生物3D打印研究及与临床前动物模型的交叉应用展望

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (3): 318-330.

生物3D打印研究及与临床前动物模型的交叉应用展望

胡敏¹(), 董乐轩²()(), 高怡²()(), 奚子芪², 沈子皓², 唐瑞阳², 栾鑫², 汤忞²()(), 张卫东¹^,²^,³

^1.上海理工大学健康科学与工程学院, 上海 200093
^2.上海中医药大学交叉科学研究院, 上海 201203
^3.中国人民解放军海军军医大学药学院, 上海 200433

收稿日期:2024-12-30 修回日期:2025-02-10 出版日期:2025-07-07 发布日期:2025-06-25
通讯作者: 汤忞（1992—），女，博士，研究员，硕士生导师，研究方向：生物3D打印在组织工程及肿瘤研究中的应用。E-mail： mit012@ shutcm.edu.cn。ORCID： 0000-0002-6084-1827
作者简介:胡敏（2000—），女，硕士研究生，研究方向：生物3D打印。E-mail： 213332692@st.usst.edu.cn。ORCID： 0009-0008-4332-8555；
董乐轩（2004—），女，本科生，研究方向：生物3D打印。E-mail：3089290965@qq.com。ORCID：0009-0006-8863-1529；
高怡（2004—），女，本科生，研究方向：生物3D打印。E-mail： a13701656307@163.com。ORCID：0009-0008-6365-4075
汤忞，博士，上海中医药大学交叉科学研究院青年研究员，硕士生导师。中国医药生物技术协会3D打印技术分会委员、上海市抗癌协会神经肿瘤专业委员会委员。研究方向聚焦于生物医学工程技术在药物研发与组织工程中的应用，包括采用生物3D打印、器官芯片、类器官等体外建模技术进行体外器官、疾病模型开发，采用人工智能辅助3D打印过程优化与药物敏感性预测。主持国家自然科学基金、上海市科委和上海市卫健委项目5项；发表SCI论文25篇，其中以第一作者或通信作者身份在Cell Research、Advanced Materials、Molecular Cancer等国际期刊上发表12篇论文，而且牵头开发的3D打印肿瘤免疫微环境模型被Nature报道认为是肿瘤和发育生物学研究新工具；参与撰写生物3D打印英文学术专著3D Bioprinting and Nanotechnology in Tissue Engineering and Regenerative Medicine和组织工程全国统编教材《组织工程》；申请获批专利6项。被评为2023年度上海市领军人才（海外）和2023年上海市浦东新区明珠计划“菁英人才”。E-mail： mit012@ shutcm.edu.cn。ORCID： 0000-0002-6084-1827
基金资助:
上海市进一步加快中医药传承创新发展三年行动计划项目“智慧中药交叉创新团队”［ZY（2021-2023）0401］;上海市卫生健康委员会科研项目“基于多模态临床数据和生物3D打印的非哺乳期乳腺炎精准治疗研究”(20244Y0130)

Prospects for 3D Bioprinting Research and Transdisciplinary Application to Preclinical Animal Models

HU Min¹(), DONG Lexuan²()(), GAO Yi²()(), XI Ziqi², SHEN Zihao², TANG Ruiyang², LUAN Xin², TANG Min²()(), ZHANG Weidong¹^,²^,³

^1.School of Health Sciences & Engineering, University of Shanghai for Science & Technology, Shanghai 200093, China
^2.Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
^3.School of Pharmacy, Naval Medical University, Shanghai 200433, China

Received:2024-12-30 Revised:2025-02-10 Published:2025-06-25 Online:2025-07-07
Contact: TANG Min (ORCID: 0000-0002-6084-1827), E-mail: mit012@shutcm.edu.cn

摘要/Abstract

摘要：

动物实验在生物医药研究中广泛用于安全性评估、毒理学分析、疗效验证以及机制探索。近年来，由于动物实验伦理审查制度日趋严格、动物福利意识不断提升，同时为了推动更高效、低成本的药物研发，美国在2022年9月通过了食品药品监督管理局（Food and Drug Administration，FDA）现代化法案2.0，首次取消了新药临床前研究必须进行动物实验的联邦强制要求。2025年4月FDA进一步提出，将在单克隆抗体等药物研发中采用人工智能计算模型、类器官毒性测试、3D微生理系统等一系列“新的替代方法”，从而逐步取代传统的动物试验模式。在这些新兴技术中，生物3D打印模型因其高仿生、高重现性和可规模化等特性，逐渐成为动物模型的重要替代和补充手段。本综述系统梳理了生物3D打印技术在生物医药领域的研究与应用进展：首先概述了生物3D打印的关键组成，包括生物材料的选择与功能化设计、多种打印策略的原理及特点，分析其在构建多细胞空间结构、微环境调控和细胞命运引导方面的优势；其次，介绍了生物3D打印模型在药物研发中的典型应用，包括通过构建肿瘤、传染病和罕见病等疾病模型实现对药效的高通量筛选，以及通过构建肝脏、心脏等器官特异性模型进行药物毒理学研究；再者，进一步探讨了生物3D打印在组织工程领域的应用范围，涵盖骨/软骨、皮肤、血管等多种功能性组织的构建，以及在再生替代等方面的最新进展。此外，本文还分析了生物3D打印模型与动物模型在疾病发生发展和药物作用机制、精准医疗、药物研发以及组织再生研究等领域的互补优势，讨论了二者交叉应用在提升建模准确性与生理相关性方面的潜力与挑战。综上，生物3D打印作为一种新兴的体外造模与制造技术，正逐步建立起涵盖疾病建模、药物筛选、毒性预测与组织再生的完整应用体系。

