3D is not enough: Building up a cell instructive microenvironment for tumoral stroma microtissues

Brancato, Virginia; Garziano, Alessandro; Gioiella, Filomena; Urciuolo, Francesco; Imparato, Giorgia; Panzetta, Valeria; Fusco, Sabato; Netti, Paolo A.

doi:10.1016/j.actbio.2016.10.007

Cited by 44 publications

(46 citation statements)

References 50 publications

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“…NF‐μTP and MCF7‐μTP were kept in contact along the array of pillars separating tumor and stromal chamber ( Figure C). The geometrical configuration was chosen to better replicate the microarchitecture of breast ductal carcinoma in situ . In Figure A–C, the bright field images of all microdevices at T 2 (48 h) are reported, showing all the 3D‐μTP (epithelial and stromal) well packed in the chambers.…”

Section: Resultsmentioning

confidence: 99%

An Engineered Breast Cancer Model on a Chip to Replicate ECM‐Activation In Vitro during Tumor Progression

Gioiella

Urciuolo

Imparato

et al. 2016

Adv Healthcare Materials

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In this work, a new model of breast cancer is proposed featuring both epithelial and stromal tissues arranged on a microfluidic chip. The main task of the work is the in vitro replication of the stromal activation during tumor epithelial invasion. The activation of tumor stroma and its morphological/compositional changes play a key role in tumor progression. Despite emerging evidences, to date the activation of tumor stroma in vitro has not been achieved yet. The tumor-on-chip proposed in this work is built in order to replicate the features of its native counterpart: multicellularity (tumor epithelial cell and stromal cell); 3D engineered stroma compartment composed of cell-assembled extracellular matrix (ECM); reliable 3D tumor architecture. During tumor epithelial invasion the stroma displayed an activation process at both cellular and ECM level. Similarly of what repeated in vivo, ECM remodeling is found in terms of hyaluronic acid and fibronectin overexpression in the stroma compartment. Furthermore, the cell-assembled ECM featuring the stromal tissue, allowed on-line monitoring of collagen remodeling during stroma activation process via real time multiphoton microscopy. Also, trafficking of macromolecules within the stromal compartment has been monitored in real time.

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Section: Resultsmentioning

confidence: 99%

An Engineered Breast Cancer Model on a Chip to Replicate ECM‐Activation In Vitro during Tumor Progression

Gioiella

Urciuolo

Imparato

et al. 2016

Adv Healthcare Materials

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“…As reported in several studies (Curcio et al, ; Glicklis, Merchuk & Cohen, ), spheroids exceeding 200 microns in size may have a limited oxygen supply with the lowest partial pressure of 12 mmHg in the core. In addition, although spheroid configuration guarantees cell–cell interaction, on the other hand, it does not preserve at all the cell–ECM interplay resulting in a 3D construct in which metabolic activity, mechanical properties, and ECM composition do not resemble the in vivo setting Brancato et al . Among the biomaterials used for this application, gelatin micro‐carries acting as microscaffolds are used in many 3D tissue models (Brancato et al, ; F Urciuolo et al, ; Francesco Urciuolo, Imparato, Totaro, & Netti, ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, although spheroid configuration guarantees cell–cell interaction, on the other hand, it does not preserve at all the cell–ECM interplay resulting in a 3D construct in which metabolic activity, mechanical properties, and ECM composition do not resemble the in vivo setting Brancato et al . Among the biomaterials used for this application, gelatin micro‐carries acting as microscaffolds are used in many 3D tissue models (Brancato et al, ; F Urciuolo et al, ; Francesco Urciuolo, Imparato, Totaro, & Netti, ). This type of cell support system provides an ECM‐like structure to the cells and, when used in combination with bioreactor culture, improves cell yield and promotes cell‐matrix interaction (De Gregorio, Imparato, Urciuolo, & Netti, , ; Imparato, Urciuolo, Casale, & Netti, ; Katt, Placone, Wong, Xu, & Searson, ; Nibourg et al, ; Rafiq, Coopman, Nienow, & Hewitt, ; Tan et al, ).…”

