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

doi:10.19401/j.cnki.1007-3639.2024.09.002

您当前的位置：

首页 >

文章列表页 >

生物3D打印在肿瘤研究及组织工程中的应用

专家述评 | 更新时间：2025-12-31

- 生物3D打印在肿瘤研究及组织工程中的应用
- Application of 3D bioprinting in cancer research and tissue engineering
- 中国癌症杂志 2024年34卷第9期页码：814-826
- 作者机构：
  
  上海中医药大学交叉科学研究院，上海 201203
- 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。" ]
- 基金信息：
  
  国家自然科学基金青年科学基金项目(32301149)
- DOI：10.19401/j.cnki.1007-3639.2024.09.002
  中图分类号： R73-33
- 收稿：2024-07-30，
  
  修回：2024-09-14，
  
  纸质出版：2024-09-30
- 稿件说明：
移动端阅览
王梓霏, 丁雅卉, 李彦, 等. 生物3D打印在肿瘤研究及组织工程中的应用[J]. 中国癌症杂志, 2024,34(9):814-826.

Zifei WANG, Yahui DING, Yan LI, et al. Application of 3D bioprinting in cancer research and tissue engineering[J]. China Oncology, 2024, 34(9): 814-826.
王梓霏, 丁雅卉, 李彦, 等. 生物3D打印在肿瘤研究及组织工程中的应用[J]. 中国癌症杂志, 2024,34(9):814-826. DOI： 10.19401/j.cnki.1007-3639.2024.09.002.

Zifei WANG, Yahui DING, Yan LI, et al. Application of 3D bioprinting in cancer research and tissue engineering[J]. China Oncology, 2024, 34(9): 814-826. DOI： 10.19401/j.cnki.1007-3639.2024.09.002.

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。

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 consid

erable 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.

关键词

Keywords

references

MURPHY S V , DE COPPI P , ATALA A . Opportunities and challenges of translational 3D bioprinting [J ] . Nat Biomed Eng , 2020 , 4 ( 4 ): 370 - 380 . DOI: 10.1038/s41551-019-0471-7 http://doi.org/10.1038/s41551-019-0471-7

MURPHY S V , ATALA A . 3D bioprinting of tissues and organs [J ] . Nat Biotechnol , 2014 , 32 ( 8 ): 773 - 785 . DOI: 10.1038/nbt.2958 http://doi.org/10.1038/nbt.2958

FANG Y , GUO Y , LIU T , et al . Advances in 3D bioprinting [J ] . Chin J Mech Eng: Addit Manuf Front , 2022 , 1 ( 1 ): 100011 .

RUCHIKA , BHARDWAJ N , YADAV S K , et al . Recent advances in 3D bioprinting for cancer research: from precision models to personalized therapies [J ] . Drug Discov Today , 2024 , 29 ( 4 ): 103924 .

MALDA J , VISSER J , MELCHELS F P , et al . 25th anniversary article: engineering hydrogels for biofabrication [J ] . Adv Mater , 2013 , 25 ( 36 ): 5011 - 5028 .

CHIMENE D , LENNOX K K , KAUNAS R R , et al . Advanced bioinks for 3D printing: a materials science perspective [J ] . Ann Biomed Eng , 2016 , 44 ( 6 ): 2090 - 2102 . DOI: 10.1007/s10439-016-1638-y http://doi.org/10.1007/s10439-016-1638-y

GU Z M , FU J Z , LIN H , et al . Development of 3D bioprinting: from printing methods to biomedical applications [J ] . Asian J Pharm Sci , 2020 , 15 ( 5 ): 529 - 557 . DOI: 10.1016/j.ajps.2019.11.003 http://doi.org/10.1016/j.ajps.2019.11.003

BRAY F , LAVERSANNE M , SUNG H , et al . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J ] . CA Cancer J Clin , 2024 , 74 ( 3 ): 229 - 263 .

SHARMA R , RESTAN PEREZ M , DA SILVA V A , et al . 3D bioprinting complex models of cancer [J ] . Biomater Sci , 2023 , 11 ( 10 ): 3414 - 3430 .

CHENG S N , LI Y X , YU C G , et al . 3D bioprinted tumor-vessel-bone co-culture scaffold for breast cancer bone metastasis modeling and drug testing [J ] . Chem Eng J , 2023 , 476 : 146685 .

DE VISSER K E , JOYCE J A . The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth [J ] . Cancer Cell , 2023 , 41 ( 3 ): 374 - 403 . DOI: 10.1016/j.ccell.2023.02.016 http://doi.org/10.1016/j.ccell.2023.02.016

TANG M , XIE Q , GIMPLE R C , et al . Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions [J ] . Cell Res , 2020 , 30 ( 10 ): 833 - 853 . DOI: 10.1038/s41422-020-0338-1 http://doi.org/10.1038/s41422-020-0338-1

LI C C , JIN B , SUN H , et al . Exploring the function of stromal cells in cholangiocarcinoma by three-dimensional bioprinting immune microenvironment model [J ] . Front Immunol , 2022 , 13 : 941289 .

