CN114606128A - 光热材料集成药物可控释放微流控器官芯片系统及其制备方法 - Google Patents
光热材料集成药物可控释放微流控器官芯片系统及其制备方法 Download PDFInfo
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Abstract
本发明涉及微流控生物芯片领域，具体涉及一种光热材料集成药物可控释放微流控器官芯片系统，该系统通过微流控技术体外构建了癌类器官三维疾病模型。将肿瘤组织临床样本进行组织块分离成碎片，利用微流控技术，在芯片中将肿瘤碎片、紫杉烷类药物和光热材料通过微通道装载到海藻酸钠水凝胶微球中，实现肿瘤组织块的包封，肿瘤碎片经体外高通量培养形成高度类似实体肿瘤的肿瘤类器官。光热材料可快速将红外光能转化为热能，进而加速负载抗癌药物紫杉烷类药物的释放，从而达到对肿瘤类器官的治疗目的。本发明的微流控芯片系统制备工艺简单，成本低且所需时间较短，可用于规模化生产。
Description
技术领域
本发明涉及一种光热材料集成药物可控释放微流控器官芯片系统，属于生物材料技术领域。
背景技术
PDMS（聚二甲基硅氧烷）微流控的器官芯片技术，是基于微流控芯片通道以相应生物材料做基底，把细胞或组织装载于模拟人体的内微环境中，实现细胞或组织在体外的长期三维培养，为解决传统药物筛选实验耗时长、耗费大的问题提供了一种新策略。紫杉烷类药物尤其是紫杉醇是一类重要的新型抗癌药物，是临床治疗卵巢癌和晚期乳腺癌的常规化疗药物。已知这一药物可与细胞微管结合并将其“冻结”，在细胞分裂过程中阻止染色体分离，进而导致分裂中细胞（尤其是快速增殖的癌细胞）死亡。在肿瘤临床治疗过程中，紫杉醇通过独特的机制发挥细胞毒作用，化疗效果显著，但这种治疗方法带来的副作用较多，因此需要进一步的评估和优化治疗方案。
迄今为止，基于微流控器官芯片的药物评估已展现出治疗各种肿瘤组织及细胞的快速高通量评估效果。尽管已经取得了许多成功，但是大多数的评估系统设计粗糙，药物释放策略也很简单，并且在可控的主动递送方面存在困难。此外，这些系统中使用的常见药物是合成化合物，而很少探索使用天然分子进行肿瘤治疗评估。因此，仍然需要开发载有生物合成活性的新型肿瘤类器官芯片，以实现有效的治疗手段。
发明内容
技术问题：本发明公开了一种光热材料集成药物可控释放微流控器官芯片系统及其制备方法，以微流控技术和类器官培养技术的结合，将肿瘤的临床样本制备成碎片最终形成癌类器官芯片系统，将柔性能源光热材料集成于微流控芯片中，通过光热治疗手段实现有效控制药物释放，该系统能够对药物反应和治疗效果提供更大预测价值的体外模型，也为抗肿瘤药物筛选和研究提供了平台。
技术方案：本发明为解决上述技术问题采用以下技术方案：
该芯片系统的制备方法为：首先将分离的癌变临床组织样本破碎后取肿瘤碎片，在PDMS芯片中利用微流控液滴技术，将肿瘤碎片、紫杉烷类药物和光热材料通过微通道装载到海藻酸钠水凝胶微球中，最终实现以微流控芯片搭载的肿瘤组织碎块的包封，对微球载体中癌组织进行大规模高通量培养，最终体外形成掺杂水凝胶微球包裹的肿瘤类器官。
微流控器官芯片通过抗肿瘤紫杉醇的释放完成对培养的肿瘤类器官的杀伤作用。
使用该微流控器官芯片，可以将肿瘤临床样本制备成小于200μm的组织碎片，通过微流控技术和类器官培养技术，体外形成类似人体实体肿瘤的类器官组织。
紫杉烷类药物可以是紫杉醇。
光热材料集成药物可控释放是通过红外光源实现，其中光热材料可以是MXene材料，其可快速将光能转化为热能，进而加速负载抗癌药物紫杉醇的释放，其中近红外光源（808 nm）在距离为8 cm处以辐射强度为1.4 A-1.8 A进行照射，照射时间为60 s-120 s。
