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      3D bioprinting for reconstituting the cancer microenvironment

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          Abstract

          The cancer microenvironment is known for its complexity, both in its content as well as its dynamic nature, which is difficult to study using two-dimensional (2D) cell culture models. Several advances in tissue engineering have allowed more physiologically relevant three-dimensional (3D) in vitro cancer models, such as spheroid cultures, biopolymer scaffolds, and cancer-on-a-chip devices. Although these models serve as powerful tools for dissecting the roles of various biochemical and biophysical cues in carcinoma initiation and progression, they lack the ability to control the organization of multiple cell types in a complex dynamic 3D architecture. By virtue of its ability to precisely define perfusable networks and position of various cell types in a high-throughput manner, 3D bioprinting has the potential to more closely recapitulate the cancer microenvironment, relative to current methods. In this review, we discuss the applications of 3D bioprinting in mimicking cancer microenvironment, their use in immunotherapy as prescreening tools, and overview of current bioprinted cancer models.

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          Most cited references77

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          Biofabrication strategies for 3D in vitro models and regenerative medicine

          Organs are complex systems composed of different cells, proteins and signalling molecules that are arranged in a highly ordered structure to orchestrate a myriad of functions in our body. Biofabrication strategies can be applied to engineer 3D tissue models in vitro by mimicking the structure and function of native tissue through the precise deposition and assembly of materials and cells. This approach allows the spatiotemporal control over cell-cell and cell-extracellular matrix communication and thus the recreation of tissue-like structures. In this Review, we examine biofabrication strategies for the construction of functional tissue replacements and organ models, focusing on the development of biomaterials, such as supramolecular and photosensitive materials, that can be processed using biofabrication techniques. We highlight bioprinted and bioassembled tissue models and survey biofabrication techniques for their potential to recreate complex tissue properties, such as shape, vasculature and specific functionalities. Finally, we discuss challenges, such as scalability and the foreign body response, and opportunities in the field and provide an outlook to the future of biofabrication in regenerative medicine.
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            Three-dimensional printing of Hela cells for cervical tumor model in vitro.

            Advances in three-dimensional (3D) printing have enabled the direct assembly of cells and extracellular matrix materials to form in vitro cellular models for 3D biology, the study of disease pathogenesis and new drug discovery. In this study, we report a method of 3D printing for Hela cells and gelatin/alginate/fibrinogen hydrogels to construct in vitro cervical tumor models. Cell proliferation, matrix metalloproteinase (MMP) protein expression and chemoresistance were measured in the printed 3D cervical tumor models and compared with conventional 2D planar culture models. Over 90% cell viability was observed using the defined printing process. Comparisons of 3D and 2D results revealed that Hela cells showed a higher proliferation rate in the printed 3D environment and tended to form cellular spheroids, but formed monolayer cell sheets in 2D culture. Hela cells in 3D printed models also showed higher MMP protein expression and higher chemoresistance than those in 2D culture. These new biological characteristics from the printed 3D tumor models in vitro as well as the novel 3D cell printing technology may help the evolution of 3D cancer study.
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              Interstitial flow influences direction of tumor cell migration through competing mechanisms.

              Interstitial flow is the convective transport of fluid through tissue extracellular matrix. This creeping fluid flow has been shown to affect the morphology and migration of cells such as fibroblasts, cancer cells, endothelial cells, and mesenchymal stem cells. A microfluidic cell culture system was designed to apply stable pressure gradients and fluid flow and allow direct visualization of transient responses of cells seeded in a 3D collagen type I scaffold. We used this system to examine the effects of interstitial flow on cancer cell morphology and migration and to extend previous studies showing that interstitial flow increases the metastatic potential of MDA-MB-435S melanoma cells [Shields J, et al. (2007) Cancer Cell 11:526-538]. Using a breast carcinoma line (MDA-MB-231) we also observed cell migration along streamlines in the presence of flow; however, we further demonstrated that the strength of the flow as well as the cell density determined directional bias of migration along the streamline. In particular, we found that cells either at high seeding density or with the CCR-7 receptor inhibited migration against, rather than with the flow. We provide further evidence that CCR7-dependent autologous chemotaxis is the mechanism that leads to migration with the flow, but also demonstrate a competing CCR7-independent mechanism that causes migration against the flow. Data from experiments investigating the effects of cell concentration, interstitial flow rate, receptor activity, and focal adhesion kinase phosphorylation support our hypothesis that the competing stimulus is integrin mediated. This mechanism may play an important role in development of metastatic disease.
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                Author and article information

                Contributors
                ito1@psu.edu
                Journal
                NPJ Precis Oncol
                NPJ Precis Oncol
                NPJ Precision Oncology
                Nature Publishing Group UK (London )
                2397-768X
                27 July 2020
                27 July 2020
                2020
                : 4
                : 18
                Affiliations
                [1 ]ISNI 0000 0001 2189 8604, GRID grid.440667.7, Centre for Healthcare Science and Technology, , Indian Institute of Engineering Science and Technology Shibpur, ; Howrah, India
                [2 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Department of Chemistry, , Penn State University, ; University Park, PA USA
                [3 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Engineering Science and Mechanics Department, , Penn State University, ; University Park, PA USA
                [4 ]The Jackson Laboratory of Genomics Medicine, Farmington, CT USA
                [5 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, The Huck Institutes of the Life Sciences, , Penn State University, ; University Park, PA USA
                [6 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Biomedical Engineering Department, , Penn State University, ; University Park, PA USA
                [7 ]ISNI 0000 0001 2097 4281, GRID grid.29857.31, Materials Research Institute, , Penn State University, ; University Park, PA USA
                Author information
                http://orcid.org/0000-0002-7045-4337
                http://orcid.org/0000-0001-8328-4528
                Article
                121
                10.1038/s41698-020-0121-2
                7385083
                32793806
                076b945e-4390-4676-8749-8fa20c366173
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 January 2020
                : 13 May 2020
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2020

                cancer microenvironment
                cancer microenvironment

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