关键词: 生物3D打印, 药物研发, 组织工程, 再生医学, 替代模型

Abstract:

Animal experiments are widely used in biomedical research for safety assessment, toxicological analysis, efficacy evaluation, and mechanism exploration. In recent years, the ethical review system has become more stringent, and awareness of animal welfare has continuously increased. To promote more efficient and cost-effective drug research and development, the United States passed the Food and Drug Administration (FDA) Modernization Act 2.0 in September 2022, which removed the federal mandate requiring animal testing in preclinical drug research. In April 2025, the FDA further proposed to adopt a series of "new alternative methods" in the research and development of drugs such as monoclonal antibodies, which included artificial intelligence computing models, organoid toxicity tests, and 3D micro-physiological systems, thereby gradually phasing out traditional animal experiment models. Among these cutting-edge technologies, 3D bioprinting models are a significant alternative and complement to animal models, owing to their high biomimetic properties, reproducibility, and scalability. This review provides a comprehensive overview of advancements and applications of 3D bioprinting technology in the fields of biomedical and pharmaceutical research. It starts by detailing the essential elements of 3D bioprinting, including the selection and functional design of biomaterials, along with an explanation of the principles and characteristics of various printing strategies, highlighting the advantages in constructing complex multicellular spatial structures, regulating microenvironments, and guiding cell fate. It then discusses the typical applications of 3D bioprinting in drug research and development,including high-throughput screening of drug efficacy by constructing disease models such as tumors, infectious diseases, and rare diseases, as well as conducting drug toxicology research by building organ-specific models such as those of liver and heart. Additionally,the review examines the role of 3D bioprinting in tissue engineering, discussing its contributions to the construction of functional tissues such as bone, cartilage, skin, and blood vessels, as well as the latest progress in regeneration and replacement. Furthermore, this review analyzes the complementary advantages of 3D bioprinting models and animal models in the research of disease progression, drug mechanisms, precision medicine, drug development, and tissue regeneration, and discusses the potential and challenges of their integration in improving model accuracy and physiological relevance. In conclusion, as a cutting-edge in vitro modeling and manufacturing technology, 3D bioprinting is gradually establishing a comprehensive application system covering disease modeling, drug screening, toxicity prediction, and tissue regeneration.

Key words: 3D Bioprinting, Drug development, Tissue engineering, Regenerative medicine, Alternative model

中图分类号:

Q95-33

胡敏,董乐轩,高怡,等. 生物3D打印研究及与临床前动物模型的交叉应用展望[J]. 实验动物与比较医学, 2025, 45(3): 318-330.

HU Min,DONG Lexuan,GAO Yi,et al. Prospects for 3D Bioprinting Research and Transdisciplinary Application to Preclinical Animal Models[J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 318-330.

图/表 2

图1 3种生物3D打印工艺类型的工作机制示意图注：A，喷墨式生物3D打印（局部加热生物墨水，并膨胀一个气泡以推动液滴从喷嘴头喷出）；B，挤出式生物3D打印（逐层打印连续的细丝状生物墨水）；C，光固化生物3D打印［利用数字微镜装置（DMD）芯片，使得紫外光或其他光源模式化投射到生物墨水上］。

Figure 1 Schematic diagram of the working principles of three types of 3D bioprinting processesNote：A， Inkjet-based 3D bioprinting， in which localized heating of the bioink inflates an air bubble to push droplets out from the nozzle； B， Extrusion-based 3D bioprinting， which prints continuous filaments of bioink layer by layer； C， Light-based 3D bioprinting， which utilizes a digital micro-mirror device （DMD） chip to project patterned UV light or other light sources onto the bioink.

表1 精准医疗常见模型对比

Table 1 Comparison of common models in precision medicine

模型类型 Model types	2D细胞模型 2D cell model	生物3D打印模型 3D bioprinting model	PDX动物模型 Patient-derived xenograft animal model
实验周期 Experimental cycle	1周内	7 d	3～6个月
成本 Cost	1 000～2 000元/例	数万元/批	数十万元/批
建模成功率 Modeling success rate	高 (＞90%) ^[51]	高 (＞80%) ^[52]	低 (＞60%) ^[53]
临床相关性 Clinical relevance	有限	高	高
遗传信息保真度Genetic information fidelity	有限	高	高
可重复性 Reproducibility	高	高	低
细胞种类 Cell types	有限	多样化，含有多种细胞	多样化，但受鼠源细胞影响
系统完整性 System integrity	低，仅细胞层面	中等，组织/器官层面，尚缺乏动态循环和整体性调控	高，具有完整生理环境
材料可控性 Material controllability	无	高	低
通量 Throughput	高	高	低

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