液粒径为20～100 nm（优选为40～80 nm）。
根据本发明的实施方案，所述的催化剂为叔胺类（如三乙烯二胺、双(二甲胺基乙基)醚）或有机金属类催化剂（如辛酸亚锡、月桂酸正丁基锡、羧酸铋）；
根据本发明的实施方案，所述有机溶剂选自丙酮、四氢呋喃中的至少一种；
根据本发明的实施方案，所述阻聚剂选自对苯二酚、对甲氧基苯酚中的至少一种；
根据本发明的实施方案，所述步骤S1中，所述催化剂的用量为200 ～600 ppm；所述聚合反应的反应温度为50～100℃，反应时间1～12 h；
根据本发明的实施方案，所述步骤S2中，所述阻聚剂的用量为50 ～1000 ppm；所述反应的反应温度为50～100℃，反应时间1～12 h；
所述二异氰酸酯、羟基封端的多元醇、带水性链段的多元醇、含羟基的（甲基）丙烯酸酯的摩尔比为1：（0.2-0.5）：（0.2-0.5）：（0.2-0.8）。
本发明中，所述的水性光固化单体选自丙烯酰胺、N-异丙基丙烯酰胺、丙烯酸羟乙酯、丙烯酸、甲基丙烯酸、N-乙烯基吡咯烷酮的至少一种；
所述的水溶性药物为任意一种或多种水溶性的具有促进软骨分化或抑制骨性关节炎的药物，如硫酸氨基葡萄糖。
所述的脂溶性药物为任意一种或多种水溶性的具有促进软骨分化或抑制骨性关节炎的药物，如卡列宁（KGN）。
所述的光引发剂选自(2 ,4 ,6-三甲基苯甲酰基)二苯基氧化膦、偶氮二甲基-2-羟丁基丙酰胺、苯基双(2 ,4 ,6-三甲基苯甲酰基)氧化膦、(2 ,4 ,6-三甲基苯甲酰基)膦酸乙酯、二苯甲酮、异丙基硫杂蒽酮、2，4-二甲基硫杂蒽酮的至少一种。
上述方法步骤1）中，优选的所述光敏树脂的原料组分按质量份数计含量如下：
水性聚氨酯（甲基）丙烯酸酯乳液 50～80份
水溶性光固化单体 10～50份
水溶性药物 500～1000 ppm
脂溶性药物 300～1000 ppm
光引发剂 0.1～2份
根据本发明的一个实施方案，所述光敏树脂的原料中各组分的质量份数为：水性聚氨酯（甲基）丙烯酸酯乳液-1 50份、丙烯酰胺30 份、丙烯酸羟乙酯19份、KGN 300 ppm、氨基葡萄糖 500 ppm、苯基双(2,4,6-三甲基苯甲酰基)氧化膦 1份。
根据本发明的一个实施方案，所述光敏树脂的原料中各组分的质量份数为：水性聚氨酯（甲基）丙烯酸酯乳液-2 70份、N-异丙基丙烯酰胺 29.5份、KGN 500 ppm、氨基葡萄糖800 ppm、（2,4,6-三甲基苯甲酰基）二苯基氧化膦 1.5份。
根据本发明的一个实施方案，所述光敏树脂的原料中各组分的质量份数为：水性聚氨酯（甲基）丙烯酸酯乳液-3 80份、丙烯酰胺 18份、KGN 300 ppm、氨基葡萄糖500 ppm、苯基双(2,4,6-三甲基苯甲酰基)氧化膦 1份。
本发明还提供上述光敏树脂的制备方法。
本发明所提供的上述光敏树脂的制备方法，包括下述步骤：按照比例称取水性聚氨酯（甲基）丙烯酸酯乳液、水性光固化单体、水溶性药物、脂溶性药物和光引发剂，倒入搅拌器中，在避光的条件下通过机械搅拌混匀即得。
进一步的，上述方法步骤2）光固化3D打印结束后，还包括对得到的样品进行清洗、后固化处理的步骤。
所述清洗可用乙醇或异丙醇对样品进行清洗，具体可为：将样品坯体放入乙醇或异丙醇中，超声清洗10 min。
所述后固化过程为：在紫外箱中采用紫外光后固化10-30 min。
所述方法还进一步包括对后固化处理的样品进行消毒的步骤。
上述方法制备得到的水凝胶型组织工程支架也属于本发明的保护范围。