NING L Q , SHIM J , TOMOV M L , et al . A 3D bioprinted in vitro model of neuroblastoma recapitulates dynamic tumor-endothelial cell interactions contrib uting to solid tumor aggressive behavior [J ] . Adv Sci , 2022 , 9 ( 23 ): e2200244 .

LORENZI F D , HANSEN N , THEEK B , et al . Engineering mesoscopic 3D tumor models with a self-organizing vascularized matrix [J ] . Adv Mater , 2024 , 36 ( 5 ): e2303196 .

CHO W W , AHN M , KIM B S , et al . Blood-lymphatic integrated system with heterogeneous melanoma spheroids via in-bath three-dimensional bioprinting for modelling of combinational targeted therapy [J ] . Adv Sci , 2022 , 9 ( 29 ): e2202093 .

YI H G , JEONG Y H , KIM Y , et al . A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy [J ] . Nat Biomed Eng , 2019 , 3 ( 7 ): 509 - 519 .

LANGER E M , ALLEN-PETERSEN B L , KING S M , et al . Modeling tumor phenotypes in vitro with three-dimensional bioprinting [J ] . Cell Rep , 2019 , 26 ( 3 ): 608 - 623 .e6.

GORI M , GIANNITELLI S M , TORRE M , et al . Biofabrication of hepatic constructs by 3D bioprinting of a cell-laden thermogel: an effective tool to assess drug-induced hepatotoxic response [J ] . Adv Healthc Mater , 2020 , 9 ( 21 ): e2001163 .

HU Q P , LIU X , LIU H F , et al . 3D printed porous microgel for lung cancer cells culture in vitro [J ] . Mater Des , 2021 , 210 : 110079 .

WANG P P , SUN L J , LI C C , et al . Study on drug screening multicellular model for colorectal cancer constructed by three-dimensional bioprinting technology [J ] . Int J Bioprint , 2023 , 9 ( 3 ): 694 .

HEINRICH M A , BANSAL R , LAMMERS T , et al . 3D-bioprinted mini-brain: a glioblastoma model to study cellular interactions and therapeutics [J ] . Adv Mater , 2019 , 31 ( 14 ): e1806590 .

TANG M , JIANG S , HUANG X M , et al . Integration of 3D bioprinting and multi-algorithm machine learning identified glioma susceptibilities and microenvironment characteristics [J ] . Cell Discov , 2024 , 10 ( 1 ): 39 .

TUNG Y T , CHEN Y C , DERR K , et al . A 3D bioprinted human neurovascular unit model of glioblastoma tumor growth [J ] . Adv Healthc Mater , 2024 , 13 ( 15 ): e2302831 .

SUN H , SUN L J , KE X D , et al . Prediction of clinical precision chemotherapy by patient-derived 3D bioprinting models of colorectal cancer and its liver metastases [J ] . Adv Sci , 2024 , 11 ( 2 ): e2304460 .

WANG X Y , YANG X N , LIU Z X , et al . 3D bioprinting of an in vitro hepatoma microenvironment model: establishment, evaluation, and anticancer drug testing [J ] . Acta Biomater , 2024 , 185 : 173 - 189 .

HONG S , SONG J M . 3D bioprinted drug-resistant breast cancer spheroids for quantitative in situ evaluation of drug resistance [J ] . Acta Biomater , 2022 , 138 : 228 - 239 .

LI Y , ZHANG T , PANG Y , et al . 3D bioprinting of hepatoma cells and application with microfluidics for pharmacodynamic test of metuzumab [J ] . Biofabrication , 2019 , 11 ( 3 ): 034102 .

DEY M , KIM M H , NAGAMINE M , et al . Biofabrication of 3D breast cancer models for dissecting the cytotoxic response of human T cells expressing engineered MAIT cell receptors [J ] . Biofabrication , 2022 , 14 ( 4 ): 044105 .

YU M , NI M D , XU F , et al . NSUN6-mediated 5-methylcytosine modification of NDRG1 mRNA promotes radioresistance in cervical cancer [J ] . Mol Cancer , 2024 , 23 ( 1 ): 139 .

AKOLAWALA Q , KEUNING F , ROVITUSO M , et al . Micro-vessels-like 3D scaffolds for studying the proton radiobiology of glioblastoma-endothelial cells co-culture models [J ] . Adv Healthc Mater , 2024 , 13 ( 6 ): e2302988 .