Section: Introductionmentioning

confidence: 99%

A three‐dimensional microfluidized liver system to assess hepatic drug metabolism and hepatotoxicity

Corrado

Gregorio

Imparato

et al. 2019

Biotech & Bioengineering

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In this study, we propose the design and fabrication of a liver system on a chip. We first chose the most suitable three‐dimensional liver‐like model between cell spheroids and microtissue precursors, both based on the use of hepatocellular carcinoma cells (HepG2) to provide proof‐of‐concept data. Spheroids displayed high cell density but low expression of the typical hepatic biomarkers, whereas microtissue precursors showed stable viability and function over the entire culture time. The two liver‐like models were compared in terms of cell viability, function, metabolism, and the P‐glycoprotein 1 (P‐gp) transport‐protein expression with the microtissue precursors showing the best performance. Thus, we cultured them into a microfluidic biochip featured with three parallel channels shaped to mimic the hepatic sinusoids. To assess the detoxification potential of the microtissue‐loaded biochip we challenged it with a model molecule (ethanol) at different concentrations and time points. Ethanol cytotoxicity was detected by a noninvasive measurement of cell viability based on cell autofluorescence. As expected, a dose‐dependent decrease of albumin and urea secretion was observed in the ethanol‐treated samples. We believe that the described totally human‐derived platform, suitable for integration into a multiorgan microfluidic system, can provide a consistent innovative platform for drug development and toxicity studies.

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“…For instance, Brancato and co-workers [203], reported that for spheroids assembled either for cancer-associated fibroblasts (CAF) or normal fibroblasts, different cell metabolism, cell growth, matrix deposition rates and mechanical properties were observed when culturing cells with or without the support of porous gelatin microparticles [203]. Through the use of such microparticles, the authors were able to better replicate the functional and metabolic differences found in vivo between healthy and neoplastic tissues containing CAFs [203]. This study exemplifies that the introduction of microparticles into spheroid-based tumor models allows to surpass such limitations.…”

Section: Microparticles For 3d Tumor Models Assemblymentioning

confidence: 99%

“…Emerging reports have described the use of microparticle-based scaffolds as a means of introducing previously lacking ECM components into 3D-MCTS, promoting stem-like or multidrug resistance profiles [197,199,203]. The production methodologies for these microparticles mainly involve the application of modified double emulsion methods and sieving, with the combination of both techniques allowing a high yield of microparticles in the desired size ranges [95,197,198,200,203]. A significant body of knowledge on the methodologies to prepare polymer and hydrogel microparticles has been accumulated in the field of drug delivery systems in the past decades [204], and could be transposed to support spherical cancer models production.…”

Section: Microparticles For 3d Tumor Models Assemblymentioning

confidence: 99%

Design of spherically structured 3D in vitro tumor models -Advances and prospects

2018

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The ability to correctly mimic the complexity of the tumor microenvironment in vitro is a key aspect for the development of evermore realistic in vitro models for drug-screening and fundamental cancer biology studies. In this regard, conventional spheroid-based 3D tumor models, combined with spherically structured biomaterials, opens the opportunity to precisely recapitulate complex cell-extracellular matrix interactions and tumor compartmentalization. This review provides an in-depth focus on current developments regarding spherically structured scaffolds engineered into in vitro 3D tumor models, and discusses future advances toward all-encompassing platforms that may provide an improved in vitro/in vivo correlation in a foreseeable future.

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3D is not enough: Building up a cell instructive microenvironment for tumoral stroma microtissues

Cited by 44 publications

References 50 publications

An Engineered Breast Cancer Model on a Chip to Replicate ECM‐Activation In Vitro during Tumor Progression

An Engineered Breast Cancer Model on a Chip to Replicate ECM‐Activation In Vitro during Tumor Progression

A three‐dimensional microfluidized liver system to assess hepatic drug metabolism and hepatotoxicity

Design of spherically structured 3D in vitro tumor models -Advances and prospects

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