所述水凝胶型组织工程支架进一步可为关节软骨支架，具体如半月板支架。
此外，上述提供的光敏树脂也属于本发明的保护范围。
本发明还提供了上述光敏树脂的应用。
本发明所提供的光敏树脂的应用，是其在光固化3D打印中的用途，尤其是在光固化立体成型（SLA）、数字光处理光固化3D打印（DLP）、连续液态界面（CLIP）打印中的用途。
以及，所述光敏树脂在制备载药水凝胶型组织工程支架中的应用。
与现有技术相比，本发明具有如下优点：
（1）本发明提供的水凝胶型支架具有良好的生物相容性、体内稳定性；
（2）本发明制备水凝胶型支架采用光固化3D打印的方式，打印精度高，可以精确控制其三维结构和多孔结构；
（3）本发明制备的水凝胶型支架可以同时负载水溶性和油溶性药物，实现双相药物缓释功能，可以促进软骨细胞的生成，同时抑制骨关节炎的发展。
附图说明
图1显示的是本发明通过数字光处理（DLP）3D打印制作的水凝胶支架模型。
图2显示的是实施例3中打印制作的水凝胶型支架的力学拉伸曲线。
图3显示的是实施例3的水凝胶支架中水溶性药物氨基葡萄糖和油溶性药物KGN的释放曲线。
图4 显示的是将实施例3中的水凝胶支架植入猪膝关节，术后8周核磁共振T2像检查照片。
图5显示的是实施例3中的水凝胶支架植入猪膝关节，术后8周解剖照片。
图6显示的是植入猪体的支架周围关节滑膜组织病理HE染色照片。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
实施例1
一种水性聚氨酯丙烯酸酯乳液的制备，具体步骤如下：
在装配有机械搅拌、氮气导入管、温度计和滴液漏斗的250 mL 圆底烧瓶中，加入16.0 g（0.008 mol）聚乙二醇（分子量2000）、10.0 g（0.001 mol）聚乙二醇（分子量10000）、16.0 g （0.008 mol）聚丙二醇（分子量为2000），将反应瓶温度升至90°C ，原料融化后，将3.36 g （0.02 mol）六亚甲基二异氰酸酯（HDI）逐滴加入三口烧瓶中，0.5 h后加入0.02 g月桂酸正丁基锡，此时保持瓶内反应体系温度90 °C。通过傅里叶红外监测反应程度，当异氰酸酯基红外特征吸收峰不再减小时，再将0.05 g对苯二酚和0.70 g（0.006 mol）丙烯酸羟乙酯的混合物逐滴加入体系中，期间保持体系温度55 °C。滴加完成后，继续反应，直至红外谱图中异氰酸酯基团的特征吸收峰完全消失，即得到聚氨酯丙烯酸酯。将体系温度降至室温，在高速搅拌（800 r/min）下逐滴加入去离子水138 g，经减压蒸馏除去有机溶剂，最终制得固含量为25 %的水性聚氨酯丙烯酸酯乳液-1（动态光散射测试平均粒径为39 nm）。
光固化3D打印水凝胶用光敏树脂的制备：
首先，按照配方比例称取原材料：光敏树脂的原料组分计按重量份数计含量如下：
水性聚氨酯丙烯酸酯乳液-1 50份
丙烯酰胺 30份
丙烯酸羟乙酯 19份
KGN 300 ppm
氨基葡萄糖 500 ppm
苯基双(2,4,6-三甲基苯甲酰基)氧化膦 1份
然后，将各组分依次倒入搅拌器中，在避光的条件下通过机械搅拌混匀得到光敏树脂。
水凝胶支架的打印：
将制得的光敏树脂导入DLP 3D打印设备的树脂槽中进行模型打印，3D打印机的打印参数根据树脂固化速度和深度进行设定，得到表面光滑且精细度高的模型。打印完成后，将样件去除支撑，并放入乙醇中超声10 min，之后放入紫外箱后固化15 min，得到水凝胶支架坯体。之后再经过去离子水浸泡、消毒等处理即得到水凝胶支架（半月板支架）。
