中国癌症杂志 ›› 2024, Vol. 34 ›› Issue (9): 814-826.doi: 10.19401/j.cnki.1007-3639.2024.09.002
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。基金资助:
WANG Zifei(), DING Yahui, LI Yan, LUAN Xin, TANG Min(
)
Received:
2024-07-30
Revised:
2024-09-14
Published:
2024-09-30
Online:
2024-10-11
Contact:
TANG Min
文章分享
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。
中图分类号:
王梓霏, 丁雅卉, 李彦, 栾鑫, 汤忞. 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.
WANG Zifei, DING Yahui, LI Yan, LUAN Xin, TANG Min. Application of 3D bioprinting in cancer research and tissue engineering[J]. China Oncology, 2024, 34(9): 814-826.
表1
生物3D打印肿瘤模型"
Cancer type | Primary focus | Bioprinting technique | Bioink or substrate | Cell type | Key outcome |
---|---|---|---|---|---|
Glioblastoma | Immunity | DLP | GelMA, GMHA | NSCs, astrocytes, GSCs, macrophages | The model simulated the cellular composition, cell density, and matrix stiffness of TME, investigating genetic and morphological changes in the presence and absence of macrophages [ |
Cholangiocarcinoma | Immunity | EBB | GelMA | RBE, TECs, TAFs, TAMs | A CCA model was established using 3D bioprinting to explore the potential applications of the immune microenvironment in pathological and drug research [ |
Neuroblastoma | Vascularized | EBB | GelMA | NB, HUVECs | Perusable blood vessels were printed using a support bath, simulating a vascularized tumor model [ |
Skin squamous cell carcinoma | Vascularized | micro-EBB | Fibrin-collagen hydrogel blend | GFP-HUVECs, fibroblasts, mesenchymal stem cells | The study developed a vascularized 3D-printed bioreactor. First, the PEEK bioreactor was coated with bioink, and vascular structures were bioprinted on top. Spheroids of cancer cells and stromal cells were then placed within the branched vascular structures, allowing for dynamic cultivation [ |
Melanoma | Metastasis | EBB | VdECM | HDMECs, HDLECs, HDF, SK-MEL-28 | The system recapitulated hallmark events of metastatic melanoma, such as tumor-stroma interactions, melanoma invasion and intravasation [ |
Glioblastoma | Stroma | EBB | BdECM, | GBM, HUVECs | The model recapitulated the structural, biochemical, and biophysical properties of the tumor, exploring the impact of mechanical properties of TME on the tumor [ |
Breast cancer | Stroma | EBB | Pronova UP LVG Sodium Alginate, gelatin | Breast cancer cell (MCF-7, SKBR3, HCC1143, MDA-MB-231), HMFs, MSCs/SPA, HUVECs | 3D bioprinted tumor models of breast cancer cells with different phenotypes exhibit distinct microenvironmental characteristics, and the different stromal cells have varying impacts on the tumors [ |
Liver cancer | Highthroughput screening | EBB | Pluronic F127 and sodium alginate | HepG2/C3A | Provide an effective in vitro model for hepatotoxicity testing [ |
Lung cancer | Drug screening | PDL | PEO/GelMA | LL/2, A549, NCI-H1975 | Compared with 2D cultured lung cancer cells, cells in porous microgel are more similar to those extracted from the existing gold standard: mouse transplanted tumors, in terms of the ROCK-actin pathway [ |
Colorectal cancer | Drug screening | EBB | Gelatin | SW480, THP-1, HUVECs | Compared with 3D bioprinted single-cell model (3D printing-S), 3D bioprinted multicellular models (3D printing-M) showed significantly improved expression of tumor-related genes, 3D printing-M group was significantly more resistant to chemotherapy [ |
表2
生物3D打印组织工程应用"
Organ/tissue type | Function | Bioprinting technique | Bioink or substrate | Cell type | Key outcome |
---|---|---|---|---|---|
Full-thickness skin model | Skin regeneration | EBB | Fibrinogen | keratinocytes, melenocytes, fibroblasts, FDPCs, DMECs, adipocytes | This study simulated a three-layered skin structure composed of the epidermis, dermis, and subcutaneous tissue. This approach promotes skin regeneration at the injury site and achieves non-fibrotic wound healing [ |
Osteochondral tissue | Osteochondral tissue repair | DLP | HAMA, GelMA | hADSCs | The bilayer structure design combines the characteristics of osteogenesis and chondrogenesis, effectively mimicking the natural bilayer structure of bone and cartilage tissues, thereby promising better tissue repair outcomes [ |
Bone organoids | Bone tissue generation | DLP | GelMA/AlgMA/HAP | BMSCs | This study conducted large-scale 3D bioprinting of bone organoids. In vivo, these bioprinted bone organoids effectively guided osteogenesis, mineralization, cell layer formation, plasticity, and remodeling [ |
Human cardiac models | Engineer components of the human heart at various scales | FRESH | Collagen | C2C12, VEGFs | The study presents a method to 3D-bioprint collagen using FRESH to engineer components of the human heart at various scales, from capillaries to the full organ [ |
Vascularized mini-liver | Liver regeneration and increases in cell proliferation | EBB | External ink (sodium alginate, gelatin fibrinogen) and an internal ink (gelatin, hyaluronic acid sodium salt, thrombin) | hASCs, HUVECs | The 3D bioprinted vascularized mini-liver, after inducing hepatocyte differentiation in vitro, shows enhanced liver function. Upon subcutaneous implantation, this mini-liver effectively improves liver regeneration in two ALF animal models [ |
Alveolar model | Simulating a vascularized alveolar model | SLATE | Photocurable hydrogels, food dyes | RBCs, HUVECs, Hepatocytes, hMSCs, Lung Fibroblasts, Epithelial-like Cells | Creating three-dimensional biomaterials with complex vascular networks capable of simulating the fluid transport and biochemical properties of real organs. Mathematical space-filling and fractal topology algorithms were used to design a 3D model that mimics alveolar morphology and oxygen delivery [ |
Cerebral cortical tissue | Personalized implantation treatments | DBB | Matrigel | hiPSCs | The study induces hiPSCs to DNs and UNs, using a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns and implanting the printed single-layer cortical tissue into brain explants [ |
Intestinal model | Simulating an intestinal model with a finger-like villus structure | EBB | Collagen, SIS | HUVECs, Caco-2 | In vitro cellular activities demonstrated that the proposed cell-laden collagen/dECM villus structure generates a more meaningful epithelium layer mimicking the intestinal structure, compared with the pure cell-laden collagen villus structure having similar villus geometry. This dECM-based 3D villus model will be helpful in obtaining a more realistic physiological small-intestine model [ |
Kidney organoid | Evaluation of nephrotoxicity of new drugs | EBB | Cell paste | iPSC | 3D bioprinted kidney organoids exhibit morphological and structural similarities to manually prepared kidney organoids. Drug response tests were conducted, and the impact of the initial cell micro-aggregates used in 3D bioprinting on the final organoids was investigated [ |
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