微流控掺杂水凝胶微球中，MXene装载浓度为0.25 mg/ml-1 mg/ml。
芯片基底材料为PDMS，微流通道的尺寸为700μm，芯片大小为5 cm×3 cm。
掺杂水凝胶微球固化过程是通过海藻酸钠水凝胶（浓度为1 wt %）和Ca-EDTA（100×10-3 M）螯合形成固体微球，整个反应在注入芯片的矿物油（浓度为3.5 vol %）中完成。有益效果：本发明采用以上技术方案与现有技术相比，具有以下技术效果：
1. 制备方法简单易行，成本低且所需时间较短，可用于规模化生产。
2. 将柔性能源新型光热材料MXene集成于微流控芯片系统中，利用光热治疗手段有效控制药物释放。
3. 微流控器官芯片系统选用的材料都是生物相容性较好的仿生材料，无体外细胞毒性。
4. 对药物反应和治疗效果提供更大预测价值的体外模型，也为抗肿瘤药物筛选和研究提供了平台。
附图说明
图1是药物可控释放微流控器官芯片系统装载示意图。
图2是MXene集成的微流控癌类器官系统使用介绍。
具体实施方式
下面结合附图对本发明的技术方案做进一步的详细说明, 下列实施例仅用于说明本发明，但并不用来限定本发明的实施范围。
本发明的光热材料集成药物可控释放微流控器官芯片系统的制备方法为：首先将分离的癌变临床组织样本破碎后取肿瘤碎片，在PDMS芯片中利用微流控液滴技术，将肿瘤碎片、紫杉烷类药物和光热材料通过各个微通道装载到海藻酸钠水凝胶微球中，最终实现以微流控芯片搭载的肿瘤组织碎块的包封，对微球载体中癌组织进行大规模高通量培养，最终体外形成掺杂水凝胶微球包裹的肿瘤类器官，其中，肿瘤器官可以是卵巢或乳腺，紫杉烷类药物可以是紫杉醇。
在微流控器官芯片中，通过抗肿瘤紫杉醇的释放完成对培养的癌肿瘤类器官的杀伤作用。
微流控器官芯片使用过程中，可以将肿瘤临床样本制备成小于200μm的组织碎片，通过微流控技术和类器官培养技术，体外形成类似人体器官实体肿瘤的类器官组织。
光热材料集成药物可控释放是通过红外光源实现，其中光热材料可以是MXene材料，其可快速将光能转化为热能，进而加速负载抗癌药物紫杉醇的释放，其中近红外光源（波长为808 nm）在距离为8 cm处以辐射强度为1.4 A-1.8 A进行照射，照射时间为60 s-120 s。
微流控掺杂水凝胶微球中，MXene装载浓度为0.25 mg/ml-1 mg/ml。
芯片基底材料为PDMS，微流通道的尺寸为700μm，芯片大小为5 cm×3 cm。
掺杂水凝胶微球固化过程是通过海藻酸钠水凝胶（浓度为1 wt %）和Ca2+-EDTA（100×10-3 M）螯合形成固体微球，整个反应在注入芯片的矿物油（浓度为3.5 vol %）中完成。
该芯片系统的制备方法具体为：
首先，通过微孔液滴技术将肿瘤碎片在微流控器官芯片中包裹于掺杂的水凝胶微球里，然后，从矿物油相中提取微球然后进行高通量培养，最终在海藻酸钠微球内形成肿瘤类器官结构。光热材料可快速将光能转化为热能，进而可控制负载抗癌药物紫杉烷类药物的释放，从而完成对癌类器官的治疗。
利用微流控液滴技术和类器官培养技术的结合，通过红外光照射实现加速负载抗癌药物紫杉烷类药物的释放实现对培养的癌肿瘤类器官的杀伤。
具体地，可以通过以下三种方式获得评估结构：
实施例1：
Step1：将癌变临床样本切碎，优选地，筛选小于200μm的肿瘤碎片；
Step2：将碎片与海藻酸钠/Ca2+-EDTA混合，随后在微流控操作中被不同液相控制包裹在液滴中。同时在液滴外膜载入光热材料。EDTA螯合Ca2+在酸性环境中被释放，以促进海藻酸钠微球的凝胶化。
Step3：加入矿物油，并从油中提取海藻酸钠微球，然后在培养皿中培养。
Step4：两周后，从基因、细胞、分子水平检测对比癌类器官和临床上实体肿瘤之间的差异以及药物评估参数。
实施例2：