实施例2
一种水性聚氨酯甲基丙烯酸酯乳液的制备，具体步骤如下：
在装配有机械搅拌、氮气导入管、温度计和滴液漏斗的250 mL 圆底烧瓶中，加入33.6 g（0.004 mol）聚乙二醇-聚丙二醇-聚乙二醇嵌段共聚物（分子量8400，聚乙二醇含量79%）、24.0 g （0.012 mol）聚己内酯二醇（分子量为2000），将反应瓶温度升至90°C ，原料融化后，将 4.44 g （0.02 mol）异佛尔酮二异氰酸酯（IPDI）逐滴加入三口烧瓶中，0.5 h后加入0.02 g 月桂酸正丁基锡，此时保持瓶内反应体系温度90 °C。通过傅里叶红外监测反应程度，当异氰酸酯基红外特征吸收峰不再减小时，再将0.05 g对苯二酚和1.04 g（0.008mol）甲基丙烯酸羟乙酯的混合物逐滴加入体系中，期间保持体系温度65 °C。滴加完成后，继续反应，直至红外谱图中异氰酸酯基团的特征吸收峰完全消失，即得到聚氨酯甲基丙烯酸酯。将体系温度降至室温，在高速搅拌（800 r/min）下逐滴加入去离子水190 g，经减压蒸馏除去有机溶剂，最终制得固含量为25 %的水性聚氨酯甲基丙烯酸酯乳液-2（动态光散射测试平均粒径为59 nm）。
光固化3D打印水凝胶用光敏树脂的制备：
首先，按照配方比例称取原材料：光敏树脂的原料组分计按重量份数计含量如下：
水性聚氨酯甲基丙烯酸酯乳液-2 70份
异丙基丙烯酰胺 29.5份
KGN 500 ppm
氨基葡萄糖 800 ppm
（2,4,6-三甲基苯甲酰基）二苯基氧化膦 1.5份
然后，将各组分依次倒入搅拌器中，在避光的条件下通过机械搅拌混匀得到光敏树脂。
水凝胶支架的打印：
将制得的光敏树脂导入DLP 3D打印设备的树脂槽中进行模型打印，3D打印机的打印参数根据树脂固化速度和深度进行设定，得到表面光滑且精细度高的模型。打印完成后，将样件去除支撑，并放入乙醇中超声10 min，之后放入紫外箱后固化15 min，得到水凝胶支架坯体。之后再经过去离子水浸泡、消毒等处理即得到水凝胶支架（半月板支架）。
实施例3
一种水性聚氨酯甲基丙烯酸酯乳液的制备，具体步骤如下：
在装配有机械搅拌、氮气导入管、温度计和滴液漏斗的250 mL 圆底烧瓶中，加入16.0 g（0.008 mol）聚乙二醇（分子量2000）、5.0 g（0.001 mol）聚乙二醇（分子量5000）、16.0 g （0.008 mol）聚四氢呋喃二醇（分子量为2000），将反应瓶温度升至90°C ，原料融化后，将3.36 g （0.02 mol）异佛尔酮二异氰酸酯（IPDI）逐滴加入三口烧瓶中，0.5 h后加入0.02 g 月桂酸正丁基锡，此时保持瓶内反应体系温度90 °C。通过傅里叶红外监测反应程度，当异氰酸酯基红外特征吸收峰不再减小时，再将0.05 g对苯二酚和0.78 g（0.006 mol）甲基丙烯酸羟乙酯的混合物逐滴加入体系中，期间保持体系温度55 °C。滴加完成后，继续反应，直至红外谱图中异氰酸酯基团的特征吸收峰完全消失，即得到聚氨酯丙烯酸酯。将体系温度降至室温，在高速搅拌（800 r/min）下逐滴加入去离子水123 g，经减压蒸馏除去有机溶剂，最终制得固含量为25 %的水性聚氨酯甲基丙烯酸酯乳液-3（动态光散射测试平均粒径为65 nm）。
光固化3D打印水凝胶用光敏树脂的制备：
首先，按照配方比例称取原材料：光敏树脂的原料组分计按重量份数计含量如下：
