生物3D打印在肿瘤研究及组织工程中的应用

王梓霏, 丁雅卉, 李彦, 栾鑫, 汤忞

  1. 上海中医药大学交叉科学研究院,上海 201203
  • 收稿日期:2024-07-30 修回日期:2024-09-14 出版日期:2024-09-30 发布日期:2024-10-11
  • 通信作者: 汤忞(ORCID: 0000-0002-6084-1827),博士,青年研究员。
  • 作者简介:王梓霏(ORCID: 0009-0007-8331-2315),硕士在读。
    汤忞,博士,上海中医药大学青年研究员,硕士研究生导师。上海市领军人才(海外)、上海市浦东新区明珠计划菁英人才、国家优秀自费留学生。研究工作聚焦于生物工程与生物制造技术在肿瘤研究和组织工程中的应用。主要研究成果包括成功开发多种光固化生物3D打印技术和装备,建立多种具有高度临床相关性的复杂组织模型和器官模型,开发能够预测药效及解析肿瘤微环境特征的人工智能算法。以第一作者或通信作者在Cell Research、Advanced Materials、Molecular Cancer等权威期刊上发表多篇论文,所开发的生物3D打印肿瘤免疫微环境模型被Nature作为肿瘤干细胞研究新工具进行专题报道。参与撰写生物3D打印英文学术专著、组织工程全国统编教材。
  • 基金资助:
    国家自然科学基金青年科学基金项目(32301149)

摘要/Abstract

摘要:

近年来生物3D打印技术快速发展,已成为肿瘤研究与组织工程领域用于组织构建、机制研究、药物评价及药物递送等研究的重要工具。本综述总结生物3D打印的基本原理及其在肿瘤研究和组织工程中的应用进展。生物3D打印是一种增材制造技术,通过数字控制逐层堆叠生物材料和活细胞以构建复杂的三维组织结构,其核心步骤是设计3D模型、选择合适的生物打印技术和材料、逐层打印、后期培养和功能化处理。在肿瘤研究中,生物3D打印可用于构建模拟肿瘤微环境的复杂模型,揭示肿瘤的发生、发展新机制。传统体外模型如二维细胞培养或动物模型难以准确模拟人类肿瘤的复杂性,而通过生物3D打印技术构建更仿生的3D肿瘤模型,模拟肿瘤细胞与免疫细胞、基质、血管等环境的动态相互作用,能够提供更接近真实肿瘤生长、侵袭及转移的研究平台。此外,生物3D打印为抗癌药物的开发、创新治疗策略的确立和个性化治疗方案的制订提供了创新平台,3D打印肿瘤模型能够提供更贴近临床的实验结果且具备高通量药物筛选的能力,可广泛应用于细胞毒类药物、靶向治疗药物和免疫治疗药物等多种类型的药物评价中;除药物开发外,生物3D打印还为肿瘤辅助治疗提供了新的解决思路。生物3D打印模型和支架,可用于个性化精准治疗,通过高效构建患者细胞构成的个性化3D模型预测患者对药物及放疗的敏感性,可建立局部支架,根据患者具体需求确定合适的药物剂型、剂量等。另外,3D打印支架可用于辅助药物递送,利用3D支架靶向递送药物或减弱药物引起的不良反应,还可辅助局部免疫检查点抑制剂疗法、局部细胞因子疗法、局部癌症疫苗疗法及局部嵌合抗原受体修饰的细胞疗法。在组织工程中,传统的组织修复方法通常难以应对复杂组织的构建需求,而生物3D打印为构建复杂组织结构和实现组织再生提供了全新的思路,骨与软骨、皮肤等结构较为基础且具备较高再生能力的组织和器官已逐渐进入临床实践,肝脏、心脏等复杂器官的修复和重建也已取得一定进展,但尚未实现临床转化。最后,本综述探讨了生物3D打印在上述领域面临的挑战及未来发展方向,以期为相关领域的研究人员提供有价值的参考。

关键词: 生物3D打印, 肿瘤研究, 组织工程, 肿瘤微环境, 药物筛选

Abstract:

In recent years, 3D bioprinting technology has developed rapidly, becoming an essential tool in the fields of cancer research, tissue engineering, disease modeling and mechanistic studies. This paper reviewed the fundamental principles of bioprinting technology and its current applications in cancer research and tissue engineering. Bioprinting is an additive manufacturing technology that constructs complex three-dimensional tissue structures by digitally controlling the layer-by-layer deposition of biomaterials and living cells. The core steps of bioprinting include designing a 3D model, selecting appropriate bioprinting techniques and materials, printing layer by layer, followed by post-processing involving cell culture and functionalization. In cancer research, 3D bioprinting can create complex tumor models that simulate the tumor microenvironment, revealing new mechanisms of tumor initiation and progression. Traditional in vitro models, such as 2D cell cultures or animal models, often fail to accurately replicate the complexity of human tumors. However, 3D bioprinted tumor models, which mimic the dynamic interactions between tumor cells and their environment such as immune cells, stroma and blood vessels, offer a more biomimetic platform for studying tumor growth, invasion and metastasis. These models provide a research platform that closely mirrors actual tumor behavior. Additionally, Bioprinted models and scaffolds can be leveraged in personalized precision therapies by efficiently constructing patient-specific 3D models from their own cells. These models enable the prediction of patient’s sensitivity to drugs and radiotherapy. Additionally, localized scaffolds can be developed to meet individual patient needs, allowing for the formulation of appropriate drug types and dosages. Furthermore, 3D-printed scaffolds can support drug delivery by targeting specific areas, reducing drug-related side effects. They can also be used to facilitate local immunotherapy, cytokine therapy, cancer vaccines, and chimeric antigen receptor cell therapy, enhancing therapeutic outcomes. In tissue engineering, traditional tissue repair methods often struggle to address the complex requirements of constructing intricate tissue structures. 3D bioprinting offers a novel solution by enabling the creation of complex tissue architectures and promoting tissue regeneration. Basic tissues, such as bone, cartilage and skin, which have higher regenerative capacities, are gradually being incorporated into clinical practice. Significant progress has also been made in the repair and reconstruction of more complex organs like the liver and heart, though considerable challenges remain before these advancements can be fully translated into clinical applications. Finally, this paper discussed the current challenges and future directions of 3D bioprinting in these fields, aiming to provide reference for researchers.

Key words: 3D bioprinting, Cancer research, Tissue engineering, Tumor microenvironment, Drug screening

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