3D Bioprinting of Tumor Models and Their Potential Applications: A Review

Academic Background

Cancer is one of the leading causes of human mortality worldwide. Its uncontrolled abnormal proliferation, rapid growth, metastasis, and high heterogeneity result in extremely low clinical translation rates for traditional two-dimensional (2D) cell culture and animal models in tumor diagnosis and therapeutic research. To overcome these limitations, researchers urgently need to develop more suitable tumor models. In recent years, three-dimensional (3D) bioprinting technology has emerged as a novel approach, enabling the precise regulation of the spatial distribution of cells, biomolecules, and matrix components to create tumor models that better replicate the spatial organization, cellular resources, and microenvironmental features (e.g., hypoxia, necrosis, and delayed proliferation) of real human tumors. This review paper aims to explore the applications of 3D bioprinting technology in tumor model construction, particularly for tumor types such as glioma, breast cancer, liver cancer, colorectal cancer, cervical cancer, ovarian cancer, and neuroblastoma. It also provides a detailed introduction to the advancements in 3D bioprinted tumor models in fields such as the tumor microenvironment, tumor vascularization, tumor stem cells, tumor drug resistance and screening, tumor immunotherapy, and precision medicine.

Source of the Paper

This review paper was co-authored by Huaixu Li, Yang Qiao, Xingliang Dai, Haotian Tian, Zhenyu Han, Sheng Cheng, Peng Gao, and Hongwei Cheng. The authors are affiliated with the Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, East China Institute of Digital Medical Engineering, Department of Medical Imaging Technology, The First Clinical College of Anhui Medical University, and Department of Neurosurgery, Affiliated Jinling Hospital, Medical School of Nanjing University. The paper was published online on November 14, 2024, in the journal Bio-design and Manufacturing, with the DOI 10.1007/s42242-024-00317-y.

Main Content of the Paper

1. 3D Bioprinting Technology and Its Applications in Tumor Models

3D bioprinting is an innovative technology capable of rapidly, precisely, and quantitatively depositing biologically active components (e.g., living cells, biomaterials, drugs, growth hormones, and genomes) to construct active tissues with complex spatial structures. Currently, the main 3D bioprinting technologies include droplet-based bioprinting (DBB), extrusion-based bioprinting (EBB), laser-assisted bioprinting (LAB), and stereolithography bioprinting (SLB/DLB). Each technology has its advantages and disadvantages. For example, DBB offers speed, flexibility, and ease of use but faces challenges such as limited bioink material selection, uneven droplet sizes, and nozzle clogging. EBB is suitable for high cell-density tissue printing but may cause cell structure deformation and viability loss.

2. Selection and Application of Bioinks

Bioinks are key materials in 3D bioprinting, typically composed of cells, matrices, and other biomaterials. Based on their source, bioinks can be classified into natural and synthetic categories. Natural bioinks, such as gelatin, hyaluronic acid, fibrin, and decellularized extracellular matrix (DECM), offer excellent biocompatibility and cell support but suffer from batch-to-batch variability and poor mechanical properties. Synthetic bioinks, such as polyethylene glycol (PEG) and poly(lactic-co-glycolic acid) (PLGA), provide tunable properties and superior mechanical performance but may have issues with cell compatibility and toxic solvents.

3. Specific Applications of 3D Bioprinted Tumor Models

3.1 Glioma Models

Glioma is one of the most common malignant tumors in the central nervous system, characterized by high malignancy, recurrence rates, and poor prognosis. 3D bioprinted glioma models can better simulate the tumor microenvironment, enabling the study of glioma stem cell enrichment and vascular endothelial transformation potential. For example, research teams have used 3D bioprinting to construct glioma stem cell models, revealing stronger invasiveness and temozolomide resistance in 3D environments.

3.2 Breast Cancer Models

Breast cancer is one of the leading threats to human health globally. 3D bioprinting can construct breast cancer models containing tumor cells, adipocytes, and matrices to study the interactions between tumor cells and adipocytes, as well as tumor invasion and drug resistance. For instance, researchers have used laser direct-write bioprinting to create breast cancer models, successfully simulating the invasion of breast cancer cells into adipose tissue.

3.3 Liver Cancer Models

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and its progression is closely related to the stiffness of the liver extracellular matrix. 3D bioprinted liver cancer models can better replicate the 3D mechanical environment of the liver, enabling the study of HCC cell proliferation and invasion. For example, researchers have used light-cured 3D bioprinting to construct liver cancer models, finding that DECM scaffolds with cirrhotic stiffness inhibit HCC cell proliferation and increase invasion markers.