水性聚氨酯甲基丙烯酸酯乳液-3 80份
丙烯酰胺 18份
KGN 300 ppm
氨基葡萄糖 500 ppm
苯基双(2,4,6-三甲基苯甲酰基)氧化膦 2份
然后，将各组分依次倒入搅拌器中，在避光的条件下通过机械搅拌混匀得到光敏树脂。
水凝胶支架的打印：
将制得的光敏树脂导入DLP 3D打印设备的树脂槽中进行模型打印，3D打印机的打印参数根据树脂固化速度和深度进行设定，得到表面光滑且精细度高的模型。打印完成后，将样件去除支撑，并放入乙醇中超声10 min，之后放入紫外箱后固化15 min，得到水凝胶支架坯体。之后再经过去离子水浸泡、消毒等处理即得到水凝胶支架（半月板支架）。
对上述实施例制备的水凝胶型组织工程支架的力学性能评价，按照GB/T2567-2008测试标准对打印的半月板支架进行力学性能评价包括拉伸强度、断裂伸长率。
结果见表1。
表1
图1显示的是本发明通过数字光处理（DLP）3D打印制作的水凝胶支架模型。
图2显示的是实施例3中打印制作的水凝胶型支架的力学拉伸曲线。
图3显示的是实施例3水凝胶支架中水溶性药物氨基葡萄糖和脂溶性药物KGN的释放曲线。其中KGN的释放采用紫外吸收光谱测试，其分子在279nm处有特征吸收峰。氨基葡萄糖通过高效液相色谱进行测试，流动相为0.05%的磷酸-丙烯腈（体积比为60：40）混合溶剂。结果表明水溶性药物氨基葡萄糖在7天内快速释放，可以缓解支架植入造成的炎症反应。脂溶性药物KGN在前10天内释放较快，而且在30天内有持续释放，对干细胞向软骨分化具有促进作用。实施例1、2制备的水凝胶支架中水溶性药物氨基葡萄糖和脂溶性药物KGN的释放曲线与图3基本相同。
水凝胶型支架的体内效果验证：
对6个月大雄性猪的膝关节进行皮肤消毒后，切开皮肤和外侧副韧带，并暴露外侧半月板。在外侧半月板体上做一个直径为1厘米的缺陷，然后植入水凝胶支架，并进行软组织缝合。
图4 显示的是将本申请实施例3中的水凝胶支架植入猪膝关节，术后8周核磁共振T2像检查照片，图中显示（箭头所示）水凝胶支架在关节间隙中结构完整，关节软骨未见明显破坏，支架周围有自体组织长入。
图5显示的是实施例3制备的水凝胶支架植入猪膝关节，术后8周解剖照片。术后8周内侧股骨髁软骨及内侧胫骨平台软骨未见明显骨性关节炎，关节软骨状态良好，说明本发明半月板支架起到了良好保护关节软骨的作用。
图6显示的是支架周围关节滑膜组织病理HE染色照片，结果显示滑膜状态良好，无明显炎症反应。
本发明制备的水凝胶组织工程支架具有良好的生物相容性和体内稳定性，打印精度高，可以定制特定三维结构和多孔结构的支架，而且可以同时负载水溶性和油溶性药物，实现药物的双相缓释功能。
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变形，本发明的范围由所附权利要求极其等同限定。
Claims (5)
1.一种用于制备具有双相药物缓释功能的水凝胶型组织工程支架的光敏树脂，其原料中各组分的质量份数为：水性聚氨酯（甲基）丙烯酸酯乳液50～80份、水溶性光固化单体10～50份、水溶性药物500-1000 ppm、脂溶性药物300-1000 ppm、光引发剂0.1～2份；
所述的水性聚氨酯（甲基）丙烯酸酯乳液，其先由二异氰酸酯与羟基封端的多元醇及带亲水性链段的多元醇反应得到异氰酸酯基封端的预聚物，然后与含羟基的(甲基)丙烯酸酯反应制备得到聚氨酯甲基丙烯酸酯树脂，再经过乳化制备得到水性聚氨酯(甲基)丙烯酸酯乳液；