Step1：将癌变临床样本切碎，优选地，筛选小于200μm的肿瘤碎片；
Step2：将碎片与海藻酸钠/Ca2+-EDTA混合，随后在微流控操作中被不同液相控制包裹在液滴中，同时在液滴外膜载入不同浓度的紫杉烷类药物，优选紫杉醇溶液(5mg/mL、10mg/mL、20mg/mL)和光热材料（优选地可以选择MXene）。EDTA螯合Ca2+在酸性环境中被释放，以促进海藻酸钠微球的凝胶化。
Step3：加入矿物油，并从油中提取海藻酸钠微球，然后在培养皿中培养。
Step4：两周后，从基因、细胞、分子水平检测对比癌类器官和临床上实体肿瘤之间的差异以及药物评估参数。
实施例3：
Step1：将癌变临床样本切碎，优选地，筛选小于200μm的肿瘤碎片；
Step2：将碎片与海藻酸钠/Ca2+-EDTA混合，随后在微流控操作中被不同液相控制包裹在液滴中，同时在液滴外膜载入光热材料（优选地可以选择MXene）和紫杉烷类药物，优选紫杉醇溶液。EDTA螯合Ca2+在酸性环境中被释放，以促进海藻酸钠微球的凝胶化。
Step3：加入矿物油，并从油中提取海藻酸钠微球，然后在培养皿中培养。
Step4：两周后，用近红外光源（波长为808 nm）在距离为8 cm处以辐射强度为1.4A、1.6A、1.8 A进行照射，照射时间设置为60s、120s，从基因、细胞、分子水平检测对比癌类器官和临床上实体肿瘤之间的差异以及药物评估参数。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入本发明要求的保护范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (9)
1.一种光热材料集成药物可控释放微流控器官芯片系统，其包括PDMS基底芯片，其特征在于：在芯片上具有微通道和注入的矿物油，其中所述通道内装载有含有肿瘤碎片和光热材料或者肿瘤碎片、MXene材料、紫杉醇的海藻酸钠水凝胶微球，该芯片需要近红外光照。
2.根据权利要求1所述的光热材料集成药物可控释放微流控器官芯片系统，其特征在于，肿瘤为乳腺肿瘤。
3.根据权利要求1所述的光热材料集成药物可控释放微流控器官芯片系统的制备方法，具体步骤如下：
step1：将癌变临床样本切碎，制作成肿瘤碎片；
step2：将所述碎片与海藻酸钠/Ca2+-EDTA混合，随后在微流控操作中使之被不同液相控制包裹在液滴中，同时在液滴外膜载入MXene材料和紫杉醇；
step3：加入矿物油，并在油中提取海藻酸钠微球，然后在培养皿中培养；
step4：两周后使用近红外光源进行照射，从基因、细胞、分子水平检测对比癌类器官和临床上实体肿瘤之间的差异以及药物评估参数。
4.根据权利要求3所述的方法，其特征在于，所述肿瘤的临床样本制备成小于200μm的组织碎片。
5.根据权利要求3所述的方法，其特征在于，所述的近红外光源，波长为808 nm，其在距离为8 cm处以辐射强度为1.4 A-1.8 A进行照射，照射时间为60 s-120 s。
6.根据权利要求3所述的方法，其特征在于，MXene装载浓度为0.25 mg/ml-1 mg/ml。
7.根据权利要求3所述的方法，其特征在于，所述的芯片的基底材料为PDMS，微流通道的尺寸为700μm，芯片大小为5 cm×3 cm。
8.根据权利要求3所述的方法，其特征在于，掺杂水凝胶微球固化过程是通过海藻酸钠水凝胶浓度为1 wt %和100×10-3 M 的Ca2+-EDTA螯合形成固体微球，整个反应在注入芯片的浓度为3.5 vol %的矿物油中完成。
9.根据权利要求3所述的方法，其特征在于，肿瘤为乳腺肿瘤。
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