3.4 Colorectal Cancer Models

Colorectal cancer is a serious disease, and its tumor microenvironment consists of tumor-associated fibroblasts and endothelial cells. 3D bioprinted colorectal cancer models can better simulate the tumor microenvironment, enabling the study of tumor cell drug resistance and drug screening. For instance, researchers have used 3D bioprinting to construct multicellular models containing tumor cells, tumor-associated macrophages, and endothelial cells, demonstrating higher drug resistance in chemotherapy screening experiments.

3.5 Cervical Cancer Models

Cervical cancer is one of the earliest tumor models studied using 3D bioprinting. 3D bioprinted cervical cancer models can better replicate the three-dimensional morphology and microenvironment of tumors, enabling the study of tumor cell invasion and migration. For example, researchers have used extrusion-based 3D bioprinting to construct cervical cancer models, revealing higher cell viability and invasiveness in 3D environments.

3.6 Ovarian Cancer Models

3D bioprinting of ovarian cancer models enables high-throughput automated production for studying the feedback mechanisms between tumor and stromal cells. For instance, researchers have used droplet-based bioprinting to construct ovarian cancer microtissue models, successfully simulating the interactions between tumor and stromal cells.

3.7 Neuroblastoma Models

Neuroblastoma is a common solid tumor in children with a poor prognosis. 3D bioprinted neuroblastoma models can better simulate the tumor microenvironment, enabling the study of tumor cell invasion and migration. For example, researchers have used pneumatic extrusion-based 3D bioprinting to construct neuroblastoma models, successfully evaluating the efficacy of two chemotherapeutic drugs.

4. Applied Research Using 3D Bioprinted Tumor Models

4.1 Construction of the Tumor Microenvironment

The tumor microenvironment is critical for tumor cell survival and development. 3D bioprinting can precisely control the spatial distribution of cells and biomaterials to construct models that better replicate the real tumor microenvironment. For example, researchers have used 3D bioprinting to construct multicellular spheroid models containing cervical cancer cells and matrices, demonstrating higher drug resistance in 3D environments.

4.2 Tumor Vascularization

3D bioprinting can construct co-culture models containing tumor cells and endothelial cells to study the mechanisms of tumor vascularization. For instance, researchers have used 3D bioprinting to create co-culture models of glioma cells and endothelial cells, finding that vascular-like structures form in 3D environments.

4.3 Tumor Stem Cells

Tumor stem cells possess the ability to self-renew and differentiate into various tumor cell types, playing a key role in tumor survival, growth, metastasis, and recurrence. 3D bioprinted tumor stem cell models can better simulate the tumor microenvironment, enabling the study of the biological characteristics of tumor stem cells. For example, researchers have used 3D bioprinting to construct glioma stem cell models, revealing more stable proliferation in 3D environments.

Significance and Value of the Paper

This review paper comprehensively summarizes the advancements in 3D bioprinting technology for tumor model construction, detailing 3D bioprinted models for various tumor types and their applications in the tumor microenvironment, tumor vascularization, tumor stem cells, tumor drug resistance and screening, tumor immunotherapy, and precision medicine. 3D bioprinted tumor models can better replicate the biological characteristics of real tumors, providing more accurate and reliable experimental platforms for tumor research and treatment. Additionally, the paper offers important references and guidance for future research, promoting the widespread application of 3D bioprinting technology in tumor studies.

Highlights and Innovations

1. Coverage of Multiple Tumor Types: The paper details 3D bioprinted models for various tumor types, including glioma, breast cancer, liver cancer, colorectal cancer, cervical cancer, ovarian cancer, and neuroblastoma, showcasing the broad application prospects of this technology.
2. Accurate Simulation of the Tumor Microenvironment: 3D bioprinted tumor models can better replicate the tumor microenvironment, providing more accurate experimental platforms for tumor biology research and anticancer drug screening.
3. Research on Tumor Vascularization and Stem Cells: The paper elaborates on the applications of 3D bioprinting in tumor vascularization and stem cell research, offering new perspectives for understanding tumor invasion and metastasis mechanisms.
4. Potential for Personalized Medicine: Patient-specific tumor models constructed using 3D bioprinting can provide critical experimental evidence for personalized medicine, advancing the development of precision medicine.

Conclusion

This review paper thoroughly explores the applications of 3D bioprinting technology in tumor model construction, demonstrating its immense potential in tumor research. 3D bioprinted tumor models can better replicate the biological characteristics of real tumors, providing more accurate and reliable experimental platforms for tumor research and treatment. In the future, with continuous technological advancements, 3D bioprinting is expected to play an even greater role in tumor research and personalized medicine.