所述的水溶性光固化单体选自丙烯酰胺，N-异丙基丙烯酰胺、丙烯酸、甲基丙烯酸、丙烯酸羟乙酯、甲基丙烯酸羟乙酯、N-乙烯基吡咯烷酮的至少一种；
所述的水溶性药物为氨基葡萄糖；
所述的脂溶性药物为卡列宁；
所述的光引发剂选自(2 ,4 ,6-三甲基苯甲酰基)二苯基氧化膦、苯基双(2 ,4 ,6-三甲基苯甲酰基)氧化膦、(2 ,4 ,6-三甲基苯甲酰基)膦酸乙酯、二苯甲酮、异丙基硫杂蒽酮、2，4-二甲基硫杂蒽酮的至少一种；
所述的二异氰酸酯选自氢化苯基甲烷二异氰酸酯、异佛尔酮二异氰酸酯、六亚甲基二异氰酸酯中的至少一种；
所述的羟基封端的多元醇选自聚醚多元醇、聚酯多元醇、聚烯烃多元醇中的至少一种；
所述的带亲水性链段的多元醇选自聚乙二醇、聚乙二醇-聚丙二醇嵌段共聚物中的至少一种；
所述的含羟基的（甲基）丙烯酸酯选自（甲基）丙烯酸羟乙酯、（甲基）丙烯酸羟丙酯中的至少一种；
所述水凝胶型组织工程支架为关节软骨支架；
所述聚醚多元醇选自聚乙二醇、聚丙二醇、聚四氢呋喃二醇中的至少一种；
所述聚酯多元醇选自聚己内酯二醇、聚乳酸二醇、聚己二酸乙二醇酯二醇、聚己二酸丁二醇酯二醇中的至少一种；
所述聚烯烃多元醇选自聚丁二烯二醇；
所述羟基封端的多元醇数均分子量为1000～10000 g/mol；
所述的水性聚氨酯（甲基）丙烯酸酯乳液按照如下步骤制备得到：
S1：在催化剂存在下，使二异氰酸酯与羟基封端的多元醇、带水性链段的多元醇混合，发生逐步加成聚合反应得到异氰酸酯基封端的聚氨酯类树脂；
S2：将上述制备的异氰酸酯基封端的聚氨酯类树脂与含羟基的（甲基）丙烯酸酯反应，期间加入阻聚剂，得到水性聚氨酯（甲基）丙烯酸酯；
S3：将上述制备的水性聚氨酯（甲基）丙烯酸酯乳化，得到固含量为15-30%的水性聚氨酯（甲基）丙烯酸酯乳液；
所述的催化剂为叔胺类或有机金属类催化剂；
所述阻聚剂选自对苯二酚、对甲氧基苯酚中的至少一种；
所述步骤S1中，所述催化剂的用量为200～600 ppm；所述聚合反应的反应温度为50～100℃，反应时间1～12 h；
所述步骤S2中，所述阻聚剂的用量为50～1000 ppm；所述反应的反应温度为50～100℃，反应时间1～12 h；
所述二异氰酸酯、羟基封端的多元醇、带水性基团的二元醇、含羟基的（甲基）丙烯酸酯的摩尔比为1：（0.2-0.5）：（0.2-0.5）：（0.2-0.8）。
2.权利要求1所述的用于制备具有双相药物缓释功能的水凝胶型组织工程支架的光敏树脂的制备方法，包括下述步骤：按照比例称取所述水性聚氨酯（甲基）丙烯酸酯乳液、水溶性光固化单体、水溶性药物、脂溶性药物和光引发剂，倒入搅拌器中，在避光的条件下通过机械搅拌混匀即得。
3.权利要求1所述光敏树脂在制备具有双相药物缓释功能的水凝胶型组织工程支架中的应用；所述水凝胶型组织工程支架为关节软骨支架。
4.一种光固化3D打印的具有双相药物缓释功能的水凝胶型组织工程支架，是将权利要求1所述的光敏树脂通过光固化3D打印得到的；所述水凝胶型组织工程支架为关节软骨支架。
5.根据权利要求4所述的光固化3D打印的具有双相药物缓释功能的水凝胶型组织工程支架，其特征在于：所述光固化3D打印结束后，还包括对得到的样品进行清洗、后固化处理的步骤；
所述清洗用乙醇或异丙醇对样品进行清洗；
所述后固化过程为：在紫外箱中采用紫外光后固化10-30 min。
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