DELGROSSO E , SCOCOZZA F , CANSOLINO L , et al . 3D bioprinted osteosarcoma model for experimental boron neutron capture therapy (BNCT) applications: preliminary assessment [J ] . J Biomed Mater Res B Appl Biomater , 2023 , 111 ( 8 ): 1571 - 1580 .

CAMPBELL A , GUTIERREZ D A , KNIGHT C , et al . Novel combinatorial strategy using thermal inkjet bioprinting, chemotherapy, and radiation on human breast cancer cells; an in-vitro cell viability assessment [J ] . Materials , 2021 , 14 ( 24 ): 7864 .

YI H G , CHOI Y J , KANG K S , et al . A 3D-printed local drug delivery patch for pancreatic cancer growth suppression [J ] . J Control Release , 2016 , 238 : 231 - 241 .

WANG Y H , SUN L , MEI Z G , et al . 3D printed biodegradable implants as an individualized drug delivery system for local chemotherapy of osteosarcoma [J ] . Mater Des , 2020 , 186 : 108336 .

SU Y , LIU Y Q , HU X Y , et al . Caffeic acid-grafted chitosan/sodium alginate/nanoclay-based multifunctional 3D-printed hybrid scaffolds for local drug release therapy after breast cancer surgery [J ] . Carbohydr Polym , 2024 , 324 : 121441 .

ZHANG X H , HUANG H F , LANG X , et al . A 3D-printed PCL/PEI/DNA bioactive scaffold for chemotherapy drug capture in vivo [J ] . Int J Biol Macromol , 2023 , 236 : 123942 .

DANG W T , CHEN W C , JU E G , et al . 3D printed hydrogel scaffolds combining glutathione depletion-induced ferroptosis and photothermia-augmented chemodynamic therapy for efficiently inhibiting postoperative tumor recurrence [J ] . J Nanobiotechnology , 2022 , 20 ( 1 ): 266 .

SHANG Q , DONG Y B , SU Y , et al . Local scaffold-assisted delivery of immunotherapeutic agents for improved cancer immunotherapy [J ] . Adv Drug Deliv Rev , 2022 , 185 : 114308 .

JIANG X , REN L , TEBON P , et al . Cancer-on-a-chip for modeling immune checkpoint inhibitor and tumor interactions [J ] . Small , 2021 , 17 ( 7 ): e2004282 .

LI R , ZHANG L , JIANG X B , et al . 3D-printed microneedle arrays for drug delivery [J ] . J Control Release , 2022 , 350 : 933 - 948 .

CAUDILL C , PERRY J L , ILIADIS K , et al . Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity [J ] . Proc Natl Acad Sci USA , 2021 , 118 ( 39 ): e2102595118 .

ZHANG Y , XU J L , FEI Z Y , et al . 3D printing scaffold vaccine for antitumor immunity [J ] . Adv Mater , 2021 , 33 ( 48 ): e2106768 .

XU Y , ZHU W , WU J , et al . 3D-printed dendritic cell vaccines for post-surgery cancer immunotherapy [J ] . Adv Funct Mater , 2024 : 2400507 .

HUA J F , WU P , GAN L , et al . Current strategies for tumor photodynamic therapy combined with immunotherapy [J ] . Front Oncol , 2021 , 11 : 738323 .

TANG M , QU Y J , HE P X , et al . Heat-inducible CAR-T overcomes adverse mechanical tumor microenvironment in a 3D bioprinted glioblastoma model [J ] . Mater Today Bio , 2024 , 26 : 101077 .

JORGENSEN A M , GORKUN A , MAHAJAN N , et al . Multicellular bioprinted skin facilitates human-like skin architecture in vivo [J ] . Sci Transl Med , 2023 , 15 ( 716 ): eadf7547 .

LEE C Y , NEDUNCHEZIAN S , LIN S Y , et al . Bilayer osteochondral graft in rabbit xenogeneic transplantation model comprising sintered 3D-printed bioceramic and human adipose-derived stem cells laden biohydrogel [J ] . J Biol Eng , 2023 , 17 ( 1 ): 74 .

WANG J , WU Y , LI G F , et al . Engineering large-scale self-mineralizing bone organoids with bone matrix-inspired hydroxyapatite hybrid bioinks [J ] . Adv Mater , 2024 , 36 ( 30 ): e2309875 .

LEE A , HUDSON A R , SHIWARSKI D J , et al . 3D bioprinting of collagen to rebuild components of the human heart [J ] . Science , 2019 , 365 ( 6452 ): 482 - 487 . DOI: 10.1126/science.aav9051 http://doi.org/10.1126/science.aav9051

ZHANG J B , CHEN X D , CHAI Y R , et al . 3D printing of a vascularized mini-liver based on the size-dependent functional enhancements of cell spheroids for rescue of liver failure [J ] . Adv Sci , 2024 , 11 ( 17 ): e2309899 .

GRIGORYAN B , PAULSEN S J , CORBETT D C , et al . Multivascular networks and functional intravascular topologies within biocompatible hydrogels [J ] . Science , 2019 , 364 ( 6439 ): 458 - 464 . DOI: 10.1126/science.aav9750 http://doi.org/10.1126/science.aav9750

JIN Y C , MIKHAILOVA E , LEI M , et al . Integration of 3D-printed cerebral cortical tissue into an ex vivo lesioned brain slice [J ] . Nat Commun , 2023 , 14 ( 1 ): 5986 .

KIM W , KIM G H . An intestinal model with a finger-like villus structure fabricated using a bioprinting process and collagen/SIS-based cell-laden bioink [J ] . Theranostics , 2020 , 10 ( 6 ): 2495 - 2508 . DOI: 10.7150/thno.41225 http://doi.org/10.7150/thno.41225

HALE L J , HOWDEN S E , PHIPSON B , et al . 3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening [J ] . Nat Commun , 2018 , 9 ( 1 ): 5167 . DOI: 10.1038/s41467-018-07594-z http://doi.org/10.1038/s41467-018-07594-z

YAN Y F , CHEN H , ZHANG H B , et al . Vascularized 3D printed scaffolds for promoting bone regeneration [J ] . Biomaterials , 2019 , 190/191 : 97 - 110 .

RATHAN S , DEJOB L , SCHIPANI R , et al . Fiber reinforced cartilage ECM functionalized bioinks for functional cartilage tissue engineering [J ] . Adv Healthc Mater , 2019 , 8 ( 7 ): e1801501 .

MAIHEMUTI A , ZHANG H , LIN X , et al . 3D-printed fish gelatin scaffolds for cartilage tissue engineering [J ] . Bioact Mater , 2023 , 26 : 77 - 87 . DOI: 10.1016/j.bioactmat.2023.02.007 http://doi.org/10.1016/j.bioactmat.2023.02.007

YANG X , LI S , REN Y , et al . 3D printed hydrogel for articular cartilage regeneration [J ] . Compos Part B Eng , 2022 , 237 : 109863 .

KANG M S , JANG J , JO H J , et al . Advances and innovations of 3D bioprinting skin [J ] . Biomolecules , 2022 , 13 ( 1 ): 55 .

JIN R H , CUI Y C , CHEN H J , et al . Three-dimensional bioprinting of a full-thickness functional skin model using acellular dermal matrix and gelatin methacrylamide bioink [J ] . Acta Biomater , 2021 , 131 : 248 - 261 . DOI: 10.1016/j.actbio.2021.07.012 http://doi.org/10.1016/j.actbio.2021.07.012

BHAR B , DAS E , MANIKUMAR K , et al . 3D bioprinted human skin model recapitulating native-like tissue maturation and immunocompetence as an advanced platform for skin sensitization assessment [J ] . Adv Healthc Mater , 2024 , 13 ( 15 ): e2303312 .

YIM W , ZHOU J J , SASI L , et al . 3D-bioprinted phantom with human skin phototypes for biomedical optics [J ] . Adv Mater , 2023 , 35 ( 30 ): e2305227 .

NOOR N , SHAPIRA A , EDRI R , et al . 3D printing of personalized thick and perfusable cardiac patches and hearts [J ] . Adv Sci , 2019 , 6 ( 11 ): 1900344 .

ALONZO M , ANILKUMAR S , ROMAN B , et al . 3D Bioprinting of cardiac tissue and cardiac stem cell therapy [J ] . Transl Res , 2019 , 211 : 64 - 83 . DOI: S1931-5244(19)30078-7 http://doi.org/S1931-5244(19)30078-7

ESSER T U , ANSPACH A , MUENZEBROCK K A , et al . Direct 3D-bioprinting of hiPSC-derived cardiomyocytes to generate functional cardiac tissues [J ] . Adv Mater , 2023 , 35 ( 52 ): e2305911 .

FALLERT L , URIGOITIA-ASUA A , CIPITRIA A , et al . Dynamic 3D in vitro lung models: applications of inorganic nanoparticles for model development and characterization [J ] . Nanoscale , 2024 , 16 ( 23 ): 10880 - 10900 .

浏览量

2755

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

MYC通过靶向CD47促进前列腺癌增殖和转移的机制研究

没食子酸增强CAR-T细胞抗实体瘤作用的研究

循环肿瘤细胞在胆管癌侵袭转移中的作用机制研究进展及展望

类器官在妇科恶性肿瘤药物筛选中的应用

普列克底物蛋白2/miR-196a信号轴介导肿瘤微环境中肺癌细胞的通讯机制研究